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King’s College London, 150 Stamford Street, London SE1 9NH, UKUniversity of Westminster, 101 New Cavendish St, Fitzrovia, London W1W 6XH, United Kingdom
Nonalcoholic fatty liver disease (NAFLD) pathogenesis and progression are complex, heterogeneous, and multifactorial.
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The human diet typically contains thousands of bioactive molecules that orchestrate a variety of metabolic and signaling processes in health and disease, comprising a natural combination approach.
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Although food composition varies widely, cumulative evidence suggests that specific dietary macronutrients and micronutrients can affect biological processes involved in NAFLD pathogenesis.
Obesity is a common feature of many metabolic diseases, including nonalcoholic fatty liver disease
Obesity was rare in ancient times, often praised and limited to the aristocracy. However, it was sometimes noted that excess body weight could lead to ill health. Hippocrates, in 400 bc, was one of the first to comment on the perils of obesity:“It is injurious to health to take in more food than the constitution will bear, when at the same time one uses no exercise to carry off this excess…”—Translated from Hippocrates, circa 400 bc.
listed ectopic fat as a causative factor of angina pectoris. By the early nineteenth century, much of the modern understanding of ectopic fat within key organs was being delineated. Although Hippocrates recognized exercise as a mitigatory factor against obesity, Ludovicus Nonnius was one of the first physicians to embrace diet as an important factor in health.
Thus, the foundations for the implications of obesity/ectopic fat and potential treatments were laid nearly 500 years ago.
Healthy eating habits, weight loss, and increased physical activity (PA) constitute the cornerstones of the management of nonalcoholic fatty liver disease (NAFLD).
This article summarizes the scientific evidence for the effects of diet on NAFLD. It also provides a perspective on how certain nutrients in food signal and regulate key molecular pathways implicated in NAFLD pathogenesis. This perspective is not intended to be a comprehensive review of every nutrient; there are many excellent references cited here that provide more in-depth information.
Based on the current evidence, this article provides a dietary framework that could form an integral part of a comprehensive management strategy for NAFLD.
Consequences and challenges of caloric imbalance
A minority of people were obese until recent history, and it is only in the last 50 years that obesity has taken on epidemic proportions. In 2016, more than 1.9 billion adults (39% of the adult population) were overweight (body mass index [BMI] 25.0 to <30 kg/m2), and 650 million (13% of the adult population) were considered obese (BMI ≥ 30.0 kg/m2).
Associated with high obesity prevalance are the sequelae of obesity-related complications: NAFLD, metabolic syndrome, type 2 diabetes (T2D), and cardiovascular disease (CVD). NAFLD is rapidly becoming the most important cause of liver disease worldwide, with an estimated global prevalence of approximately 24%.
Both T2D and CVD are also effect modifiers of NAFLD; overall prevalence of NAFLD in patients with T2D nearly triples (∼60%), and CVD is the primary cause of death in patients with NAFLD.
The obesity epidemic and its sequelae also affect children and adolescents. Hepatic steatosis prevalence among children and adolescents within the European Union was found to be ∼28% (∼1.5 million), with nearly one-fifth of obese children and adolescents having significant acquired cardiovascular risk factors before adulthood, and 4.6% having metabolic syndrome and increased risk of progression to heart disease.
In the United States, hepatic steatosis was found in 9.6% of individuals aged 2 to 19 years and in 38% of obese children autopsied between 1993 and 2003.
The current recommendation for adults from United Kingdom’s Scientific Advisory Committee on Nutrition is to consume a diet of 50% carbohydrate (CHO) and less than 35% fat of the daily total energy intake (TEI), in conjunction with 0.75 g of protein per kilogram of body weight.
Public Health England Government dietary recommendations: government recommendations for energy and nutrients for males and females aged 1–18 years and 19+ years.
The recommended daily macronutrient intake and the actual daily intake reported from a cohort of 210,106 participants from the UK Biobank database are presented in Table 1. Twenty-four-hour dietary recall questionnaires revealed that 32% of men and 42% of women were consuming more energy than the recommended daily amount, although the average of the cohort was at or less than the recommended TEI.
Although women on average exceeded the recommended intake of total sugar, both genders exceeded recommended saturated fat intake, were at less than the recommended levels for polyunsaturated fat intake, and significantly deficient in dietary fiber intake (see Table 1). These dietary findings likely present a best-case scenario because people generally over-report healthy foods and under-report unhealthy foods, and the population sampled in the UK Biobank is considered to be generally healthy.
Thus, it can be surmised that a more realistic picture of a typical Western diet would include inadequate and/or imbalanced nutrient profiles.
Table 1United Kingdom recommended daily macronutrient intake and actual intake in a cohort of 210,106 generally healthy participants from the UK Biobank
Modified from Bennett E, Peters SAE, Woodward M. Sex differences in macronutrient intake and adherence to dietary recommendations: findings from the UK Biobank. BMJ Open. 2018;8(4):e020017; with permission.
in most cases the primary cause of obesity is energy imbalance. The obesity epidemic can be attributed primarily to the increasing propensity for a sedentary lifestyle and the ready availability of food, especially energy-dense foods.
Measures to modulate energy homeostasis and nutrient balance remain woefully inadequate. Consequently, interventions that treat obesity and ectopic fat, particularly behavioral modifications to enhance PA and support healthy diet, are of great interest to the clinical and research communities.
Nonalcoholic fatty liver disease pathogenesis
During the past decade, extensive multidisciplinary efforts have contributed to a deeper understanding of the complex pathophysiology of the NAFLD spectrum. Broadly, the disease seems to progress from fat accumulation (ie, steatosis or nonalcoholic fatty liver [NAFL]) to inflammation (ie, nonalcoholic steatohepatitis [NASH]) to fibrosis and eventually cirrhosis.
Two core principles on the critical nodes of NAFLD pathogenesis have emerged in the context of metabolic substrate overload:
1.
Disease establishment node: insulin resistance and lipotoxicity.
Ectopic fat depots within muscle and liver that commonly occur with obesity can contribute to metabolic inflexibility, the inability to adequately regulate fuel substrates (glucose and free fatty acids [FFAs]).
Metabolic inflexibility results in insulin resistance and contributes to mitochondrial dysfunction, affecting lipid metabolism (Chakravarthy M.V., Neuschwander-Tetri B.A. Submitted for publication). Perturbation of metabolic processes leads to accumulation of intracellular triglycerides and accelerated lipolysis (secondary to adipose tissue insulin resistance), releasing FFAs, which are the precursors of lipotoxic molecules (eg, ceramides, sphingomyelins, lysophospholipids, and others) that cause cellular damage.
