Mechanisms of NAFLD development and therapeutic strategies

Friedman, Scott L.; Neuschwander-Tetri, Brent A.; Rinella, Mary; Sanyal, Arun J.

doi:10.1038/s41591-018-0104-9

Cited by 4,354Liver Disease Diagnosis and TreatmentLiver physiology and pathologyAlcohol Consumption and Health Effects

Mechanisms of NAFLD development and therapeutic strategies

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Friedman, Scott L., Neuschwander-Tetri, Brent A., Rinella, Mary, Sanyal, Arun J.·2018·Nature Medicine

DOI 10.1038/s41591-018-0104-9PMC PMC6553468

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Abstract

There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

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Crossref · 10.1038/s41591-018-0104-9

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Accumulation of triglycerides in hepatocytes due to disrupted lipid homeostasis forms the basis of MASLD pathology.
“The accumulation of TG in hepatocytes, stemming from disrupted lipid homeostasis, forms the basis of MASLD patholog.6,7”
From The Impact of Omega-3 Fatty Acids on Triglyceride Levels in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-Analysis of Randomized Controlled Trials with Subgroup Analysis by Diabetes Status (2026) · cites this paper as [7]
Gut microbiome plays critical roles in pathophysiological scenarios in the gut and can influence other organs such as the liver and the immune system.
“Gut microbiome 33 plays critical roles in the pathophysiological scenarios in the gut; they can influence other organs such as the liver 34,35 and the immune system 37 .”
From Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction (2022) · cites this paper as [35]
MASH is a severe form of MASLD associated with inflammation and fibrosis and can progress to advanced fibrosis, cirrhosis, and liver cancer.
“metabolic dysfunction-associated steatohepatitis (MASH or previously non-alcoholic steatohepatitis/NASH), which is associated with inflammation and fibrosis (1-4).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [3]
No drugs are approved for MASH, making it a major unmet medical need.
“Despite the scale and urgency of the disease, there are currently no approved drugs for MASH, making it a major unmet need (3, 12).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [3]
Up to 75% of type II diabetes patients also develop MASLD.
“The prevalence of co-morbid diabetes and MASH is high, with up to 75% of type II diabetes patients also developing MASLD (3).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [3]

