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Recent Updates in the Prevention of Nonalcoholic Fatty Liver Disease

  • Mohamed El-Kassas1,* ,
  • Abeer Awad2 and
  • Nahum Méndez-Sánchez3,4
 Author information
Gene Expression   2023;22(1):19-27

doi: 10.14218/GE.2022.00005S

Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the leading causes of hepatic fibrosis and liver-related mortality worldwide, despite efficient hepatitis B and C antiviral therapies that have dramatically lowered the disease load. Although significant efforts have been exerted to understand the molecular basis of disease pathogenesis, there are currently few therapeutic alternatives available for NAFLD-associated fibrosis. Thus, NAFLD prevention is critical before the development of disease-related complications. In this context, there is a tremendous substantial global burden on public health systems to actively search for effective preventive and therapeutic targets for NAFLD. In this review, we highlight the current strategies to prevent progression and poor outcomes of NAFLD and to avoid complications associated with disease fibrosis, notably cirrhosis, portal hypertension, and liver cancer. We discuss different nonpharmacological measures, such as lifestyle modifications (weight loss, exercise, healthy diet) and other pharmacological interventions that could prevent NAFLD.

Graphical Abstract

Keywords

Nonalcoholic steatohepatitis, Nonalcoholic fatty liver disease, Prevention, Lifestyle modifications, Pharmacological interventions

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed countries, affecting a large percentage of the adult population.1 NAFLD is defined as a spectrum of liver diseases that include cirrhosis, steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC).2 In a consensus statement in 2020, an international panel of experts recommended a change in NAFLD to metabolic-associated fatty liver disease owing to the heterogeneous pathogenesis of the disease.3 The main advantage of this new nomenclature is a move away from alcohol usage or other concurrent liver diseases and toward a diagnosis of inclusion based on the metabolic dysfunction that is the primary cause of the disease,4 particularly for children.5 Nonetheless pathogenesis of NAFLD is complex and multifactorial. Environmental factors, obesity, insulin resistance, alterations in the microbiome, and predisposing genetic variations interact in a complicated way to cause disordered lipid homeostasis and an abnormal accumulation of triglycerides and other lipid compounds in hepatocytes.6

Frequently associated metabolic dysfunctions such as type 2 diabetes mellitus (T2DM), obesity, or dyslipidemia are seen in NAFLD patients.1 Fatty liver disease is categorized into NAFLD or NASH based on histology. NAFLD is defined as the presence of more than 5% hepatic steatosis in the absence of hepatocyte injury. NASH is defined as hepatic steatosis with concomitant lobular inflammation and hepatocyte damage (such as hepatocyte ballooning), with or without fibrosis.7,8

Promoting a healthy anti-oxidant status is essential for maintaining normal cellular homeostasis. Oxidative stress is considered a major factor that contributes to the pathophysiology of inflammatory chronic liver diseases and, in turn, the development of NAFLD. This highlights the significance of controlling Ox, to prevent the development and progression of NAFLD.9

In this context, NAFLD carries a high risk for cardiovascular diseases and cardiovascular events and increases the burden of NAFLD-related HCC, underscoring the urgent need for early identification and prevention of disease progression.1

Modifiable and nonmodifiable predisposing risk factors for NAFLD

Obesity is a significant driver of NAFLD and NASH,10 with the prevalence of NAFLD increasing relative to increases in body mass index (BMI).11 The increase in T2DM echoes that of obesity worldwide, adding another risk factor for NAFLD and NASH.11 The prevalence of T2DM among NAFLD and NASH patients is over 60%. T2DM also increases the risk of an accelerated course of NAFLD and is a predictor of advanced fibrosis and mortality.1,12 Visceral obesity, associated with insulin resistance, is a crucial factor in NAFLD development.13 Insulin resistance causes increased lipolysis in adipose tissue that causes decreased glucose absorption in skeletal muscle. As a result, the amount of free fatty acids in the circulation and liver rises.14,15

The possibility of NAFLD and NAFLD-related fibrosis increases with aging.11,12 It has been observed that older individuals have higher stages of fibrosis.16 Female sex is also associated with an increased risk of NAFLD, as stated in some reports from Sri Lanka and Thailand. A study from Thailand including 34,709 individuals (27,073 females and 7,636 males) reported the prevalence of NAFLD at 22.9% in females and 18.3% in males.17 However, some studies conducted in the USA, China, and Spain reported higher rates of NAFLD in males.18–20

As previously mentioned, ethnicity and race can be categorized as nonmodifiable risk factors for NAFLD.12,21 In many studies conducted in the USA, Hispanic Americans had the highest prevalence of NAFLD, followed by Americans of European origin and African Americans, despite a higher prevalence of obesity among non-Hispanics.22,23 The higher prevalence of NAFLD among Hispanics may be explained by greater sensitivity to recognized risk factors (e.g., visceral adiposity, diabetes, and an undesirable gene variant) relative to other ethnic subgroups. However, socio-economic and cultural factors that may affect the risk of developing NAFLD are rarely considered in the sense of NAFLD.23

Genome-wide association studies have identified multiple loci associated with NAFLD.24,25 The genes that have been related to NAFLD include transmembrane 6 superfamily member 2, PNPLA3, MBOAT7, glucokinase regulator, and hydroxysteroid 17-beta dehydrogenase-13.26 Multiple other genes, and reversible epigenetic changes, such as miRNA-122, miRNA-34a, and miRNA-192, have been reported in many studies, suggesting the existence of heritable factors for NAFLD.27,28

A functional role for the microbiota in NAFLD pathogenesis has been identified. Gut bacteria from obese and lean humans have different impacts on the risk of fat accumulation in germ-free mice, but there is little data available on the role of gut microbiota in NAFLD in humans.29 Recently published data suggest that the microbiome and gut microbiome-derived metabolites could be used to predict advanced fibrosis and cirrhosis in NAFLD patients.30,31

