Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans

Pafili, Kalliopi; Roden, Michael

doi:10.1016/j.molmet.2020.101122

Cited by 330Liver Disease Diagnosis and TreatmentDiet, Metabolism, and DiseaseAlcohol Consumption and Health Effects

Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans

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Pafili, Kalliopi, Roden, Michael·2021·Molecular Metabolism

DOI 10.1016/j.molmet.2020.101122PMC PMC8324683

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Abstract

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or with inflammation (nonalcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes of liver disease. NAFLD is developing as a burgeoning health challenge, mainly due to the worldwide obesity and diabetes epidemics. SCOPE OF REVIEW: This review summarizes the knowledge on the pathogenesis underlying NAFLD by focusing on studies in humans and on hypercaloric nutrition, including effects of saturated fat and fructose, as well as adipose tissue dysfunction, leading to hepatic lipotoxicity, abnormal mitochondrial function, and oxidative stress, and highlights intestinal dysbiosis. These mechanisms are discussed in the context of current treatments targeting metabolic pathways and the results of related clinical trials. MAJOR CONCLUSIONS: Recent studies have provided evidence that certain conditions, for example, the severe insulin-resistant diabetes (SIRD) subgroup (cluster) and the presence of an increasing number of gene variants, seem to predispose for excessive risk of NAFLD and its accelerated progression. Recent clinical trials have been frequently unsuccessful in halting or preventing NAFLD progression, perhaps partly due to including unselected cohorts in later stages of NAFLD. On the basis of this literature review, this study proposed screening in individuals with the highest genetic or acquired risk of disease progression, for example, the SIRD subgroup, and developing treatment concepts targeting the earliest pathophysiolgical alterations, namely, adipocyte dysfunction and insulin resistance.

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Adipose tissue insulin resistance develops, paralleled by altered adipokine secretion and impaired mitochondrial function, further promoting adipose tissue inflammation.
“As a consequence, adipose tissue insulin resistance develops, paralleled by altered adipokine (i.e., adiponectin, leptin) secretion and impaired mitochondrial function, further promoting adipose tissue inflammation [19,20].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [19]
The Adipose tissue dysfunction section (page unavailable) links obesity-related insulin resistance with adipose macrophage infiltration and inflammatory cytokines, and reports altered adiponectin and leptin levels in NAFLD. It also says adipose insulin resistance can occur without concurrent inflammation. The mitochondrial findings in the cited passages concern the liver, not adipose tissue, and the paper does not establish the claimed sequence in which impaired adipose mitochondrial function further promotes inflammation. (LLM, conf=0.85)
Experimental — accuracy not yet measured
NEFA promote hepatic triglyceride storage and gluconeogenesis when the capacity of the liver to oxidize these substrates or export them as VLDL is depleted.
“Here, NEFA promote hepatic triglyceride storage and gluconeogenesis [26], when the capacity of the liver to oxidize these substrates or export them as very-low-density lipoproteins (VLDL) is depleted [19].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [19]