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The role of ER stress in lipid metabolism and lipotoxicity
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The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial
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ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development
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An improved mouse model that rapidly develops fibrosis in non‐alcoholic steatohepatitis
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Adipokines in liver diseases #
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Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease
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Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition
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NASH: a mitochondrial disease
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NGM282 for treatment of non-alcoholic steatohepatitis: A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
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Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation
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Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis
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Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro
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Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: A 20 year‐community study
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Long-Term Efficacy of Rosiglitazone in Nonalcoholic Steatohepatitis: Results of the Fatty Liver Improvement by Rosiglitazone Therapy (Flirt 2) Extension Trial
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A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma
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Three Pillars for the Neural Control of Appetite
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Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population‐based study
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The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation
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The pan‐caspase inhibitor Emricasan ( IDN ‐6556) decreases liver injury and fibrosis in a murine model of non‐alcoholic steatohepatitis
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Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance
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Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment
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Pharmacotherapy for NASH: Current and emerging
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Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease
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Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice
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Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis
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Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats
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The Fatty Acid–Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease
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Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity
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The Natural History of Nonalcoholic Fatty Liver Disease—An Evolving View
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Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis
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Fibroblast Growth Factor 21—Metabolic Role in Mice and Men
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The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells
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Metabolomic identification of subtypes of nonalcoholic steatohepatitis
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Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes
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Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications
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Development of Novel Combination Therapies
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Non-alcoholic fatty liver and the gut microbiota
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The Role of Cytokines in Non-Alcoholic Fatty Liver Disease
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Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease
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Nutritional model of steatohepatitis and metabolic syndrome in the Ossabaw miniature swine #
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Farnesoid X Receptor Deficiency Induces Nonalcoholic Steatohepatitis in Low-Density Lipoprotein Receptor-Knockout Mice Fed a High-Fat Diet
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Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD
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Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition
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Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes
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Incomplete absorption of pure fructose in healthy subjects and the facilitating effect of glucose.
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NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
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Intestinal Microbiota and Nonalcoholic Steatohepatitis
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Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science
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Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis
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Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-β agonist
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Clinical relevance of the bile acid receptor TGR5 in metabolism
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Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis
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Ability of the Normal Human Small Intestine to Absorb Fructose: Evaluation by Breath Testing
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Role of Fat Body Lipogenesis in Protection against the Effects of Caloric Overload in Drosophila
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Fibroblast Growth Factor Signaling in Metabolic Regulation
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BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis
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Changes in the Intestinal Microbiome and Alcoholic and Nonalcoholic Liver Diseases: Causes or Effects?
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Long term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease
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The roles of c‐Jun NH2‐terminal kinases (JNKs) in obesity and insulin resistance
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Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice
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Cardiovascular Disease and Myocardial Abnormalities in Nonalcoholic Fatty Liver Disease
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Obstructive Sleep Apnea Is Associated with Fatty Liver and Abnormal Liver Enzymes: a Meta-analysis
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Interactions between bile salts, gut microbiota, and hepatic innate immunity
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Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer
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Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis
Mauer, A. S., Hirsova, P., Maiers, J. L., Shah, V. H., & Malhi, H. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00222.2016 · Cited by 96 · see citing works
Predicting Fibrosis Worsening in Obese Patients With NASH Through Parenchymal Fibronectin, HOMA-IR, and Hypertension
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Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin
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Renin-Angiotensin System Inhibitors, Type 2 Diabetes and Fibrosis Progression: An Observational Study in Patients with Nonalcoholic Fatty Liver Disease
Pelusi, S., Petta, S., Rosso, C., Borroni, V. N., Fracanzani, A. L., Dongiovanni, P., Craxı̀, A., Bugianesi, E., Fargion, S. R., & Valenti, L. V. C. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163069 · Cited by 82 · see citing works
Transgenic mice expressing nuclear sterol regulatory element–binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis
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Association between MRI-derived hepatic fat fraction and blood pressure in participants without history of cardiovascular disease
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A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition
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Using Big Data to Discover Diagnostics and Therapeutics for Gastrointestinal and Liver Diseases
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Non-alcoholic fatty liver disease with and without metabolic syndrome: Different long-term outcomes
Käräjämäki, A. J., Bloigu, R., Kauma, H., Kesäniemi, Y. A., Koivurova, O., Perkiömäki, J. S., Huikuri, H. V., & Ukkola, O. H. (2016) · Metabolism · doi:10.1016/j.metabol.2016.06.009 · Cited by 68 · see citing works
Genetic modifiers of non-alcoholic fatty liver disease progression
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Nonalcoholic fatty liver disease and increased risk of 1-year all-cause and cardiac hospital readmissions in elderly patients admitted for acute heart failure
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Liraglutide, a Glucagon-Like Peptide-1 Analog, Increased Insulin Sensitivity Assessed by Hyperinsulinemic-Euglycemic Clamp Examination in Patients with Uncontrolled Type 2 Diabetes Mellitus
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A Lipidomic Readout of Disease Progression in A Diet-Induced Mouse Model of Nonalcoholic Fatty Liver Disease.
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Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration
Alvarado, T. F., Puliga, E., Preziosi, M., Poddar, M., Singh, S., Columbano, A., Nejak‐Bowen, K. N., & Monga, S. P. (2016) · Gene Expression · doi:10.3727/105221616x691631 · Cited by 47 · see citing works
Liver-directed microRNA-7a depletion induces nonalcoholic fatty liver disease by stabilizing YY1-mediated lipogenic pathways in zebrafish
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ERRγ Preserves Brown Fat Innate Thermogenic Activity
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Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis
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Mutant PNPLA3 I148M protein as pharmacological target for liver disease
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The Intestinal Microbiome in Nonalcoholic Fatty Liver Disease
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Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats
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Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis
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Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain
Horwath, J. A., Hurr, C., Butler, S. D., Guruju, M. R., Cassell, M. D., Mark, A. L., Davisson, R. L., & Young, C. N. (2017) · JCI Insight · doi:10.1172/jci.insight.90170 · Cited by 27 · see citing works
Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: Recommendations From the Liver Forum
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Drug development: Sprint finish
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Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing
Pouladi, N., Bime, C., Garcia, J. G. N., & Lussier, Y. A. (2015) · Translational research · doi:10.1016/j.trsl.2015.04.016 · Cited by 16 · see citing works