Smoking has been reported to be an independent risk factor for fibrosis progression in patients with NAFLD.32 However, drinking coffee was found to prevent liver fibrosis in NAFLD patients while conflicting reports are available about its role in reducing NAFLD incidence in the general population.33 Additionally, elevated serum markers, such as uric acid and ferritin, have been significantly correlated with the existence and progression of NAFLD.34,35 The associations of metabolic syndrome, predominantly obesity and insulin resistance, with NAFLD prevalence can increase the likelihood of liver fibrosis progression, leading to cirrhosis, HCC, and death.36,37

The burden of NAFLD-related HCC is increasing rapidly. In 2010, a study from northeast England reported that 35% of diagnosed HCC cases were associated with NAFLD (41 of 118 cases), which was a significant 10-fold increase over a 10-year period.38 In another study, the reported incidence of HCC among patients with NAFLD was 0.44 per 1,000 person-years. Stages F3 and F4 NAFLD-related fibrosis increased by an estimated 7-fold for the risk of HCC compared to individuals without liver disease. NAFLD-related HCC can also arise in the absence of cirrhosis, as seen in the chronic hepatitis B virus.39,40 According to published data, there has been a 9% annual increase in NAFLD-related HCC associated with a 1.2-fold higher risk of mortality within 1-year compared to other liver diseases.41 Another study demonstrated that NAFLD was associated with a 7.3-fold increased risk of HCC (OR: 7.3, 95%CI 1.52–34.76) in patients with chronic hepatitis B virus infection.42 Patients with noncirrhotic NASH had an almost 3-fold increase in the risk of HCC development compared to noncirrhotic individuals with liver disease due to other causes (OR 2.61; 95% CI 1.27–5.35; p = 0.009).43 A study from South Korea including 329 patients reported an increase in NAFLD-related HCC cases from 3.8% in 2001–2005 to 12.2% in 2006–2010.44

Figure 1 summarizes the main modifiable and nonmodifiable risk factors for the occurrence and progression of NAFLD.

The main modifiable and nonmodifiable risk factors for the occurrence and progression of nonalcoholic fatty liver disease.
Fig. 1  The main modifiable and nonmodifiable risk factors for the occurrence and progression of nonalcoholic fatty liver disease.

HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease.

Prevention of NAFLD

Nonpharmacological measures

Despite great efforts in finding pharmacological strategies for NAFLD prevention, nonpharmacological measures remain the first and critical issue for NAFLD prevention. Lifestyle modifications, including weight loss, dietary modifications, and exercise, also serve as a primary line of prevention.

Lifestyle modification

Dietary change

It is estimated that most consumed fats are saturated and that fresh fruit and vegetable intake rates are low.45 For example, among Egyptian women, approximately 40% of the diet includes saturated fat.46 Additionally, weight gain, obesity, and NAFLD have all been linked to increased caloric intake, particularly when combined with the consumption of more saturated fat, complex carbohydrates, sugary beverages, and high fructose intake.47,48 Lifestyle modification programs, in addition to weight loss, are proven measures for reducing hepatic fat, the disappearance of steatohepatitis, and fibrosis regression, subsequently improving the quality of life of NAFLD patients. Six weeks of a Mediterranean diet were shown to be linked to appreciable reductions in hepatic steatosis based compared with increased fat and reduced carbohydrate diet.49 Interestingly, some published data suggest that the timing of meals also affects NAFLD; eating before sleep and consuming a majority of calories at dinner increases the chance of developing NAFLD.50 However, some herbs and foods are thought to be protective against the disease.51 Green tea catechins are thought to have hepatoprotective effects due to their anti-inflammatory, anti-oxidant, and hypolipidemic qualities. One study involving patients with biopsy-proven NASH reported an improvement in insulin resistance with a decrease in BMI but without a change in alanine transaminase (ALT) and aspartate aminotransferase levels compared to controls. Due to debates in the respective research fields, preclinical models have been developed to address toxicological concerns before conducting further research to explore the possible benefits of green tea in NAFLD.52

There is some literature on the effects of coffee and other caffeinated drinks on NAFLD prevention. One study reported that coffee could reverse NAFLD by reducing ALT, macrovesicular steatosis, and hepatocyte ballooning.52 Several bioactive substances in coffee could mediate this protective mechanism. The antifibrotic action, as a result of caffeine’s antagonism of the adenosine receptor A2a, could result in the inactivation of hepatic stellate cells.53,54 A meta-analysis of 20,064 participants and a large population-based study of a cohort of 18,550 people found that caffeine consumption was protective against NAFLD, as evidenced by altered levels of the liver enzymes aspartate aminotransferase and ALT.55

In conclusion, energy intake restrictions, such as reduced saturated fat, carbohydrate, and sugar consumption, and an increase in consumption of green tea, coffee, and caffeine, could be beneficial dietary changes for NAFLD prevention.

Physical activity

A lack of physical activity is associated with an increased risk of NAFLD; the lower the level of habitual physical activity the greater the risk of intrahepatic fat content.56 Even without weight loss, a suitable exercise regimen is a crucial factor in NAFLD prevention. However, there is no established ideal physical activity/exercise frequency, intensity, duration, and type to promote NAFLD resolution.57,58 Both aerobic and resistance exercise are associated with a significant reduction in hepatic fat content, and the choice between both types should be based on patient preference.47,59 European clinical guidelines for NAFLD suggest resistance training together with 150–200 minutes per week of moderate-intensity aerobic physical activity, such as brisk walking or stationary cycling in 3–5 sessions. This exercise benefit could be associated with improvement in musculoskeletal fitness and metabolic risk factors.47 A large pool of published data reported an improvement in the degree of hepatic steatosis with exercise; however, there is insufficient data evaluating the impact of exercise on liver histology in NASH.47 In this context, exercise type and duration should be designed based on patient preference and compliance with the exercise protocol.58