Thus, any treatment approach (dietary or pharmacologic) for NAFLD should consider the underlying lipotoxic environment as a key interventional node.
2.
Disease progression node: lipotoxic fatty acids (FAs) lead to cellular damage, inflammation, and fibrogenesis.
Current evidence indicates that the degree of liver fibrosis is the prognostic marker that is most directly correlated to eventual morbidity and mortality in patients with NASH.
Processes that lead to fibroinflammatory disease have been an intense area of research that has shed light on the pathways that control apoptosis, autophagy, endoplasmic reticulum (ER) stress, tissue repair mechanisms, gut barrier function, and fibrogenesis.
There is heterogeneity in disease progression, likely caused by differences in genetic, microbiome, diet, and other factors. Thus, another key interventional node for NAFLD is to target core pathways that control progression toward more advanced disease.
Given the pathophysiology of NAFLD, which involves multiple pathways, it raises the question of whether engaging a single molecular target could be sufficient to adequately treat such a complex disease. NAFLD is unlikely to be explained by a single gene defect; it is more likely to involve simultaneous dysregulation of several biochemical functions mediated through a complex set of molecular networks.
Thus, it is difficult to identify single molecular targets that could sufficiently treat the full spectrum of this heterogeneous disease. Consequently, the authors propose that multiple biochemical pathways that regulate hepatic metabolism, inflammation, and fibrogenesis need to be considered and simultaneously modulated in NAFLD treatment.
Rationale for combinatorial approaches
Multiple lines of evidence have converged to support the notion that NAFLD treatment requires a combination therapy approach from both a biological and patient-centric standpoint owing to the complexity, heterogeneity, and multifactorial pathogenesis of the disease. In the Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment (REGENERATE) trial, 931 individuals with biopsy-confirmed NASH and significant or severe fibrosis (stages F2 or F3) were randomized to receive OCA 10 mg/d (n = 312), OCA 25 mg/d (n = 308), or placebo (n = 311); placebo-subtracted response in NASH resolution or fibrosis improvement was seen in only 3.7% and 11.2% of patients, respectively, in the 25 mg/d OCA group.
Recent data show patients with NAFLD often have multiple comorbidities and are typically maintained on multiple medications. In a study of 95 patients with T2D and NAFLD, polypharmacy (5–9 medications) and hyperpolypharmacy (≥10 medications) were present in 59% and 31% of patients, respectively.
Therefore, from a patient-centric standpoint, it is desirable to avoid, to the extent possible, additional polypharmacy by considering options that simultaneously address the multiple mechanisms of NAFLD in an integrated manner, including fixed dose combinations instead of sequential additions of multiple individual agents.
Although scientific debate about the ideal pharmacologic combination continues, one advantage of dietary approaches is that they naturally combine a variety of nutrient and non-nutrient components. The human diet typically contains thousands of bioactive molecules that orchestrate a variety of metabolic and signaling processes in health and disease.
In addition, these nutrients also modulate some of the same biological pathways and molecular targets as do pharmacologic agents, as discussed later. When considering a complex disease with an incomplete pathophysiologic understanding and the need for a clean safety profile, dietary approaches may be particularly valuable because they offer holistic benefits and address patient-centered needs. For example, dietary approaches have been shown to have a role in improving not only certain features of the NAFLD spectrum but also the concomitant comorbidities of dyslipidemia, insulin resistance, and cardiovascular risk in a safe manner.
Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study.
This article describes the roles of key dietary macronutrients and micronutrients, reviews the current understanding of how these nutrients engage some of the same molecular targets as current pharmacotherapeutic strategies, and describes how such approaches may be leveraged to affect core pathogenic features of NAFLD.
Macronutrients and micronutrients in nonalcoholic fatty liver disease
Nutrients significantly influence disease outcomes across several chronic diseases.
The effect of evidence-based nutrition clinical care pathways on nutrition outcomes in adult patients receiving non-surgical cancer treatment: a systematic review.
This article briefly reviews the key nutrients (Fig. 1) and their molecular mediators (Fig. 2) that have shown significant activity on the multifactorial biology of NAFLD, including changes in liver fat and fibroinflammation.
Fig. 1Interactions of macronutrients and micronutrients and their impact on NAFLD pathogenesis and progression. Balanced and/or appropriate levels of dietary macronutrients and micronutrients can act to slow or halt the progression of NAFLD. An imbalance (eg, high levels of fructose or inadequate amounts of polyunsaturated FAs) can contribute to the pathogenesis and progression of NAFLD, which could lead to further cellular damage, inflammation, and fibrogenesis.
Macronutrients and Nonalcoholic Fatty Liver Disease
Carbohydrates
Although the typical human diet is naturally rich in CHOs, a refined CHO diet in the context of caloric excess leads to the deposition of intrahepatic triglyceride (IHTG).
Nonetheless, under isocaloric conditions it is the type of CHO ingested and not the proportion of dietary energy from CHO that is most relevant. For example, fructose seems to contribute to IHTG even under isocaloric conditions, particularly in liquid form.
Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.
Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.
Fructose stimulates de novo lipogenesis, inhibits hepatic lipid oxidation by blocking the activity of peroxisome proliferator-activated receptor alpha (PPARα),
Cumulatively, these fructose-driven biochemical changes lead to obesity, steatosis, insulin resistance, inflammation, hepatic fibrosis, and leaky gut (see Fig. 2).
Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time.
However, fructose consumed at a limit that reflects usual whole-food intake (eg, fructose as found in fruits) does not meaningfully contribute to de novo lipogenesis, insulin resistance, or hypertriglyceridemia.
A randomized study of the effects of additional fruit and nuts consumption on hepatic fat content, cardiovascular risk factors and basal metabolic rate.
Habitual fructose intake relates to insulin sensitivity and fatty liver index in recent-onset type 2 diabetes patients and individuals without diabetes.
Importantly, fermentable polysaccharides such as inulin or pectin are metabolized by gut microbiota to produce short-chain FAs (SCFAs), which not only ameliorate insulin resistance
but also inhibit histone deacetylases (HDACs) and activate G protein–coupled receptors (GPR41/43) to induce epigenetic and antiinflammatory effects, respectively, to modulate metabolic disease status (see Fig. 2).