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MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease
Eslam, M., Sanyal, A. J., George, J., Sanyal, A., Neuschwander-Tetri, B., Tiribelli, C., Kleiner, D. E., Brunt, E., Bugianesi, E., Yki-Järvinen, H., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.312 · Cited by 3,286 · see citing works
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Non-alcoholic fatty liver disease
Powell, E. E., Wong, V. W.-S., & Rinella, M. (2021) · The Lancet · doi:10.1016/s0140-6736(20)32511-3 · Cited by 2,789 · see citing works
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AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease
Rinella, M. E., Neuschwander-Tetri, B. A., Siddiqui, M. S., Abdelmalek, M. F., Caldwell, S., Barb, D., Kleiner, D. E., & Loomba, R. (2023) · Hepatology · doi:10.1097/hep.0000000000000323 · Cited by 2,667 · see citing works
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Molecular and cellular mechanisms of liver fibrosis and its regression
Kisseleva, T., & Brenner, D. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00372-7 · Cited by 2,024 · see citing works
Resolving the fibrotic niche of human liver cirrhosis at single-cell level
Ramachandran, P., Dobie, R., Wilson-Kanamori, J. R., Dora, E. F., Henderson, B. E. P., Luu, N. T., Portman, J. R., Matchett, K. P., Brice, M., Marwick, J. A., et al. (2019) · Nature · doi:10.1038/s41586-019-1631-3 · Cited by 1,784 · see citing works
NASH limits anti-tumour surveillance in immunotherapy-treated HCC
Pfister, D., Núñez, N. G., Pinyol, R., Govaere, O., Pinter, M., Szydlowska, M., Gupta, R., Qiu, M., Deczkowska, A., Weiner, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03362-0 · Cited by 1,294 · see citing works
Gut microbiota and intestinal FXR mediate the clinical benefits of metformin
Sun, L., Xie, C., Wang, G., Wu, Y., Wu, Q., Wang, X., Liu, J., Deng, Y., Xia, J., Chen, B., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0222-4 · Cited by 1,011 · see citing works
Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis
Sanyal, A. J., Newsome, P. N., Kliers, I., Østergaard, L. H., Long, M. T., Kjær, M. S., Cali, A. M. G., Bugianesi, E., Rinella, M. E., Roden, M., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2413258 · Cited by 1,115 · see citing works
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Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
Schwabe, R. F., Tabas, I., & Pajvani, U. B. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.311 · Cited by 671 · see citing works
The intricate relationship between type 2 diabetes mellitus (T2DM), insulin resistance (IR), and nonalcoholic fatty liver disease (NAFLD)
Tanase, D. M., Gosav, E. M., Costea, C. F., Ciocoiu, M., Lacatusu, C. M., Maranduca, M. A., Ouatu, A., & Floria, M. (2020) · Journal of Diabetes Research · doi:10.1155/2020/3920196 · Cited by 627 · see citing works
Immune cell-mediated features of non-alcoholic steatohepatitis
Huby, T., & Gautier, E. L. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00639-3 · Cited by 573 · see citing works
Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH
Dudek, M., Pfister, D., Donakonda, S., Filpe, P., Schneider, A., Laschinger, M., Hartmann, D., Hüser, N., Meiser, P., Bayerl, F., et al. (2021) · Nature · doi:10.1038/s41586-021-03233-8 · Cited by 512 · see citing works
Targeting mitochondria-located circrna scar alleviates nash via reducing mros output
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Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis
Dobie, R., Wilson-Kanamori, J. R., Henderson, B. E. P., Smith, J. R., Matchett, K. P., Portman, J. R., Wallenborg, K., Picelli, S., Zagorska, A., Pendem, S. V., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.024 · Cited by 420 · see citing works
Hepatic fibrosis 2022: Unmet needs and a blueprint for the future
Friedman, S. L., & Pinzani, M. (2022) · Hepatology · doi:10.1002/hep.32285 · Cited by 430 · see citing works
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Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis