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Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease
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A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial
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Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance
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Glucokinase Regulatory Protein Gene Polymorphism Affects Liver Fibrosis in Non-Alcoholic Fatty Liver Disease
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Are Lifestyle Therapies Effective for NAFLD Treatment?
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Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans
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The Adaptive Endoplasmic Reticulum Stress Response to Lipotoxicity in Progressive Human Nonalcoholic Fatty Liver Disease
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New insight into inter-organ crosstalk contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD)
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Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors
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MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease
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Effect of Vildagliptin on Hepatic Steatosis
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Loss of hepatic Mboat7 leads to liver fibrosis
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Three weeks on a high-fat diet increases intrahepatic lipid accumulation and decreases metabolic flexibility in healthy overweight men
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Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial
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Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: A pre-specified secondary study on ectopic fat accumulation
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Anti-NASH Drug Development Hitches a Lift on PPAR Agonism
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Lobeglitazone, a Novel Thiazolidinedione, Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness
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Glucagon-like peptide-1 receptor: mechanisms and advances in therapy
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Mitochondrial alterations in fatty liver diseases
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Inter-organ crosstalk during development and progression of type 2 diabetes mellitus
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Insulin resistance and insulin sensitizing agents
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Health Promoting Properties of Bee Royal Jelly: Food of the Queens
Collazo, N., Carpena, M., Núñez-Estévez, B., Otero, P., Simal‐Gándara, J., & Prieto, M. A. (2021) · Nutrients · doi:10.3390/nu13020543 · Cited by 174 · see citing works
MicroRNAs in non-alcoholic fatty liver disease: Progress and perspectives
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Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease?
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The detrimental effects of micro-and nano-plastics on digestive system: An overview of oxidative stress-related adverse outcome pathway
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Combined ASBT Inhibitor and FGF15 Treatment Improves Therapeutic Efficacy in Experimental Nonalcoholic Steatohepatitis
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Uncoupling hepatic insulin resistance – hepatic inflammation to improve insulin sensitivity and to prevent impaired metabolism-associated fatty liver disease in type 2 diabetes
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Nanomedicines Targeting Metabolic Pathways in the Tumor Microenvironment: Future Perspectives and the Role of AI
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Exploring the Changes of Peroxisomal Polarity in the Liver of Mice with Nonalcoholic Fatty Liver Disease
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Recent progress in small molecule fluorescent probes for imaging and diagnosis of non-alcoholic fatty liver disease
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Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2
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Non-Pharmacological Approach to Diet and Exercise in Metabolic-Associated Fatty Liver Disease: Bridging the Gap between Research and Clinical Practice
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Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice
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4‐Octyl Itaconate Prevents Free Fatty Acid‐Induced Lipid Metabolism Disorder through Activating Nrf2‐AMPK Signaling Pathway in Hepatocytes
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Exposure to volatile organic compounds and polycyclic aromatic hydrocarbons is associated with the risk of non-alcoholic fatty liver disease in Korean adolescents: Korea National Environmental Health Survey (KoNEHS) 2015–2017
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Mechanisms and therapeutic implications of selective autophagy in nonalcoholic fatty liver disease
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Serum Afamin a Novel Marker of Increased Hepatic Lipid Content
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Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis
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Non-alcoholic fatty liver disease through the female lifespan: the role of sex hormones
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Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor)
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Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine
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Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review
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Elucidating cuproptosis in metabolic dysfunction-associated steatotic liver disease
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Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review
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The quality and reliability of TikTok videos on non-alcoholic fatty liver disease: a propensity score matching analysis
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Hydrogen Sulfide and Liver Health: Insights into Liver Diseases
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Role of lifestyle and glucagon‐like peptide‐1 receptor agonists for weight loss in obesity, type 2 diabetes and steatotic liver diseases
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Nonalcoholic Fatty Liver Disease and Staging of Hepatic Fibrosis
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ER–mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin
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5-Methoxyflavone ameliorates non-alcoholic fatty liver disease through targeting the cytochrome P450 1A1
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Functional benefits of mulberry leaf tea or extracts to alleviate metabolic diseases: Current opinion and perspectives
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PIM1 alleviated liver oxidative stress and NAFLD by regulating the NRF2/HO-1/NQO1 pathway
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SPP1 and CXCL9 Promote Non-alcoholic Steatohepatitis Progression Based on Bioinformatics Analysis and Experimental Studies
Wang, W. J., Liu, X., Wei, P., Ye, F., Chen, Y., Shi, L., Zhang, X., Li, ., Lin, S., & Yang, X. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.862278 · Cited by 24 · see citing works
Dietary patterns in the progression of metabolic dysfunction-associated fatty liver disease to advanced liver disease: a prospective cohort study
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Inducible nitric oxide synthase accelerates nonalcoholic fatty liver disease progression by regulating macrophage autophagy
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The Role of Epigenetic Control of Mitochondrial (Dys)Function in MASLD Onset and Progression
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Immune response gene 1 deficiency aggravates high fat diet-induced nonalcoholic fatty liver disease via promotion of redox-sensitive AKT suppression
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The combination of metformin with morin alleviates hepatic steatosis via modulating hepatic lipid metabolism, hepatic inflammation, brown adipose tissue thermogenesis, and white adipose tissue browning in high-fat diet-fed mice
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Limosilactobacillus fermentum MG4294 and Lactiplantibacillus plantarum MG5289 Ameliorates Nonalcoholic Fatty Liver Disease in High-Fat Diet-Induced Mice
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Dairy product consumption and risk of non-alcoholic fatty liver disease: A systematic review and meta-analysis of observational studies
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The emerging significance of mitochondrial targeted strategies in NAFLD treatment
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Adherence to an antioxidant diet and lifestyle is associated with reduced risk of cardiovascular disease and mortality among adults with nonalcoholic fatty liver disease: evidence from NHANES 1999–2018
Li, Y., & Liu, Y. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1361567 · Cited by 21 · see citing works
Decreasing the burden of non-alcoholic fatty liver disease: From therapeutic targets to drug discovery opportunities
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Melatonin Prevents Alcohol- and Metabolic Dysfunction- Associated Steatotic Liver Disease by Mitigating Gut Dysbiosis, Intestinal Barrier Dysfunction, and Endotoxemia
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Similar weight loss with semaglutide regardless of diabetes and cardiometabolic risk parameters in individuals with metabolic dysfunction‐associated steatotic liver disease: Post hoc analysis of three randomised controlled trials
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Ginsenoside Re Improves Inflammation and Fibrosis in Hepatic Tissue by Upregulating PPARγ Expression and Inhibiting Oxidative Stress in db/db Mice
Jiang, Y., Sui, D., Li, M., Xu, H., Yu, X., Liu, J., & Yu, Q. (2021) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2021/9003603 · Cited by 19 · see citing works
Extraction, purification, structural characterization, and hepatoprotective effect of the polysaccharide from purple sweet potato
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Non-alcoholic fatty liver disease: Dietary and nutraceutical approaches
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Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice
Zhao, W.-W., Xiao, M., Wu, X., Li, X., Li, X.-X., Zhao, T., Yu, L., & Chen, X.-Q. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.771976 · Cited by 18 · see citing works
Excess cardiovascular mortality in men with non-alcoholic fatty liver disease: A cause for concern!
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Helminth infection and helminth-derived products: A novel therapeutic option for non-alcoholic fatty liver disease
Liu, X., Jiang, Y., Ye, J., & Wang, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.999412 · Cited by 17 · see citing works
Preventive and therapeutic effects of natural products and herbal extracts on nonalcoholic fatty liver disease / nonalcoholic steatohepatitis
Cao, Y., Fang, X., Sun, M., Zhang, Y., Shan, M., Lan, X., Zhu, D., & Luo, H. (2023) · Phytotherapy Research · doi:10.1002/ptr.7932 · Cited by 17 · see citing works
Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?
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Lipid Hormones at the Intersection of Metabolic Imbalances and Endocrine Disorders
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Diabetes mellitus as a multisystem disease: understanding subtypes, complications, and the link with steatotic liver diseases in humans
Giannakogeorgou, A., Roden, M., & Pafili, K. (2025) · HORMONES · doi:10.1007/s42000-025-00701-y · Cited by 17 · see citing works
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Fenretinide Inhibits Obesity and Fatty Liver Disease But Induces Smpd3 to Increase Serum Ceramides and Worsen Atherosclerosis in LDLR-/- Mice
Thompson, D., Mahmood, S., Morrice, N., Kamli-Salino, S., Dekeryte, R., Hoffmann, P. A., Doherty, M. K., Whitfield, P. D., Delibegović, M., & Mody, N. (2022) · Scientific Reports · doi:10.1038/s41598-023-30759-w · Cited by 16 · see citing works
PRDX1 Cys52Ser variant alleviates nonalcoholic steatohepatitis by reducing inflammation in mice
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Exploring Fibrosis Pathophysiology in Lean and Obese Metabolic-Associated Fatty Liver Disease: An In-Depth Comparison
Vesković, M. N., Pejović, M., Šutulović, N., Hrnčić, D., Rašić-Marković, A., Stanojlović, O. P., & Mladenović, D. R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137405 · Cited by 17 · see citing works
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Self-citation