The anti-inflammatory effects of short chain fatty acids on lipopolysaccharide- or tumor necrosis factor alpha-stimulated endothelial cells via activation of GPR41/43 and inhibition of HDACs.
Some studies have shown favorable effects of dietary fiber on body composition parameters such as reduced body fat percentage, waist circumference, and BMI,
Studies investigating the impact of dietary fiber on liver fat and other NAFLD features are limited. In 1 study of 43 subjects with prediabetes, fiber intake of 20 g/d did not reduce liver fat levels over 12 weeks compared with the control diet of 10 g/d fiber.
Thus, dietary FAs can facilitate the development, prevention, or reversal of some NAFLD features depending on FA composition, carbon chain length, and the molecular targets they engage.
Excessive intake of saturated long-chain FAs found in foods such as animal products promotes oxidative stress, mitochondrial dysfunction, and inflammation (see Fig. 2).
Overingestion of saturated FAs promotes fatty liver, impairs insulin signaling, and induces hepatic ER stress, a precursor to hepatocyte cellular dysfunction and apoptosis.
Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death.
Am J Physiol Endocrinol Metab.2010; 298: E1027-E1035
Saturated FA–induced oxidative stress results in the activation of the JNK pathway, a key mechanism in the pathophysiology of NASH and insulin resistance.
In contrast, dietary monounsaturated FAs (MUFAs; eg, oleic acid) and polyunsaturated FAs (eg, linoleic acid [n-6], alpha-linolenic acid [n-3], and arachidonic acid), found in foods such as nuts, olive oil, and avocados, have been shown in some studies to reduce IHTG accumulation and inflammation (see Fig. 2). For example, 12 weeks of an MUFA diet (28% of TEI from MUFA, with 50% of the MUFA from olive oil) in 43 subjects with prediabetes decreased hepatic fat and improved both hepatic and total insulin sensitivity.
One gram of daily polyunsaturated FA (n-3) supplementation for 12 months promoted lipid oxidation, ameliorated hepatic steatosis, and improved insulin sensitivity in both adult (n = 56; mean age, 58 years)
Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study.
patients with NAFLD. However, the precise roles of the types of polyunsaturated FAs to affect liver-related parameters remain unresolved because their effects are complicated by both the ratio of n-3 to n-6 and the confounding influence of background dietary CHO or protein levels.
Dietary intake of polyunsaturated FAs in a cross-sectional study of patients with NAFLD showed that more than 80% of patients did not reach the daily recommended intake of linolenic and linoleic acids.
Well-controlled human clinical trials show that n-6 polyunsaturated FA (linoleic acid) compared with saturated FA (butter or palm oil) prevents IHTG in the context of 7 weeks of overfeeding (n = 39)
In addition, administering the n-3 polyunsaturated FA, docosahexaenoic acid, at 250 mg/d for 18 months to 20 children (mean age, 10 years) with biopsy-proven NAFLD significantly improved histologic parameters of steatosis, ballooning, and lobular inflammation, but not fibrosis.
This finding may reflect the independent role of n-3s in influencing NASH pathogenesis rather than any detrimental role attributed specifically to n-6. Treatment with glucagon like peptide-1 (GLP-1) analogue (exendin-4) improves steatohepatitis and modulates the hepatic n-3/n-6 ratio, specifically by the regulation of hepatic FA metabolism.
Exendin4, a glucagonlike peptide1 receptor agonist, modulates hepatic fatty acid composition and Delta5desaturase index in a murine model of nonalcoholic steatohepatitis.
FAs are potent endogenous ligands for canonical nutrient-sensed transcription factors, such as PPARs, which alter tissue FA compositions and induce cell-signaling pathways to regulate genes implicated in lipid synthesis and oxidation.
underscoring that it is the type of fat, and not the amount of fat or its caloric value, that modulates PPAR activity and, consequently, hepatic lipid metabolism.
Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay.
Although attention has largely been focused on CHO and fat with respect to their roles in T2D and CVD development, protein has received less attention. This omission is now beginning to change and a growing body of data suggests that a high protein intake could help reduce liver fat levels. Increased dietary protein content has been shown to attenuate the increased IHTG level observed following hypercaloric feeding with fructose or fat.
A prospective study of 37 patients with T2D and NAFLD fed a high-protein diet (30% protein, 40% CHO) showed a 36% to 48% reduction in IHTG level assessed by MRI, regardless of whether the protein came from animal or plant sources and independent of body weight changes.
Adipose tissue insulin resistance index and levels of markers of hepatic necroinflammation were reduced, and serum levels of FGF21 decreased by 50%, the latter significantly correlated with loss of hepatic fat.
In a subset of the PREVIEW (Prevention of Diabetes Through Lifestyle Intervention and Population Studies in Europe and Around the World) cohort, 25 patients with NAFLD who were obese and insulin resistant were administered a weight-maintaining diet containing either 15% or 25% protein for up to 2 years following an initial weight loss period of 8 weeks. Both groups reduced IHTG levels, visceral adipose tissue (VAT) levels, subcutaneous adipose tissue levels, homeostatic model assessment score for insulin resistance (HOMA-IR), and insulin sensitivity index independent of body weight.
Long-term effects of increased protein intake after weight loss on intrahepatic lipid content and implications for insulin sensitivity: a PREVIEW study.
Am J Physiol Endocrinol Metab.2018; 315: E885-E891
Long-term effects of increased protein intake after weight loss on intrahepatic lipid content and implications for insulin sensitivity: a PREVIEW study.
Am J Physiol Endocrinol Metab.2018; 315: E885-E891
showing a dose dependent effect of protein. A recent trial combining moderate CHO restriction (30% of calories) with a high-protein diet (30%) reduced the absolute hepatic fat content by 2.4% in adults with T2D compared with a 0.2% increase observed in those on a high-CHO (50%), normal-protein (17%) diet.
A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial.
Nevertheless, protein has been linked to insulin resistance. In human studies, a higher-protein (1.2 g/kg/d) versus lower-protein (0.8 g/kg/d) hypocaloric diet attenuated the weight loss–mediated improvement in insulin sensitivity in 34 sedentary, obese, postmenopausal women.
Another study by the same group evaluated the effects of a diet consisting of either 0.6 g protein per kilogram fat-free mass (containing 0.0684 g of leucine per kilogram fat-free mass) or leucine matched to protein (0.0684 g leucine per kilogram fat-free mass) in 30 obese, insulin-resistant women with NAFLD.
