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Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases
Open accessAbstract
NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.
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“For instance, in cases of concurrent diabetes and insulin resistance, oxidative stress in other tissues due to hyperglycaemia may compound lipotoxicity in the liver.34”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [34]
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Impact de surnutritions expérimentales sur le tissu adipeux chez l’homme sain
Segrestin, B. (2019) · theses.fr (ABES) · doi:10.70675/95d575a7zf5b3z4111z891ez25e032d657ee
Homéostasie des céramides et hépatopathies métaboliques
Régnier, M. (2018) · theses.fr (ABES) · doi:10.70675/2fb92711z373cz4b27z8082z7aa3f8930e63
Canivet, C. M. (2019) · theses.fr (ABES) · doi:10.70675/d03174c8z45cez439ezba77z41b6ed9403b3
Implications du microbiote intestinal et de la pectine dans la stéato-hépatite non-alcoolique
Houron, C. (2020) · theses.fr (ABES) · doi:10.70675/282e9d85z4f3dz4f5bz9045zd1ce6da72037
Influence du sexe dans la susceptibilité aux hépatopathies métaboliques
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The inner nuclear membrane protein SUN1 regulates cullin-3 neddylation to maintain insulin signalingPreprint
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“…steatotic liver disease (MASLD) is now estimated to affect nearly one-third of the population worldwide, with a rising incidence that parallels increases in obesity, metabolic syndrome, insulin resistance, and type 2 diabetes (Cotter & Rinella, 2020; Rinella et al , 2023; Samuel & Shulman, 2018).”
Feng, X., Feng, Y., Raza, S. H. A., Ma, Y. P., & Deng, H. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1781941 · Cited by 1
“…collectively clarify the cellular heterogeneity underlying NAFLD progression from simple steatosis to inflammatory NASH (Diehl and Day, 2017; Samuel and Shulman, 2018) and the potential transition towards cirrhosis, where hepatocytes are replaced by collagen-rich scar tissue (Diehl and Day,…”
“From trials to treatment: resmetirom as the first approved drug for NASH”
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Metadata
- Authors
- Samuel, V. T., & Shulman, G. I.
- Affiliations
- United States Department of Veterans Affairs (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Samuel, Varman T.
- Shulman, Gerald I.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 27
- Issue
- 1
- Pages
- 22-41
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5762395
- OpenAlex
- W2752428556
- Cited by
- 745
- References
- 263
- Citations by year
- 2026: 72 · 2025: 84 · 2024: 90 · 2023: 109 · 2022: 88 · 2021: 91 · 2020: 81 · 2019: 71 · 2018: 50
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Celgene
- Novo Nordisk
- National Institutes of Health (DK-40936, DK-45735, DK-R01 DK 11398401)
- AstraZeneca
- Gilead Sciences
- Merck
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- non-alcoholic fatty liver disease, hepatic insulin resistance, diacylglycerol, protein kinase C epsilon, insulin receptor, glycogen synthesis, lipogenesis, gluconeogenesis, pyruvate carboxylase, bariatric surgery, weight loss, PPAR agonists, farnesoid X receptor, FGF21, glucagon-like peptide-1, acetyl-CoA carboxylase, stearoyl-CoA desaturase, mitochondrial uncoupling, therapeutic target
- MeSH terms
- Animals, Glucose, Humans, Insulin, Insulin Resistance, Metabolic Diseases, Lipid Metabolism, Non-alcoholic Fatty Liver Disease
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