Authors: Pafili, K., & Roden, M.
Affiliations: Deutsches Diabetes-Zentrum e.V. (DE)
Corresponding author: Roden, Michael
ORCID: Pafili, Kalliopi
Roden, Michael
Venue: Molecular Metabolism
Publisher: Elsevier BV
Published: 2021-08
Volume: 50
Pages: 101122
ISSN: 2212-8778 (ISSN-L)
DOI: 10.1016/j.molmet.2020.101122
PMC: PMC8324683
OpenAlex: W3104053913
Cited by: 330
References: 244
Citations by year: 2026: 47 · 2025: 63 · 2024: 85 · 2023: 73 · 2022: 40 · 2021: 19 · 2020: 2 · 2012: 1
FWCI: 4.89
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Molecular Metabolism (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia
Deutsche Forschungsgemeinschaft (CRC 1116/2)
Bundesministerium für Bildung und Forschung
Bundesministerium für Gesundheit
Topics: Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords: non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatic steatosis, liver fibrosis, saturated fat, fructose, adipose tissue dysfunction, hepatic lipotoxicity, mitochondrial dysfunction, oxidative stress, gut dysbiosis, severe insulin-resistant diabetes, genetic risk variants, NAFLD progression, NAFLD screening, insulin resistance, NAFLD treatment
MeSH terms: Diabetes Mellitus, Type 2, Fatty Acids, Humans, Insulin Resistance, Liver, Mitochondria, Obesity, Genetic Variation, Adipocytes, Oxidative Stress, Disease Progression, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Lipid Metabolism, Non-alcoholic Fatty Liver Disease

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Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans

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