Ingestion of protein, but not leucine, decreased insulin-stimulated glucose disposal and prevented both the insulin-mediated decrease in levels of plasma 3-hydroxyisobutyrate, an insulin resistance–inducing valine metabolite,
suggest that high-protein diets may have negative effects on insulin sensitivity, whereas low-protein diets exert metabolic benefits, supporting the observations noted earlier in humans.
These findings underscore the importance of balancing the quantity and quality of dietary protein relative to other nutrients as a key determinant of metabolic health.
Certain amino acids in the diet may preferentially modulate key biological processes. For instance, recent studies in flies reported that, when specific dietary amino acids are matched to protein-coding genes, growth and reproduction are optimized without affecting lifespan.
Specific dietary amino acids have also been shown to modulate several aspects of NAFLD pathogenesis, including glucose homeostasis, fibroinflammation, and gut epithelial barrier integrity, as summarized here.
Branched-chain amino acids:
Leucine, isoleucine, and valine (together termed branched-chain amino acids [BCAAs]) regulate several important hepatic metabolic signaling pathways, including insulin signaling, glucose regulation, and efficient channeling of carbon substrates for oxidation through mitochondrial tricarboxylic acid (TCA) cycle. An impaired BCAA-mediated upregulation of the TCA cycle is thought to be a core defect resulting in mitochondrial dysfunction in NAFLD.
may not only reflect abnormal glucose metabolism but also increased muscle protein breakdown coupled with downregulation of BCAA catabolizing enzymes, all of which may represent an adaptive physiologic response to hepatic stress in patients with NAFLD.
BCAA supplementation has been shown to improve steatosis, plasma lipid levels, and glucose tolerance in both rodent NASH models and in patients with NASH-related cirrhosis.
Improvements in steatosis, inflammation, and fibrosis in NASH mouse models seem to be mediated via activation of mammalian target of rapamycin complex 1 (mTORC-1), inhibition of hepatic lipogenic enzymes such as FA synthase (FAS), and via transforming growth factor β (TGFβ)–mediated and Wnt/β-catenin–signaling pathways (see Fig. 2).
Levels of glutamine, serine, and glycine, which collectively affect glutathione synthesis, inflammation, and oxidative stress pathways, are also altered in NAFLD. A glutamate-serine-glycine index (glutamate/[serine + glycine]) was correlated with hepatic insulin resistance and γ-glutamyltransferase, independent of BMI, and was able to discriminate fibrosis F3 to F4 from F0 to F2.
Glutamine is the most abundant amino acid in both the intracellular and extracellular compartments, and was found to be critical to maintaining intestinal mucosal integrity
Macrophage activation is considered a critical event for NASH progression, and glutamine is necessary to maintain the anti-inflammatory alternative activation pathway in macrophages.
Macrophages depleted of glutamine express a proinflammatory transcriptome and phenocopy PPARγ-deficient unstimulated macrophages, indicating the requirement of PPARγ for glutamine metabolism (see Fig. 2).
was shown to directly affect cellular acylcarnitine levels, a signature of altered mitochondrial function and, consequently, impaired fuel use from FAs leading to mitochondrial fragmentation.
In a detailed metabolomic study, enzymatic expression and DNA methylation analyses were performed in a high-fat, high-fructose fed NAFLD murine model that showed 30% depletion of hepatic methionine, whereas s-adenosylhomocysteine and homocysteine were significantly increased (25%–35%) and serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted during NASH development.
In contrast, serine supplementation in high-fat fed mice increased insulin sensitivity and reduced hepatic lipid accumulation without affecting body weight by epigenetic modulation of glutathione synthesis–related genes through 5′ adenosine monophosphate–activated protein kinase (AMPK) activation (see Fig. 2).
Serine prevented high-fat diet-induced oxidative stress by activating AMPK and epigenetically modulating the expression of glutathione synthesis-related genes.
Serine supplementation of 20 g/d for 14 days in a small (n = 6) cohort of patients with NAFLD decreased serum alanine aminotransferase (ALT) level and improved hepatic steatosis.
Glycine supplementation in preclinical models was found to exert antiinflammatory, immunomodulatory, cytoprotective, platelet-stabilizing, and antiangiogenic effects in part mediated by blunted activation of p38 mitogen-activated protein kinase and JNK and decreased Fas ligand expression (see Fig. 2).
Lower glycine levels were significantly associated with increasing numbers of metabolic syndrome components in a population-based, cross-sectional survey of 472 Chinese individuals.
Oral ingestion of a hydrolyzed gelatin meal in subjects with normal weight and in obese patients: postprandial effect on circulating gut peptides, glucose and insulin.
mimicking the actions of the native hormone oxyntomodulin, which is released from intestinal L cells in response to meals and activates both the GLP-1 and GCG receptors.
Oxyntomodulin (glicentin-(33-69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs.
The pharmacologic unimolecular dual GLP-1/GCG coagonist has been shown to induce a 15% to 20% weight loss, modestly decrease food intake, while boosting thermogenesis, decreasing hepatic and serum triglyceride and cholesterol levels, improving insulin sensitivity, and counteracting leptin resistance in diet-induced obese mice and nonhuman primates.
In a randomized, double-blinded crossover study, coinfusion of GLP-1 (0.8 pmol/kg/min) and GCG (50 ng/kg/min) increased energy expenditure and decreased food intake in obese volunteers,
Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia.
underscoring a key reason for the many coagonists currently being evaluated in clinical trials.
A glycine-induced dual action on GLP-1 and GCG in the liver may explain the observations of glycine supplementation to counteract the fructose-mediated increase in IHTG level.
Although glycine supplementation did not induce weight loss or suppress calorie intake in sucrose-fed mice, it reduced visceral fat stores by more than 50%, increased thermogenic potential of hepatic mitochondria by increasing state 4 respiration, alleviated hepatic steatosis, and improved insulin sensitivity and serum lipid levels (see Fig. 2),
phenocopying some of the effects observed with the coagonist drugs.
Arginine and citrulline:
Dietary arginine and citrulline seem to affect gut epithelial barrier integrity, a process increasingly recognized as a core pathogenic feature of NASH progression.