Wang, H., Zhang, H., Wang, Y., Brown, Z. J., Xia, Y., Huang, Z., Shen, C., Hu, Z., Beane, J., Ansa-Addo, E. A., et al. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.07.032 · Cited by 398 · see citing works
Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer
Malehmir, M., Pfister, D., Gallage, S., Szydlowska, M., Inverso, D., Kotsiliti, E., Leone, V., Peiseler, M., Surewaard, B. G. J., Rath, D., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0379-5 · Cited by 398 · see citing works
Adaptive immunity: an emerging player in the progression of NAFLD
Sutti, S., & Albano, E. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0210-2 · Cited by 374 · see citing works
Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment
Llovet, J. M., Willoughby, C. E., Singal, A. G., Greten, T. F., Heikenwälder, M., El-Serag, H. B., Finn, R. S., & Friedman, S. L. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00754-7 · Cited by 354 · see citing works
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Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease
Hammoutene, A., & Rautou, P.-E. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.02.012 · Cited by 364 · see citing works
Advanced Liver Fibrosis Is Common in Patients With Type 2 Diabetes Followed in the Outpatient Setting: The Need for Systematic Screening
Lomonaco, R., Godinez Leiva, E., Bril, F., Shrestha, S., Mansour, L., Budd, J., Portillo Romero, J., Schmidt, S., Chang, K.-L., Samraj, G., et al. (2021) · Diabetes Care · doi:10.2337/dc20-1997 · Cited by 354 · see citing works
Gut Akkermansia muciniphila ameliorates metabolic dysfunction-associated fatty liver disease by regulating the metabolism of L-aspartate via gut-liver axis
Rao, Y., Kuang, Z., Li, C., Guo, S., Xu, Y., Zhao, D., Hu, Y., Song, B., Jiang, Z., Ge, Z., et al. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1927633 · Cited by 356 · see citing works
Western diet as a trigger of Alzheimer’s disease: From metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration
Więckowska-Gacek, A., Mietelska-Porowska, A., Wydrych, M., & Wojda, U. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101397 · Cited by 343 · see citing works
A Gut Microbiome Signature for Cirrhosis Due to Nonalcoholic Fatty Liver Disease
Caussy, C., Tripathi, A., Humphrey, G., Bassirian, S., Singh, S., Faulkner, C., Bettencourt, R., Rizo, E., Richards, L., Xu, Z. Z., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09455-9 · Cited by 338 · see citing works
Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts
Alexander, M., Loomis, A. K., van der Lei, J., Duarte-Salles, T., Prieto-Alhambra, D., Ansell, D., Pasqua, A., Lapi, F., Rijnbeek, P., Mosseveld, M., et al. (2019) · BMC Medicine · doi:10.1186/s12916-019-1321-x · Cited by 317 · see citing works
Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors
Francque, S., Szabo, G., Abdelmalek, M. F., Byrne, C. D., Cusi, K., Dufour, J.-F., Roden, M., Sacks, F., & Tacke, F. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00366-5 · Cited by 316 · see citing works
Natural history and progression of metabolic dysfunction-associated steatotic liver disease
Hagström, H., Shang, Y., Hegmar, H., & Nasr, P. (2024) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(24)00193-6 · Cited by 310 · see citing works
Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease.
Baggio, L. L., & Drucker, D. J. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101090 · Cited by 299 · see citing works
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
Sanyal, A. J., Kaplan, L. M., Frias, J. P., Brouwers, B., Wu, Q., Thomas, M. K., Harris, C., Schloot, N. C., Du, Y., Mather, K. J., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03018-2 · Cited by 315 · see citing works
Self-citation
Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis
Gu, J., Liu, S., Du, S., Zhang, Q., Xiao, J., Dong, Q., & Xin, Y. (2019) · European Radiology · doi:10.1007/s00330-019-06072-4 · Cited by 276 · see citing works
Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial
Harrison, S. A., Frias, J. P., Neff, G., Abrams, G. A., Lucas, K. J., Sanchez, W., Gogia, S., Sheikh, M. Y., Behling, C., Bedossa, P., et al. (2023) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(23)00272-8 · Cited by 276 · see citing works