Weight loss

Weight loss can have a significant impact on overweight or obese NAFLD patients.60 Many studies reported that weight loss via a comprehensive lifestyle program for 12 months could improve histologic NASH-related features.61 Interestingly, it was reported that a 5% reduction in body weight was associated with an approximate 30% reduction in liver fat content with a subsequent improvement in metabolic abnormalities; meanwhile, a 7–10% reduction in weight loss was reported to be associated with a reduction in hepatocyte inflammation, and a 10% reduction was associated with significant fibrosis regression.62–64 In contrast, some published data illustrated that weight reduction is not significantly associated with reducing hepatic fat content or restoring normal liver function.65

Sleep

National Sleep Foundation guidelines state that a reasonable sleep duration differs according to age. Normal, healthy adults should sleep between 7 and 9 hours every night, while infants, young children, and teenagers require even more sleep to support growth and development, and persons over 65 years need between 7 and 8 hours of sleep every night.66 Some studies reported that poor quality of sleep and sleep deviation contribute to NAFLD pathogenesis and that sleep quality is associated with obesity, diabetes, and multiple behavioral influences.67,68 The underlying mechanism is attributed to increases in inflammatory cytokines, such as interleukin 6 and tumor necrosis factor-alpha, that are exacerbated by sleep disorders. Such increases, in turn, can enhance adipocyte lipolysis affecting hepatic overflow of free fatty acids.69 Changes in sleep quality may also lead to increased liver fat storage via its effect on the hypothalamus-pituitary-adrenal axis and cortisol metabolism.70 Although the discoordination between central and peripheral circadian rhythms plays a crucial role in pathogenesis. Thus, circadian clock proteins that maintain energy homeostasis by coordinating cellular processes within and between organ systems could also lead to NAFLD.71 Therefore, proper sleep patterns and duration combined with other behavioral factors are important in NAFLD prevention.

Bariatric (metabolic) surgery

Due to the superior efficacy of sustained weight loss and physical activity in NAFLD prevention, bariatric surgery represents an alternative nonpharmacological management option for obese patients with NAFLD.72 Recent systematic reviews and meta-analyses reported a marked decrease in mean NAFLD activity score following bariatric surgery.73,74 Many articles have also reported potential positive effects of bariatric surgery on several outcomes for NASH owing to its effect on reducing BMI, improving insulin resistance, altering glucose metabolism, reducing transaminases levels, and improving histological changes associated with simple steatosis, NASH, and fibrosis.75,76 However, there is still lack of information on adverse events.75 Until now, there have been no recommendations to support or reject bariatric surgery in the treatment of NAFLD.75

Gut microbiota

The gut plays a pivotal role in the development of NAFL and NASH.77 Trillions of microorganisms inhabit the different parts of the gastrointestinal tract at different concentrations.77 The gut microbiome is responsible for regulating the fermentation and metabolism of food-derived nutrients that impact the aggravation and mitigation of the course of NAFLD. The microbiome also plays an important role in the development and function of the host’s innate and adaptive immune systems by depleting harmful substances that promote inflammation, boosting the host immune response, and preventing insulin resistance, steatosis, and, consequently, NAFLD.78 Increased Proteobacteria (phylum), Enterobacteriaceae (family), Escherichia, Bacteroides, Dorea, and Peptoniphilus (genus) and decreased Rikenellaceae, Ruminococcaceae (family), Faecalibacterium, Coprococcus, Anaerosporobacter, and Eubacterium (genera) are considered the most consistent gut microbiota signatures associated with NAFLD. Other metabolic disorders could overlap with NAFLD-associated microbiota signatures such as reduced levels of Faecalibacterium prausnitzii, which is considered a beneficial anti-inflammatory microbe in cirrhotic patients, as well as in obese patients, patients with T2DM, or in some gut diseases, such as irritable bowel syndrome and inflammatory bowel disease. In advanced fibrosis, Bacteroides vulgatus is more prevalent and is linked to marked obesity, insulin resistance, and elevated levels of haemoglobin A1c. It is noteworthy that the gut mycobiome is consistent among NAFLD patients, unlike patients with cirrhosis and alcoholic liver diseases.79Figure 2 provides an overview of the gut microbiota signature in NAFLD. In this context, microbial metabolic manipulation via the microbiome and its metabolites could represent a potential option for NAFLD prevention, but more extensive research is required.80

Gut microbiota signature in nonalcoholic fatty liver disease.
Fig. 2  Gut microbiota signature in nonalcoholic fatty liver disease.

NAFLD, Nonalcoholic fatty liver disease.

Table 1 demonstrates the most recent reports of gut microbial alterations in patients with NAFLD.30,81–86

Table 1

Recent reports of gut microbial alterations in patients with nonalcoholic fatty liver disease

StudyYearSample sizeMicrobiomeMetabolites
Rau et al.81201832 NAFLD; 14 NAFL; 18 NASH; 27 HCsFusobacteria; Fusobacteriaceae; Fusobacterium; Prevotella; Eubacterium biformePropionate; Butyrate; Acetate
Kim et al.822019453 Non-NAFLD; 40 Developed NAFLD; 35 Regressed NAFLD; 238 Persistent (G3)Christensenellaceae; Odoribacteraceae; Oscillospira; Odoribacter; Coprococcus; Ruminococcaceae; Porphyromonadaceae; Christensenellaceae; Oscillospira; Ruminococcus; CoprococcusNot described
Caussy et al.30201954 Non-NAFLD; 18 NAFLD without advanced; fibrosis; 26 NAFLD-cirrhosisStreptococcus; Megasphaera; Bacillus; Lactococcus; Gallibacterium; Faecalibacterium; Prausnitzii; Catenibacterium Rikenellaceae; Mogibacterium; PeptostreptococcaceaeNot described
Chen F. et al.83202030 Lean control; 46 non-lean control; 99 Lean NAFLDDorea; Marvinbryantia; ChristensenellaceaeTotal BA; Total primary BA; Total secondary BA; CDCA; DCA
Adams et al.84202055 Control; 58 NAFLD Fibrosis F0-2; 9 NAFLD Fibrosis F3/4Firmicutes Proteobacteria; Actinobacteria; Bacteroidetes Actinomycetaceae; Lachnospiraceae; BacteroidaceaeTotal BA; Primary conjugated; BA; GCA; Secondary conjugated; BA; DCA
Behary et al.85202130 Non-NAFLD control; 28 NAFLD-fibrosis; 32 NAFLD-HCCProteobacteria; Enterobacteriaceae; Oscillospiraceae Erysipelotrichaceae; Coriobacteriaceae; Muribaculaceae; Odoribacteraceae; Prevotellaceae; Bacteroides caecimuris; Veillonella parvulaXaloacetate; Acetylphosphate; Isocitrate; Acetate; Butyrate; Formate; Butyrate; Propionate
Demir et al.86202216 Controls; 24 NAFL; 54 NASHMucor sp.; Cyberlindnera jadinii; C.albicans Salinispora sp. Babjeviella; inositovoraNot described