Western-style diet–fed mice were supplemented separately with arginine and citrulline. Both amino acids preserved tight junction protein levels in duodenum and decreased bacterial endotoxin in portal plasma and hepatic toll-like receptor 4 (TLR4) messenger RNA, underscoring their importance in maintaining intestinal immunohomeostasis.
Citrulline-fed mice also had decreased plasma proinflammatory cytokine (interleukin 6 [IL6] and tumor necrosis factor alpha [TNFα]) levels and improved plasma triglyceride and insulin levels, whereas in the colon they had decreased TNFα and TLR4 gene expression, increased tight junction protein (claudin-1) levels, and induced growth of the gut-protective Bacteroides/Prevotella (see Fig. 2).
Recent studies also suggest a central role for arginine in modulating the nitric oxide pathway, critical in the maintenance of gut mucosal integrity in an inducible nitric oxide synthase–dependent manner
Clinically, arginine supplementation (8.3 g/d for 21 days) in a group of 16 obese, insulin-resistant patients with T2D improved glucose homeostasis, waist circumference, blood pressure, lipid parameters, and endothelial function
Beneficial effects of a long-term oral L-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients.
Am J Physiol Endocrinol Metab.2006; 291: E906-E912
; however, effects of dietary arginine on specific liver-related parameters remain to be determined in patients with NAFLD/NASH.
Fibroblast growth factor 21, sensor of dietary protein status and cellular stress:
Although protein and amino acids in food induce a plethora of cellular effects, multiple lines of evidence have converged to support FGF21 as a critical sensor of dietary protein and amino acid status. FGF21, a liver-derived metabolic hormone, is robustly induced by the restriction of dietary protein or amino acids, including leucine, methionine, cysteine, asparagine, and several other nonessential amino acids, regardless of the CHO content or total caloric load of the diet.
FGF21 therefore responds to a nutritional state that is different from leptin and other energy balance signals coordinating the adaptive behavioral and metabolic responses to protein restriction.
Various manipulations that trigger cellular stress increase FGF21 production, even in tissues such as muscle that normally do not produce significant quantities of FGF21, via the activating transcription factor 4 (ATF4)–dependent pathway,
Fibroblast growth factor 21 is regulated by the IRE1alpha-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis.
ATF4 is a key molecular mediator of the classic integrated stress response, which coordinates the cellular response to various stressors via activation of the amino acid sensor GCN2 (general control nonderepressible 2), increased eIF2a (eukaryotic translation initiation factor 2a) phosphorylation, and subsequent binding of ATF4 to amino acid response elements on the FGF21 promoter, which increases FGF21 expression.
Thus, connection between hepatic FGF21 secretion and obesity, steatohepatitis, and metabolic stress has led to a broader view of FGF21, specifically its increase, as a signal of both nutrient (protein/amino acid restriction) and cellular (oxidative/ER) stress (see Fig. 2).
Micronutrients and Nonalcoholic Fatty Liver Disease
Choline
Choline is metabolized largely in the liver into phosphatidylcholine and plays an important role in the assembly and secretion of lipoproteins and the host–gut microbiota interactions.
and is routinely used to stimulate NAFLD in animal models. Human dietary choline requirements vary depending on estrogen status and genetic polymorphisms.
Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups.
From a cross-sectional analysis of patients in the NASH Clinical Research Network, deficiency of choline was associated with a worsening of liver fibrosis in postmenopausal women even after adjusting for common factors (age, obesity, T2D, serum triglycerides, steroid use) linked to NAFLD in multiple ordinal logistic regression models.
A significant negative correlation between scores of fatty liver index (FLI) and choline consumption was recently reported in a study of 20,643 persons, with a 14% lower risk of NAFLD in those with the highest choline intake; those with higher BMI had greater reductions in FLI with increasing choline intake.
Although associations between dietary choline and NAFLD exist, no controlled interventional studies are currently available; therefore, the precise role for choline/phosphatidylcholine supplementation in the progression of NAFLD to steatohepatitis and serious hepatic consequences remains to be elucidated.
Polyphenols
Polyphenols, commonly found in foods such as fruit, vegetables, wine, and coffee, have been shown to reduce IHTG through several mechanisms, including inhibition of lipogenesis via SREBP1c downregulation and by inducing antioxidant and anti-inflammatory effects.
Although polyphenol deficiency per se is poorly understood in patients with NAFLD, various members of the polyphenol family, such as resveratrol, curcumin, quercetin, and green tea catechins, have shown a potential to reduce lipid peroxidation, liver enzyme levels, and inflammatory biomarker levels.
For example, daily supplementation with both 150 mg and 500 mg of resveratrol reduced total cholesterol and aspartate transaminase (AST)/ALT levels while improving both insulin sensitivity and NAFLD pathogenesis.
However, no clinical trials incorporating polyphenol supplementation have collected liver biopsies; therefore, histologic data are not currently available.
Vitamin D
Recent epidemiologic evidence shows that patients with NAFLD are more frequently deficient in vitamin D than the general population, and circulating vitamin D levels are proportional to the degree of fibrotic evolution.
In cell and rodent models, vitamin D supplementation produced multiple beneficial effects, from improvements in insulin sensitivity to anti-inflammatory effects in both adipose and liver to slowing down hepatic fibrosis.
However, despite 24 weeks of 2000 IU/d vitamin D supplementation in 65 patients with T2D with NAFLD, neither hepatic steatosis nor markers of inflammation, fibrosis, or cardiovascular/metabolic parameters improved.
No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial.
showed that, despite 24 months of 4000-IU/d vitamin D supplementation, which doubled serum vitamin D levels, risk of new-onset diabetes was not significantly decreased compared with placebo.
Vitamin E
In addition to being one of the most potent antioxidants in nature, vitamin E is regarded as the main lipid-soluble antioxidant involved in the regulation of gene expression, inflammatory responses, and modulation of cellular signaling.
Sources of vitamin E are similar to those of polyunsaturated FAs and include olive oil, nuts, and green vegetables; therefore, vitamin E deficiency is also likely to be observed in the typical Western diet. Vitamin E supplementation, prescribed as either monotherapy or as part of a combination therapy approach, has successfully improved liver histology scores and reduced the odds of hepatic steatosis in patients with NAFLD and NASH.
Findings from the landmark PIVENS (Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis) clinical trial showed vitamin E supplementation had greater reductions in hepatocyte ballooning and lobular inflammation compared with pioglitazone treatment.
Consequently, both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver guidelines recognize vitamin E supplementation as an effective short-term treatment option for nondiabetic patients with biopsy-proven NASH.
