The DOI matches its Crossref record; 261 of the 263 references it cites were found in a registry or an index.
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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Cites
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Mechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002
“Othermetabolic causes of NAFLD andNASH, which are most often genetically related, include (1) defects in intrahepatic lipolysis (e.g., decreased ATGL/CGI-58 activity); (2) defects in triglyceride export (e.g., defective Apo-B 100, MTTP activity); (3) increased glucokinase activity, resulting in increased hepatic DNL;…”
BackgroundInfluentialSelf-citationRole of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease
Chen, Z., Tian, R., She, Z., Cai, J., & Li, H. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.02.025 · Cited by 1,340
The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments
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Stefan, N., Häring, H., & Cusi, K. J. (2018) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30154-2 · Cited by 874
Mitochondria as a therapeutic target for common pathologies
Murphy, M. P., & Hartley, R. C. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.174 · Cited by 846
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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