Pharmacological interventions

Pharmacological therapies have had significant effects on NAFLD prevention, especially for patients in high-risk groups, such as those with concomitant T2DM.1 Glucagon-like peptide-1 agonists that stimulate the secretion of insulin in a glucose-dependent manner, as well as sodium-glucose transport protein 2 inhibitors that prevent glucose reabsorption in the kidney, are examples of new antidiabetic medications that could have a positive effect on weight reduction. Liraglutide and semaglutide, glucagon-like peptide-1 receptor agonists, are now being studied in a placebo-controlled phase 2 study in NASH patients.87 The nuclear receptor obeticholic acid, which can control liver inflammation, lipoprotein composition, bile acid synthesis, and glucose and lipid metabolism, is a new medication that exhibits agonistic farnesoid X receptor activity.88,89 and has been demonstrated in several placebo-controlled trials to be significantly helpful in enhancing insulin sensitivity in NAFLD patients with T2DM.90,91 Based on the promising results of a phase 2 trial that demonstrated notable reductions in inflammation and fibrosis in patients with NAFLD, obeticholic acid is currently being investigated in a sizable long-term phase 3 study with more than 2,400 NASH patients, including approximately 2,100 patients with moderate hepatic fibrosis.92,93

Proliferator-activated receptors (PPARs) agonists are a group of transcription factors that serve as fat sensors in several tissues and are essential for controlling adipogenesis, triglyceride metabolism, and liver homeostasis.94 Three different receptors (PPARα, PPARβ/δ, and PPARγ) in this family are antidiabetic targets of the thiazolidinediones class, also known as “glitazones”.95 Pioglitazone and Rosiglitazone target PPARγ, which can ameliorate fibrosis,96 reduce hepatic fat, inflammation and transaminase levels, and improve histological features in NAFLD.97,98

Several other drugs are in phase 2 randomized placebo-controlled trials with promising results. Firsocostat (GS-0976) and PF-05221304 are involved in inhibiting acetyl-coenzyme carboxylase catalyzing the rate-limiting step in de novo lipogenesis.99 Selonsertib, an apoptosis signal-regulating kinase 1 inhibitor, was tested as a target for “anti-inflammatory” interventions in phase 3 trials but with less satisfactory results.100 Another phase 3 trial evaluating cenicriviroc, a chemokine CCR2/CCR5 receptor inhibitor, in NASH patients with liver fibrosis is currently ongoing.101 Cenicriviroc is thought to effectively inhibit monocyte recruitment and macrophage accumulation in the liver,102 which is a crucial step in NASH progression towards fibrosis.103,104

Adipokines are secreted from adipose tissues and are considered the primary fatty acid provider, which is the main contributor to NAFLD development.105 Adiponectin is a vital adipokine that improves hepatic steatosis and inflammation and prevents NAFLD development.106,107 Coincident dyslipidemia should be treated with LDL-cholesterol-lowering agents, such as statins.8,15 Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors are also promising medications because of their ability to target the renin–angiotensin–aldosterone system in NAFLD pathogenesis.6,15 Leptin is an appetite-suppressing hormone secreted by fat cells; however, its effects on NAFLD development in humans are not clear yet.108 Ghrelin is an anti-inflammatory adipokine that improves hepatic lipid metabolism, inflammation, oxidative stress, and apoptosis, and could be a promising target for NAFLD prevention.109

Many preclinical and clinical studies suggest that various polyphenols, either flavonoids or nonflavonoids, could prevent steatosis and its progression to nonalcoholic steatohepatitis, as well as ameliorate NAFLD. Therefore, adding polyphenol-rich foods to one’s diet may be an appropriate recommendation for NAFLD patients. However, more clinical studies are needed to confirm this hypothesis.110 Several polyphenols, including resveratrol, curcumin, caffeine, and quercetin, are among the micronutrients that were investigated in preclinical and clinical trials by preventing the formation of intracellular reactive oxygen species. These micronutrients include vitamins E, C, and D, which can inhibit circulating blood cells from infiltrating the liver or target signaling pathways and mediators critical to producing extracellular matrix substances. However, most of these benefits have only been shown in experimental models.111,112 Vitamin E is a widely investigated micronutrient in preclinical and clinical studies for NAFLD management,113 which led to the recommendation of its use in the 2018 practice guidelines of the American Association of Liver Disease for treating biopsy-proven, nondiabetic patients with NASH.8 Many studies have reported promising benefits for silymarin which is regulated through a decrease of oxidative stress and inflammation. One large meta-analysis that included five clinical trials found a significant reduction of transaminases when silymarin was administered as a monotherapy.114 The benefits of using omega-3 fatty acids in NAFLD are still debatable. A meta-analysis including seven trials with omega-3 fatty acid supplementation in patients with NAFLD reported a significant decrease in transaminases, reduction in serum triacylglycerols, and increase in high-density lipoprotein levels compared to placebo. Meanwhile, two extensive well-controlled studies failed to show any benefits of omega-3 fatty acids in the treatment of NAFLD.115

Conclusions

NAFLD prevention is important before the development of disease-related complications. Many efforts are being made toward NAFLD prevention and management, mainly through controlling the modifiable predisposing risk factors, with many pharmacological agents still under investigation.