European Association for the Study of the LiverEuropean Association for the Study of DiabetesEuropean Association for the Study of Obesity EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
Although an essential nutrient in multiple cellular processes and erythropoiesis, an excessive amount of iron is commonly observed in patients with NAFLD and is associated with organ dysfunction secondary to the formation of reactive oxygen species.
Furthermore, subversion of iron metabolism and an increased facilitation of iron storage have been reported following hepatocyte exposure to FFAs and in patients with NAFLD and copper deficiency.
Zinc deficiency initiates insulin resistance, iron overload, and hepatic steatosis, which follows the impairment of zinc homeostasis caused by chronic liver disease.
Taken together, the ready accessibility of energy-dense foods, market saturation of hidden sugars in foods such as breakfast cereals, and a general trend toward highly processed convenience foods contribute to an imbalanced, nutrient-poor diet and, consequently, metabolic disease in Western society.
As described earlier, the imbalance and inadequacies of specific macronutrients and micronutrients affects key processes associated with NAFLD pathogenesis and progression (see Figs. 1 and 2). These observations also highlight another key concept that is further expanded below: it is the ratio and the type of nutrients, in addition to the absolute amount or caloric value, that dictates long-term health.
Modulation of metabolism: interventions for nonalcoholic fatty liver disease with diet and physical activity
Regulation of energy balance is highly complex and dynamically interrelated such that a simplistic arithmetical approach of calories in and calories out does not account for counterbalancing homeostatic processes and is unsubstantiated by current evidence.
Thus, the authors advocate modulating metabolism in an integrated manner to simultaneously affect the interdependent variables of energy intake and expenditure (Fig. 3).
Fig. 3Modulation of energy metabolism in NAFLD treatment. Simultaneous modulation of energy output and energy intake can be used as part of a comprehensive NAFLD treatment regimen. Implementing PA as well as consuming diets that are rich in bioactive nutrients such as FAs, amino acids, and polyphenols can contribute to improvements in NAFLD and related parameters. Dietary changes that encompass restriction of certain nutrients (eg, CHO) or balanced nutrition via the Mediterranean diet could also be used in the treatment of NAFLD. Currently available data support the Mediterranean diet as a consistently effective dietary approach to produce benefits on metabolic syndrome, NAFLD, T2D, and CVD. BHB, β-hydroxybutyrate; CHOL, cholesterol; DAG, diacylglycerol.
Metabolic Modulation by Dietary Changes: Restriction, Induction, Balance
The individual macronutrients and micronutrients discussed earlier have shown the ability to improve measures of liver and metabolic health through various biological mechanisms. It follows that adjusting the composition of the diet by consumption of foods with bioactive components, such as specific FAs, amino acids, and polyphenols, should be considered as part of a comprehensive dietary approach for NAFLD. At present, the most consistent and robust evidence seems to be for a balanced diet versus nutrient restriction or induction, all of which are briefly reviewed here.
Carbohydrate restriction
CHO restriction as a successful strategy to induce weight loss may be partly explained via suppression of the usual weight loss–mediated increase in ghrelin level.
However, research on CHO restriction is often confounded by weight loss and protein/fat composition of the CHO-restricted interventional diet.
For example, a short, 14-day intervention with an isocaloric, CHO-restricted, increased-protein diet in 17 obese individuals with NAFLD reduced liver fat levels paralleled by (1) decreases in hepatic de novo lipogenesis, (2) increases in serum β-hydroxybutyrate concentration, (3) increases in folate-producing Streptococcus and serum folate concentration, and (4) downregulation of the lipogenic pathway with upregulation of folate-mediated 1-carbon metabolism and FA oxidation pathways from transcriptomic analysis of liver biopsy samples (see Fig. 3).
Other CHO-restricted studies in which the CHO was replaced almost entirely with dietary fat had either no reduction or showed an increase in IHTG levels.
Effects of ketogenic diets (KDs) in both rodents and humans with NAFLD remain unclear. In rodent models, KD feeding resulted in hepatic insulin resistance, increased hepatic diacylglycerol content, and increased lipid accumulation and inflammation (see Fig. 3).
Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: an open-label, non-randomised controlled study.
Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: an open-label, non-randomised controlled study.
making it difficult to ascertain whether the beneficial effects are driven directly by the increase in plasma ketone levels. Ketosis induced by CHO restriction was associated with increased levels of cholesterol and inflammatory markers (see Fig. 3) and decreased insulin-mediated antilipolysis in overweight and obese men.
To circumvent the unwanted dietary restriction of adhering to a caloric-restricted or CHO-restricted diet, or a KD, and therefore to examine a pure ketone-driven effect, an edible form of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone ester (KE) was administered to healthy human participants.
At rest, KE intake induced a 3-fold increase in intramuscular concentrations of β-hydroxybutyrate and suppression of all measured muscle glycolytic intermediates after an exercise bout. This physiologic state induced by exogenous KE is opposite to that of endogenous ketosis induced by low CHO intake, in which replete glucose reserves, an intact insulin axis, and increased levels of ketone bodies would never usually coexist.
it is surmised that such increase in fat oxidation would lead to increased energy expenditure and consequently to body fat loss, the basis of the original Atkins diet.
However, the experimental evidence does not support such a metabolic advantage. A systematic review and meta-analysis of 32 controlled-feeding studies (n = 563) by Hall and Guo
on the effects on daily energy expenditure and body fat of isocaloric diets differing in their CHO and fat content but with equal protein found that both energy expenditure (26 kcal/d) and fat loss (16 g/d) were significantly greater with lower-fat diets. It is possible that KDs with the fat predominantly derived from unsaturated fat sources might produce reductions in liver fat. Nonetheless, in light of the available evidence, higher-protein diets seem to confer advantages on energy expenditure, body composition, and liver fat more than a CHO-restricted KD in humans.
Balanced composition
A consistently successful example of a dietary intervention to improve metabolic health is the Mediterranean diet (MEDd).
Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study.
The MEDd is typically low in simple sugars and high in fiber, fresh fruit and vegetables, olives, avocados, nuts, and fish. These foods are rich in bioactive FAs, such as MUFAs and polyunsaturated FAs, and potent antioxidants, such as vitamin E and polyphenols, which are critical regulators of nutrient-sensed transcription factors (eg, SREBP-1c, PPARα, and PPARγ), which regulate core metabolic pathways (see Fig. 3).
Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study.
In a randomized controlled, 6-week crossover dietary intervention study comparing a MEDd with low-fat/high-CHO diet in 12 insulin-resistant subjects with biopsy-proven NAFLD, MEDd significantly reduced mean IHTG levels and HOMA-IR by 39% and 36%, respectively, without change in body weight.
(n = 1199) revealed that the Adherence to MEDd Score was a significant independent predictor of hepatic steatosis severity.
A precise understanding of which specific components of the MEDd mediate the beneficial effects remains unclear. It most likely is a combination of all the nutrients discussed earlier. It is also difficult to precisely define a MEDd because it is a broad pattern. Nonetheless, the PREDIMED (Prevención con Dieta Mediterránea)
study provided robust clinical trial evidence for intervention diets consisting of 40% CHO, 16% protein, and 44% fat, the fat being predominantly MUFAs (22% of calories) with saturated FAs at 9% and polyunsaturated FAs at 6% in the prevention of CVD. Thus, the authors propose a MEDd that replaces some CHO with protein (ideally 25%–30% calories from protein) as an optimal diet for NAFLD.
Metabolic Modulation by Decreasing Energy Intake
Irrespective of nutrient composition, both progressive (1200–1500 kcal/d restriction) and severe methods of calorie restriction, such as bariatric surgery, are effective in inducing weight loss and improving metabolic health outcomes in patients with NAFLD
(see Fig. 3). For example, results from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study (n = 218) showed that 6 months of 25% calorie restriction while maintaining sufficient nutrition resulted in ∼10% progressive decline in body weight accompanied by 29% decrease in fasting plasma insulin level, 27% reduction in both subcutaneous and visceral fat, and 37% decrease in hepatic lipid level.
Significant weight loss following bariatric surgery resulted in complete regression of NAFLD and necroinflammatory activity in 82% and 93%, respectively, in a study of 284 obese patients.
In a separate cohort of 109 morbidly obese patients with biopsy-proven NASH undergoing bariatric surgery, 85% had complete resolution of NASH, and fibrosis was reduced in 33.8% of patients after 1 year of follow-up.
Another approach to decreasing energy input is by intermittent fasting (see Fig. 3), which has been shown to significantly reduce obesity, fasting insulin level, and leptin level.
However, most studies to date have focused on changes related to body weight and in metabolic parameters for T2D and CVD, and not specifically for NAFLD. In addition, human studies have been limited to observational studies of religious fasting (eg, during Ramadan), cross-sectional studies of eating patterns, and small experimental studies, underscoring the need for robust study designs to adequately examine intermittent fasting in humans.
Although calorie-reducing interventions could be effective short-term strategies to improve metabolic health, long-term adherence has not been sufficiently explored. It is likely that poor adherence to such approaches and regression to normal caloric consumption may limit the effectiveness, as shown by the high dropout rates
Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: a randomized clinical trial.
during alternate-day fasting interventions. Thus, education on optimal nutrient compositions should continue to be an integral consideration in the overall management of NAFLD.
Metabolic Modulation by Increasing Energy Output
Only a small reduction in body weight is necessary to elicit significant improvements in liver health and metabolic parameters. For example, a 25% to 43% reduction in IHTG levels has been reported following body weight loss of just 5%, with improvements seen in necroinflammation, reductions in NAFLD activity score, resolution of NASH, and regression of fibrosis with progressive weight loss of greater than 10%.
Although it is well established that both intake (decreased) and output (increased) must be modulated to attain net energy loss, the laws of thermodynamics make it highly inefficient to lose body weight purely via increasing energy output alone. Nonetheless, the literature strongly supports the role of PA in the management of NAFLD (see Fig. 3).
Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial).
Effects of aerobic vs. resistance training on visceral and liver fat stores, liver enzymes, and insulin resistance by HOMA in overweight adults from STRRIDE AT/RT.
Am J Physiol Endocrinol Metab.2011; 301: E1033-E1039
In a prospective cohort study of 1149 people with baseline NAFL studied over 7 to 9 years, only vigorous-intensity PA (≥7 metabolic equivalent of tasks (MET)), but not moderate-low–intensity (3–5 MET) or moderate-high–intensity (5–7 MET) PA, was able to prevent the progression from NAFL to NASH.
advocate a prescription of 150 to 300 min/wk of moderate-intensity to vigorous-intensity (50%–70% Vo2 [maximum oxygen uptake] peak) aerobic exercise, performed on a minimum of 3 d/wk, which resulted in mean relative reduction in IHTG level of 28% for hepatic benefits in patients with NAFLD.
The mechanisms mediating PA and improvements in metabolic disease are complex and still not fully understood. However, strong similarities between existing pharmacologic target approaches and PA on cellular metabolism have been identified. For example, both metformin and PA are potent activators of AMPK within skeletal muscle, adipose, and liver tissue that increase mitochondrial oxidative capacity and shift substrate metabolism toward fat oxidation while downregulating lipogenic enzymes by suppressing SREBP-1c.
Protective effects of aerobic swimming training on high-fat diet induced nonalcoholic fatty liver disease: regulation of lipid metabolism via PANDER-AKT pathway.
In aggregate, taking the best evidence to date and, in particular, the powerful effects of certain nutrients in food on human physiology, the authors recommend a dietary framework for NAFLD as shown in Table 2. This construct could serve as a standardizing approach to dietary recommendations in a clinical practice setting, as well as provide a foundation for dietary control in NAFLD clinical trials given the substantial placebo effect in this disease setting.
Table 2Dietary recommendations for nonalcoholic fatty liver disease based on the available current evidence
•
Prioritize intact starches such as brown rice, quinoa, and steel-cut oats, and limit or avoid refined starches such as white bread and white rice
•
Replace some of the CHO, especially refined CHO, in the diet with additional protein from a mixture of animal or vegetable sources, including chicken, fish, cheese, tofu, and pulses
•
Include a variety of bioactive compounds in the diet by consuming fruits, vegetables, coffee, tea, nuts, seeds, and extra virgin olive oil
•
Get most fat from unsaturated sources, such as olive oil (ideally extra virgin), rapeseed oil, sunflower oil, safflower oil, canola oil, or nuts and seeds
•
Limit or avoid added sugars, whether sucrose, fructose, maltose, maltodextrin, or any syrups. If any of these words appear in the first 3–5 ingredients of any food item, it is best to avoid that item and choose a no-sugar version instead. Examples are yogurts and commercial cereals
•
In particular, avoid liquid sugar such as carbonated sugary drinks/sodas, lemonade, any juices, smoothies, and added sugar to tea and coffee
Exact portion sizes differ based on an individual's energy requirements. Energy balance is the biggest driver of liver fat change; therefore, a weight-maintaining or weight-reducing diet should be advised if an individual is overweight.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
Unsaturated fats, such as n-3 or n-6 polyunsaturated FAs, or MUFAs, have been shown to improve insulin sensitivity and decrease IHTG levels when they replace saturated fat.