Resolution of NASH and hepatic fibrosis by the GLP-1R and GCGR dual-agonist cotadutide via modulating mitochondrial function and lipogenesis
Boland, M. L., Laker, R. C., Mather, K., Nawrocki, A., Oldham, S., Boland, B. B., Lewis, H., Conway, J., Naylor, J., Guionaud, S., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0209-6 · Cited by 270 · see citing works
Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development
Wang, X., He, Q., Zhou, C., Xu, Y., Liu, D., Fujiwara, N., Kubota, N., Click, A., Henderson, P., Vancil, J., et al. (2023) · Immunity · doi:10.1016/j.immuni.2022.11.013 · Cited by 262 · see citing works
Lytic cell death in metabolic liver disease
Gautheron, J., Gores, G. J., & Rodrigues, C. M. P. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.04.001 · Cited by 225 · see citing works
“Although metabolic alterations caused by free fatty acid overload is considered a major cause for hepatocyte damage, the mechanisms driving disease progression from simple steatosis to NASH remain incompletely understood [72].”
Background
Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet—a randomised controlled trial
Holmer, M., Lindqvist, C., Petersson, S., Moshtaghi-Svensson, J., Tillander, V., Brismar, T. B., Hagström, H., & Stål, P. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100256 · Cited by 224 · see citing works
Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis
Gao, H., Jin, Z., Bandyopadhyay, G., Wang, G., Zhang, D., Rocha, K. C. E., Liu, X., Zhao, H., Kisseleva, T., Brenner, D. A., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.07.006 · Cited by 224 · see citing works
CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells
Koda, Y., Teratani, T., Chu, P.-S., Hagihara, Y., Mikami, Y., Harada, Y., Tsujikawa, H., Miyamoto, K., Suzuki, T., Taniki, N., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24734-0 · Cited by 219 · see citing works
Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis
Krenkel, O., Hundertmark, J., Abdallah, A. T., Kohlhepp, M., Puengel, T., Roth, T., Branco, D. P. P., Mossanen, J. C., Luedde, T., Trautwein, C., et al. (2020) · Gut · doi:10.1136/gutjnl-2019-318382 · Cited by 220 · see citing works
Intestinal absorption of bile acids in health and disease
Ticho, A. L., Malhotra, P., Dudeja, P. K., Gill, R. K., & Alrefai, W. A. (2019) · Comprehensive physiology · doi:10.1002/cphy.c190007 · Cited by 215 · see citing works
CD36 promotes de novo lipogenesis in hepatocytes through INSIG2-dependent SREBP1 processing
Zeng, H., Qin, H., Liao, M., Zheng, E., Luo, X., Xiao, A., Li, Y., Chen, L., Wei, L., Zhao, L., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101428 · Cited by 211 · see citing works
XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis
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Authors: Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M., & Sanyal, A. J.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Northwestern University (US)
Virginia Commonwealth University (US)
Corresponding author: Friedman, Scott L.
ORCID: Friedman, Scott L.
Rinella, Mary
Sanyal, Arun J.
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2018-07
Volume: 24
Issue: 7
Pages: 908-922
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-018-0104-9
PMC: PMC6553468
OpenAlex: W2810423511
Cited by: 4,354
References: 181
Citations by year: 2026: 546 · 2025: 650 · 2024: 727 · 2023: 714 · 2022: 633 · 2021: 534 · 2020: 335 · 2019: 180 · 2018: 26 · 2015: 1 · 2014: 1
FWCI: 38.74
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Alcohol Abuse and Alcoholism (R01AA020709, P20AA017067)
National Institute of Diabetes and Digestive and Kidney Diseases (R56DK056621, R01DK056621)
Topics: Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords: non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, pathogenesis, metabolic syndrome, diabetes mellitus, liver cirrhosis, liver cancer, in vitro model, drug discovery targets, combination therapy, clinical trial design, disease progression
MeSH terms: Animals, Clinical Trials as Topic, Disease Models, Animal, Humans, Risk Factors, Disease Progression, Non-alcoholic Fatty Liver Disease

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