Abbreviations

ALT: 

alanine transaminase

BMI: 

body mass index

HCC: 

hepatocellular carcinoma

NAFLD: 

nonalcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

PPAR: 

proliferator-activated receptor

T2DM: 

type 2 diabetes mellitus

Declarations

Acknowledgement

None.

Funding

This is non-funded work.

Conflict of interest

MEK has been an editorial board member of Gene Expression since February 2023. The authors have no other conflict of interests related to this publication.

Authors’ contributions

MEK and AA contributed to the conception and design of the work and literature review. AA wrote the first draft of the manuscript. MEK and NMS provided critical revision and editing. All authors revised and approved the final version of the manuscript.

References

  1. El-Kassas M, Cabezas J, Coz PI, Zheng MH, Arab JP, Awad A. Nonalcoholic fatty liver disease: current global burden. Semin Liver Dis 2022;42(3):401-412 View Article PubMed/NCBI
  2. Frank J, Kisters K, Stirban OA, Obeid R, Lorkowski S, Wallert M, et al. The role of biofactors in the prevention and treatment of age-related diseases. Biofactors 2021;47(4):522-550 View Article PubMed/NCBI
  3. Polyzos SA, Kang ES, Tsochatzis EA, Kechagias S, Ekstedt M, Xanthakos S, et al. Commentary: Nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name. Metabolism 2020;113:154413 View Article PubMed/NCBI
  4. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 2020;73(1):202-209 View Article PubMed/NCBI
  5. Eslam M, Sanyal AJ, George J, International Consensus Panel. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158(7):1999-2014.e1 View Article PubMed/NCBI
  6. Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol 2018;13:321-350 View Article PubMed/NCBI
  7. Hernandez-Tejero M, Clemente-Sanchez A, Bataller R. Spectrum, screening, and diagnosis of alcohol-related liver disease. J Clin Exp Hepatol 2023;13(1):75-87 View Article PubMed/NCBI
  8. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67(1):328-357 View Article PubMed/NCBI
  9. Arroyave-Ospina JC, Wu Z, Geng Y, Moshage H. Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: Implications for prevention and therapy. Antioxidants (Basel) 2021;10(2):174 View Article PubMed/NCBI
  10. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363(9403):157-163 View Article PubMed/NCBI
  11. Hamed AE, Elwan N, Naguib M, Elwakil R, Esmat G, El Kassas M, et al. Diabetes association with liver diseases: an overview for clinicians. Endocr Metab Immune Disord Drug Targets 2019;19(3):274-280 View Article PubMed/NCBI
  12. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15(1):11-20 View Article PubMed/NCBI
  13. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012;56(3):943-951 View Article PubMed/NCBI
  14. Samuel VT, Shulman GI. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab 2018;27(1):22-41 View Article PubMed/NCBI
  15. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018;24(7):908-922 View Article PubMed/NCBI
  16. Mongraw-Chaffin M, Golden SH, Allison MA, Ding J, Ouyang P, Schreiner PJ, et al. The sex and race specific relationship between anthropometry and body fat composition determined from computed tomography: Evidence from the multi-ethnic study of atherosclerosis. PLoS One 2015;10(10):e0139559 View Article PubMed/NCBI
  17. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51(6):1972-1978 View Article PubMed/NCBI
  18. Llop E, Iruzubieta P, Perelló C, Fernández Carrillo C, Cabezas J, Escudero MD, et al. High liver stiffness values by transient elastography related to metabolic syndrome and harmful alcohol use in a large Spanish cohort. United European Gastroenterol J 2021;9(8):892-902 View Article PubMed/NCBI
  19. Eguchi Y, Hyogo H, Ono M, Mizuta T, Ono N, Fujimoto K, et al. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: A multicenter large retrospective study. J Gastroenterol 2012;47(5):586-595 View Article PubMed/NCBI
  20. Nagral A, Bangar M, Menezes S, Bhatia S, Butt N, Ghosh J, et al. Gender differences in nonalcoholic fatty liver Disease. Euroasian J Hepatogastroenterol 2022;12(Suppl 1):S19-S25 View Article PubMed/NCBI
  21. Frith J, Day CP, Henderson E, Burt AD, Newton JL. Non-alcoholic fatty liver disease in older people. Gerontology 2009;55(6):607-613 View Article PubMed/NCBI
  22. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40(6):1387-1395 View Article PubMed/NCBI
  23. Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, et al. Global Perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2019;69(6):2672-2682 View Article PubMed/NCBI
  24. Balakrishnan M, Kanwal F, El-Serag HB, Thrift AP. Acculturation and nonalcoholic fatty liver disease risk among hispanics of mexican origin: findings from the national health and nutrition examination survey. Clin Gastroenterol Hepatol 2017;15(2):310-312 View Article PubMed/NCBI
  25. Eslam M, George J. Genetic and epigenetic mechanisms of NASH. Hepatol Int 2016;10(3):394-406 View Article PubMed/NCBI
  26. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol 2018;68(2):268-279 View Article PubMed/NCBI
  27. Liu CH, Ampuero J, Gil-Gómez A, Montero-Vallejo R, Rojas Á, Muñoz-Hernández R, et al. miRNAs in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Hepatol 2018;69(6):1335-1348 View Article PubMed/NCBI
  28. Pirola CJ, Fernández Gianotti T, Castaño GO, Mallardi P, San Martino J, Mora Gonzalez Lopez Ledesma M, et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015;64(5):800-812 View Article PubMed/NCBI