Although foods rich in unsaturated fats rather than saturated fats should be emphasized, there is some evidence that fermented dairy foods, including yogurts, have a neutral or even protective effect against cardiovascular disease.
Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
Unsaturated fats, such as n-3 or n-6 polyunsaturated FAs, or MUFAs, have been shown to improve insulin sensitivity and decrease IHTG levels when they replace saturated fat.
Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Unsaturated fats, such as n-3 or n-6 polyunsaturated FAs, or MUFAs, have been shown to improve insulin sensitivity and decrease IHTG levels when they replace saturated fat.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
Unsaturated fats, such as n-3 or n-6 polyunsaturated FAs, or MUFAs, have been shown to improve insulin sensitivity and decrease IHTG levels when they replace saturated fat.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Unsaturated fats, such as n-3 or n-6 polyunsaturated FAs, or MUFAs, have been shown to improve insulin sensitivity and decrease IHTG levels when they replace saturated fat.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Unsaturated fats, such as n-3 or n-6 polyunsaturated FAs, or MUFAs, have been shown to improve insulin sensitivity and decrease IHTG levels when they replace saturated fat.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Although foods rich in unsaturated fats rather than saturated fats should be emphasized, there is some evidence that fermented dairy foods, including yogurts, have a neutral or even protective effect against cardiovascular disease.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
Unsaturated fats, such as n-3 or n-6 polyunsaturated FAs, or MUFAs, have been shown to improve insulin sensitivity and decrease IHTG levels when they replace saturated fat.
Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
Foods rich in polyphenols and other bioactive compounds may decrease inflammatory pathways implicated in liver disease.
a Exact portion sizes differ based on an individual's energy requirements. Energy balance is the biggest driver of liver fat change; therefore, a weight-maintaining or weight-reducing diet should be advised if an individual is overweight.
b Partly or completely indigestible CHO increase the production of SCFAs via colon fermentation and gut microbiota, which modulate whole-body insulin sensitivity via a variety of mechanisms, as discussed in this article. The low-glycemic load of this diet has also been linked with lower liver fat levels.
c Proteins and amino acids could decrease IHTG levels without weight loss via several mechanisms that affect metabolism, inflammation, oxidative stress, and gut epithelial barrier physiology.
d Foods rich in polyphenols and other bioactive compounds may decrease inflammatory pathways implicated in liver disease.
e Unsaturated fats, such as n-3 or n-6 polyunsaturated FAs, or MUFAs, have been shown to improve insulin sensitivity and decrease IHTG levels when they replace saturated fat.
f Although foods rich in unsaturated fats rather than saturated fats should be emphasized, there is some evidence that fermented dairy foods, including yogurts, have a neutral or even protective effect against cardiovascular disease.
The concept of energy balance to allay metabolic maladies was recognized nearly half a millennium ago; however, it is only in the last few decades that clinicians have begun to systematically understand the biochemical and molecular underpinnings of those initial observations. Lifestyle-related factors remain the single biggest modifiable component of people’s health. The current evidence suggests that it is possible to reduce the burden of diseases related to caloric excess and disordered metabolism, such as NAFLD, with a structured approach to diet and PA. Experimental studies have started to identify mechanisms by which certain dietary nutrients may exert influence on the multifactorial aspects of NAFLD and provide a strong scientific foundation to support the possibility for combinatorial effects of nutritive components of food.
Although current evidence strongly supports the role of lifestyle modification as a foundation for the management of NAFLD,
it is also clear from the increasing incidence of NAFLD that such an approach alone may not be sufficient or sustainable, especially for more severe stages of the disease. Large changes (eg, in FA compositions) in the diet are often needed for modest (0.5%) absolute reductions in liver fat levels.
The amounts of macronutrients and micronutrients differ depending on the food source and on the individual’s activity level or muscle mass, and optimal amounts of various foods still remain to be elucidated.
Thus, although dietary measures should remain integral to any NAFLD management approach, it is likely that additional interventions are also needed that are not solely dependent on weight loss to achieve benefits on NAFLD pathogenesis and progression.
Recent advances in large-scale omics data-mining, machine learning, and systems biology are now allowing cross-disciplinary predictive insights to harness the power of people’s own bodies to fight disease and restore health, opening the possibility toward promising interventions beyond a dietary approach, such as leveraging key endogenous bioactive signaling intermediates, which may also exert influence on some of the same biological pathways and molecular targets as pharmacotherapies.
The effect of evidence-based nutrition clinical care pathways on nutrition outcomes in adult patients receiving non-surgical cancer treatment: a systematic review.
Bespoke combinations of such endogenous metabolic modulators have the potential to be used as treatments in combination with both an underlying dietary framework as well as possible pharmacologic agents, expanding therapeutic options for patients across the NAFLD spectrum. Adequately controlled randomized clinical trials of sufficient duration and size are needed to determine whether such approaches are tractable in the real world and can form a mainstay of public health policy and recommendations for the management of NAFLD.
Acknowledgments
Editing assistance was provided by Caryne Craige, PhD, of Fishawack Communications Inc; funding for this assistance was provided by Axcella Health, Inc.
Disclosures
M.V. Chakravarthy is an employee of Axcella Health, Inc, and holds stock options in the company. T. Waddell and R. Banerjee are employees of Perspectum Diagnostics and hold shares and share options in the company. N. Guess has received research and fellowship funding from Diabetes UK, Diabetes Research and Wellness Foundation, Medical Research Council, Winston Churchill Memorial Trust, the American Overseas Dietetic Association, and Oviva. N. Guess has received consulting fees from Fixing Dad (a low-CHO app), Babylon Health, and Boehringer Ingelheim.
This article reflects the independent perspectives of the individual authors and their interpretations of the scientific literature; it does not represent the views or positions of their respective employers/institutions.
Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study.
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