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Mechanisms of NAFLD development and therapeutic strategies
Open accessAbstract
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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“The accumulation of TG in hepatocytes, stemming from disrupted lipid homeostasis, forms the basis of MASLD patholog.6,7”
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“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]
In the citing paper
“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]
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“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]
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“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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“where lipid overload as a result of increased fatty acid influx due to insulin resistance in the adipose tissue leads to metabolically stressed hepatocytes with activation of cell death and proinflammatory signalling pathways.6”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [6]
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“Weight loss exceeding 10% has demonstrated superior efficacy in resolving MASLD and MASH, exhibiting regression of fibrosis and inflammation (6, 7).”
From Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility (2024) · cites this paper as [7]
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Metadata
- 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.
- Venue
- Nature Medicine
- Published
- 2018-07
- Volume
- 24
- Issue
- 7
- Pages
- 908-922
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- 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
- 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 › Hepatology › 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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