  29. Guo J, Shi CX, Zhang QQ, Deng W, Zhang LY, Chen Q, et al. Interventions for non-alcoholic liver disease: A gut microbial metabolites perspective. Therap Adv Gastroenterol 2022;15:17562848221138676 View Article PubMed/NCBI
  30. Caussy C, Tripathi A, Humphrey G, Bassirian S, Singh S, Faulkner C, et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun 2019;10(1):1406 View Article PubMed/NCBI
  31. Caussy C, Hsu C, Lo MT, Liu A, Bettencourt R, Ajmera VH, et al. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology 2018;68(3):918-932 View Article PubMed/NCBI
  32. Premkumar M, Anand AC. Tobacco, cigarettes, and the liver: The smoking gun. J Clin Exp Hepatol 2021;11(6):700-712 View Article PubMed/NCBI
  33. Kositamongkol C, Kanchanasurakit S, Auttamalang C, Inchai N, Kabkaew T, Kitpark S, et al. Coffee Consumption and non-alcoholic fatty liver disease: An umbrella review and a systematic review and meta-analysis. Front Pharmacol 2021;12:786596 View Article PubMed/NCBI
  34. Darmawan G, Hamijoyo L, Hasan I. Association between serum uric acid and non-alcoholic fatty liver disease: A meta-analysis. Acta Med Indones 2017;49(2):136-147 PubMed/NCBI
  35. Qu HJ, Wang L, Zhuang ZJ, Yang WJ, Ding JP, Shi JP. Studying the correlation between ferritin and non-alcoholic fatty liver disease. Zhonghua Gan Zang Bing Za Zhi 2021;29(11):1089-1094 View Article PubMed/NCBI
  36. Younossi ZM, Stepanova M, Ong J, Yilmaz Y, Duseja A, Eguchi Y, et al. Effects of alcohol consumption and metabolic syndrome on mortality in patients with nonalcoholic and alcohol-related fatty liver disease. Clin Gastroenterol Hepatol 2019;17(8):1625-1633.e1 View Article PubMed/NCBI
  37. Young K, Aguilar M, Gish R, Younossi Z, Saab S, Bhuket T, et al. Lower rates of receiving model for end-stage liver disease exception and longer time to transplant among nonalcoholic steatohepatitis hepatocellular carcinoma. Liver Transpl 2016;22(10):1356-1366 View Article PubMed/NCBI
  38. Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J, Das D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014;60(1):110-117 View Article PubMed/NCBI
  39. Ertle J, Dechêne A, Sowa JP, Penndorf V, Herzer K, Kaiser G, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011;128(10):2436-2443 View Article PubMed/NCBI
  40. Mohamad B, Shah V, Onyshchenko M, Elshamy M, Aucejo F, Lopez R, et al. Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis. Hepatol Int 2016;10(4):632-639 View Article PubMed/NCBI
  41. Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 2015;62(6):1723-1730 View Article PubMed/NCBI
  42. Chan AW, Wong GL, Chan HY, Tong JH, Yu YH, Choi PC, et al. Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B. J Gastroenterol Hepatol 2017;32(3):667-676 View Article PubMed/NCBI
  43. Mittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z, Temple S, et al. Hepatocellular carcinoma in the absence of cirrhosis in united states veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2016;14(1):124-31.e1 View Article PubMed/NCBI
  44. Cho EJ, Kwack MS, Jang ES, You SJ, Lee JH, Kim YJ, et al. Relative etiological role of prior hepatitis B virus infection and nonalcoholic fatty liver disease in the development of non-B non-C hepatocellular carcinoma in a hepatitis B-endemic area. Digestion 2011;84(Suppl 1):17-22 View Article PubMed/NCBI
  45. Mahmood A. Nutritional status and anthropometric measurements among women in Egypt, National Survey 2001–2002. Arab J Food Nutr 2004;11:98-107
  46. Zaki M, Hussein L, Gouda M, Bassuoni R, Hassanein A. Nutritional epidemiological study to estimate usual intake and to define optimum nutrient profiling choice in the diet of Egyptian Youths. Food Nutr Sci 2015;6:1422-1436 View Article
  47. European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-1402 View Article PubMed/NCBI
  48. Barrera F, George J. The role of diet and nutritional intervention for the management of patients with NAFLD. Clin Liver Dis 2014;18(1):91-112 View Article PubMed/NCBI
  49. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 2013;59(1):138-143 View Article PubMed/NCBI
  50. El-Agroudy NN, Kurzbach A, Rodionov RN, O’Sullivan J, Roden M, Birkenfeld AL, et al. Are lifestyle therapies effective for NAFLD treatment?. Trends Endocrinol Metab 2019;30(10):701-709 View Article PubMed/NCBI
  51. Sun M, Ye H. Natural foods for the treatment of nonalcoholic fatty liver disease. J Med Food 2023;26(1):1-13 View Article PubMed/NCBI
  52. Fukuzawa Y, Kapoor MP, Yamasaki K, Okubo T, Hotta Y, Juneja LR. Effects of green tea catechins on nonalcoholic steatohepatitis (NASH) patients. J Funct Foods 2014;9:48-59 View Article
  53. Vitaglione P, Mazzone G, Lembo V, D’Argenio G, Rossi A, Guido M, et al. Coffee prevents fatty liver disease induced by a high-fat diet by modulating pathways of the gut-liver axis. J Nutr Sci 2019;8:e15 View Article PubMed/NCBI
  54. Wang H, Guan W, Yang W, Wang Q, Zhao H, Yang F, et al. Caffeine inhibits the activation of hepatic stellate cells induced by acetaldehyde via adenosine A2A receptor mediated by the cAMP/PKA/SRC/ERK1/2/P38 MAPK signal pathway. PLoS One 2014;9(3):e92482 View Article PubMed/NCBI
  55. Birerdinc A, Stepanova M, Pawloski L, Younossi ZM. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2012;35(1):76-82 View Article PubMed/NCBI
  56. Huh Y, Cho YJ, Nam GE. Recent epidemiology and risk factors of nonalcoholic Fatty Liver Disease. J Obes Metab Syndr 2022;31(1):17-27 View Article PubMed/NCBI
  57. Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 2020;14(6):889-919 View Article PubMed/NCBI
  58. Fouad Y, Esmat G, Elwakil R, Zakaria S, Yosry A, Waked I, et al. The egyptian clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Saudi J Gastroenterol 2022;28(1):3-20 View Article PubMed/NCBI
  59. Bacchi E, Negri C, Targher G, Faccioli N, Lanza M, Zoppini G, et al. Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). Hepatology 2013;58(4):1287-1295 View Article PubMed/NCBI
  60. Koutoukidis DA, Astbury NM, Tudor KE, Morris E, Henry JA, Noreik M, et al. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: A systematic review and meta-analysis. JAMA Intern Med 2019;179(9):1262-1271 View Article PubMed/NCBI
  61. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149(2):367-378.e5 View Article PubMed/NCBI
  62. Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol 2019;7(4):313-324 View Article PubMed/NCBI
  63. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51(1):121-129 View Article PubMed/NCBI
  64. Glass LM, Dickson RC, Anderson JC, Suriawinata AA, Putra J, Berk BS, et al. Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis. Dig Dis Sci 2015;60(4):1024-1030 View Article PubMed/NCBI
  65. Worm N. Beyond body weight-loss: Dietary strategies targeting intrahepatic fat in NAFLD. Nutrients 2020;12(5):1316 View Article PubMed/NCBI
  66. Hirshkowitz M, Whiton K, Albert SM, Alessi C, Bruni O, DonCarlos L, et al. National Sleep Foundation’s sleep time duration recommendations: methodology and results summary. Sleep Health 2015;1(1):40-43 View Article PubMed/NCBI
  67. Patel SR, Malhotra A, White DP, Gottlieb DJ, Hu FB. Association between reduced sleep and weight gain in women. Am J Epidemiol 2006;164(10):947-954 View Article PubMed/NCBI
  68. Hsieh SD, Muto T, Murase T, Tsuji H, Arase Y. Association of short sleep duration with obesity, diabetes, fatty liver and behavioral factors in Japanese men. Intern Med 2011;50(21):2499-2502 View Article PubMed/NCBI
  69. Langin D, Arner P. Importance of TNFalpha and neutral lipases in human adipose tissue lipolysis. Trends Endocrinol Metab 2006;17(8):314-320 View Article PubMed/NCBI
  70. Targher G, Bertolini L, Rodella S, Zoppini G, Zenari L, Falezza G. Associations between liver histology and cortisol secretion in subjects with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 2006;64(3):337-341 View Article PubMed/NCBI
  71. Saran AR, Dave S, Zarrinpar A. Circadian rhythms in the pathogenesis and treatment of fatty liver disease. Gastroenterology 2020;158(7):1948-1966.e1 View Article PubMed/NCBI
  72. Hafeez S, Ahmed MH. Bariatric surgery as potential treatment for nonalcoholic fatty liver disease: a future treatment by choice or by chance?. J Obes 2013;2013:839275 View Article PubMed/NCBI
  73. Głuszyńska P, Lemancewicz D, Dzięcioł JB, Razak Hady H. Non-alcoholic fatty liver disease (NAFLD) and Bariatric/metabolic surgery as its treatment option: A review. J Clin Med 2021;10(24):5721 View Article PubMed/NCBI
  74. Pafili K, Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab 2021;50:101122 View Article PubMed/NCBI
  75. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010;2010(1):CD007340 View Article PubMed/NCBI
  76. Aguilar-Olivos NE, Almeda-Valdes P, Aguilar-Salinas CA, Uribe M, Méndez-Sánchez N. The role of bariatric surgery in the management of nonalcoholic fatty liver disease and metabolic syndrome. Metabolism 2016;65(8):1196-1207 View Article PubMed/NCBI
  77. Qamar AA. Probiotics in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis. J Clin Gastroenterol 2015;49(Suppl 1):S28-S32 View Article PubMed/NCBI
  78. Yu SY, Xu L. The interplay between host cellular and gut microbial metabolism in NAFLD development and prevention. J Appl Microbiol 2021;131(2):564-582 View Article PubMed/NCBI
  79. Hrncir T, Hrncirova L, Kverka M, Hromadka R, Machova V, Trckova E, et al. Gut microbiota and NAFLD: Pathogenetic mechanisms, microbiota signatures, and therapeutic interventions. Microorganisms 2021;9(5):957 View Article PubMed/NCBI
  80. Tarantino G, Finelli C. Systematic review on intervention with prebiotics/probiotics in patients with obesity-related nonalcoholic fatty liver disease. Future Microbiol 2015;10(5):889-902 View Article PubMed/NCBI
  81. Rau M, Rehman A, Dittrich M, Groen AK, Hermanns HM, Seyfried F, et al. Fecal SCFAs and SCFA-producing bacteria in gut microbiome of human NAFLD as a putative link to systemic T-cell activation and advanced disease. United European Gastroenterol J 2018;6(10):1496-1507 View Article PubMed/NCBI
  82. Kim HN, Joo EJ, Cheong HS, Kim Y, Kim HL, Shin H, et al. Gut microbiota and risk of persistent nonalcoholic fatty liver diseases. J Clin Med 2019;8(8):1089 View Article PubMed/NCBI
  83. Chen F, Esmaili S, Rogers GB, Bugianesi E, Petta S, Marchesini G, et al. Lean NAFLD: A distinct entity shaped by differential metabolic adaptation. Hepatology 2020;71(4):1213-1227 View Article PubMed/NCBI
  84. Adams LA, Wang Z, Liddle C, Melton PE, Ariff A, Chandraratna H, et al. Bile acids associate with specific gut microbiota, low-level alcohol consumption and liver fibrosis in patients with non-alcoholic fatty liver disease. Liver Int 2020;40(6):1356-1365 View Article PubMed/NCBI
  85. Behary J, Amorim N, Jiang XT, Raposo A, Gong L, McGovern E, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun 2021;12(1):187 View Article PubMed/NCBI
  86. Demir M, Lang S, Hartmann P, Duan Y, Martin A, Miyamoto Y, et al. The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol 2022;76(4):788-799 View Article PubMed/NCBI
  87. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387(10019):679-690 View Article PubMed/NCBI
  88. Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012;17(17-18):988-997 View Article PubMed/NCBI
  89. Shah RA, Kowdley KV. Obeticholic acid for the treatment of nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2020;14(5):311-321 View Article PubMed/NCBI
  90. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016;375(7):631-643 View Article PubMed/NCBI
  91. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145(3):574-582.e1 View Article PubMed/NCBI
  92. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial. Lancet 2015;385(9972):956-965 View Article PubMed/NCBI
  93. Ratziu V, Sanyal AJ, Loomba R, Rinella M, Harrison S, Anstee QM, et al. REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis. Contemp Clin Trials 2019;84:105803 View Article PubMed/NCBI
  94. Fougerat A, Montagner A, Loiseau N, Guillou H, Wahli W. Peroxisome proliferator-activated receptors and their novel ligands as candidates for the treatment of non-alcoholic fatty liver disease. Cells 2020;9(7):1638 View Article PubMed/NCBI
  95. Alam F, Islam MA, Mohamed M, Ahmad I, Kamal MA, Donnelly R, et al. Efficacy and safety of pioglitazone monotherapy in type 2 diabetes mellitus: A systematic review and meta-analysis of randomised controlled trials. Sci Rep 2019;9(1):5389 View Article PubMed/NCBI
  96. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: A meta-analysis. JAMA Intern Med 2017;177(5):633-640 View Article PubMed/NCBI
  97. Fuchs CD, Traussnigg SA, Trauner M. Nuclear Receptor Modulation for the treatment of nonalcoholic fatty liver disease. Semin Liver Dis 2016;36(1):69-86 View Article PubMed/NCBI
  98. Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol 2018;16(4):558-566.e2 View Article PubMed/NCBI
  99. Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology 2018;155(5):1463-1473.e6 View Article PubMed/NCBI
  100. Schwabe RF, Luedde T. Apoptosis and necroptosis in the liver: a matter of life and death. Nat Rev Gastroenterol Hepatol 2018;15(12):738-752 View Article PubMed/NCBI
  101. Tacke F. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis. Expert Opin Investig Drugs 2018;27(3):301-311 View Article PubMed/NCBI
  102. Anstee QM, Neuschwander-Tetri BA, Wong VW, Abdelmalek MF, Younossi ZM, Yuan J, et al. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design. Contemp Clin Trials 2020;89:105922 View Article PubMed/NCBI
  103. Lefere S, Tacke F. Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism. JHEP Rep 2019;1(1):30-43 View Article PubMed/NCBI
  104. Krenkel O, Tacke F. Macrophages in nonalcoholic fatty liver disease: A role model of pathogenic immunometabolism. Semin Liver Dis 2017;37(3):189-197 View Article PubMed/NCBI
  105. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115(5):1343-1351 View Article PubMed/NCBI
  106. You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 2005;42(3):568-577 View Article PubMed/NCBI
  107. Otabe S, Yuan X, Fukutani T, Wada N, Hashinaga T, Nakayama H, et al. Overexpression of human adiponectin in transgenic mice results in suppression of fat accumulation and prevention of premature death by high-calorie diet. Am J Physiol Endocrinol Metab 2007;293(1):E210-218 View Article PubMed/NCBI
  108. Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann Intern Med 2010;152(2):93-100 View Article PubMed/NCBI
  109. Li Y, Hai J, Li L, Chen X, Peng H, Cao M, et al. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. Endocrine 2013;43(2):376-386 View Article PubMed/NCBI
  110. Bayram HM, Majoo FM, Ozturkcan A. Polyphenols in the prevention and treatment of non-alcoholic fatty liver disease: An update of preclinical and clinical studies. Clin Nutr ESPEN 2021;44:1-14 View Article PubMed/NCBI
  111. Weiskirchen R. Hepatoprotective and anti-fibrotic agents: It’s time to take the next step. Front Pharmacol 2015;6:303 View Article PubMed/NCBI
  112. Ullah R, Rauf N, Nabi G, Ullah H, Shen Y, Zhou YD, et al. Role of nutrition in the pathogenesis and prevention of non-alcoholic fatty liver disease: recent updates. Int J Biol Sci 2019;15(2):265-276 View Article PubMed/NCBI
  113. Traber MG, Burton GW, Ingold KU, Kayden HJ. RRR- and SRR-alpha-tocopherols are secreted without discrimination in human chylomicrons, but RRR-alpha-tocopherol is preferentially secreted in very low density lipoproteins. J Lipid Res 1990;31(4):675-685 PubMed/NCBI
  114. Zhong S, Fan Y, Yan Q, Fan X, Wu B, Han Y, et al. The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease: A meta-analysis (PRISMA) of randomized control trials. Medicine (Baltimore) 2017;96(49):e9061 View Article PubMed/NCBI
  115. He XX, Wu XL, Chen RP, Chen C, Liu XG, Wu BJ, et al. Effectiveness of Omega-3 polyunsaturated fatty acids in non-alcoholic fatty liver disease: A meta-analysis of randomized controlled trials. PLoS One 2016;11(10):e0162368 View Article PubMed/NCBI
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Recent Updates in the Prevention of Nonalcoholic Fatty Liver Disease

Mohamed El-Kassas, Abeer Awad, Nahum Méndez-Sánchez
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