Insulin Regulation of Hepatic Lipid Homeostasis
Open accessAbstract
The incidence of obesity, insulin resistance, and type II diabetes (T2DM) continues to rise worldwide. The liver is a central insulin-responsive metabolic organ that governs whole-body metabolic homeostasis. Therefore, defining the mechanisms underlying insulin action in the liver is essential to our understanding of the pathogenesis of insulin resistance. During periods of fasting, the liver catabolizes fatty acids and stored glycogen to meet the metabolic demands of the body. In postprandial conditions, insulin signals to the liver to store excess nutrients into triglycerides, cholesterol, and glycogen. In insulin-resistant states, such as T2DM, hepatic insulin signaling continues to promote lipid synthesis but fails to suppress glucose production, leading to hypertriglyceridemia and hyperglycemia. Insulin resistance is associated with the development of metabolic disorders such as cardiovascular and kidney disease, atherosclerosis, stroke, and cancer. Of note, nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases encompassing fatty liver, inflammation, fibrosis, and cirrhosis, is linked to abnormalities in insulin-mediated lipid metabolism. Therefore, understanding the role of insulin signaling under normal and pathologic states may provide insights into preventative and therapeutic opportunities for the treatment of metabolic diseases. Here, we provide a review of the field of hepatic insulin signaling and lipid regulation, including providing historical context, detailed molecular mechanisms, and address gaps in our understanding of hepatic lipid regulation and the derangements under insulin-resistant conditions. © 2023 American Physiological Society. Compr Physiol 13:4785-4809, 2023.
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Insulin resistance is a central factor in the pathogenesis of MASLD.
“Given that insulin resistance (IR) is widely recognized as the key underlying mechanism of metabolic syndrome, it is reasonable to consider IR as a central factor in the pathogenesis of MASLD, which can be viewed as the hepatic manifestation of metabolic syndrome [2,9-12].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [12]
Increased FFA flux, as observed in IR states, increases intracellular availability of TG and indirectly stimulates the assembly and secretion of VLDL particles.
“Increased FFA flux, as observed in IR states, has been suggested to increase intracellular availability of TG and indirectly stimulate the assembly and secretion of VLDL particles [12,107,109].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [12]
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Flagged first, then by citations
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- Authors
- Uehara, K., Santoleri, D., Whitlock, A. E. G., & Titchenell, P. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Titchenell, Paul M.
- Venue
- Comprehensive Physiology
- Publisher
- Wiley
- Published
- 2023-06-26
- Volume
- 13
- Issue
- 3
- Pages
- 4785-4809
- ISSN
- 2040-4603 (ISSN-L)
- PMC
- PMC10760932
- OpenAlex
- W4382011091
- Cited by
- 49
- References
- 362
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 19 · 2023: 3
- Type
- other
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Comprehensive physiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (NRSA F31)
- National Institute of Diabetes and Digestive and Kidney Diseases (F31DK128876, R01DK125497, P30DK019525)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- insulin signaling, hepatic lipid metabolism, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, hepatic glucose production, fatty acid degradation, triglyceride synthesis, hypertriglyceridemia, hyperglycemia, obesity, liver
- MeSH terms
- Diabetes Mellitus, Type 2, Glycogen, Homeostasis, Humans, Insulin, Insulin Resistance, Liver, Triglycerides, Lipid Metabolism, Non-alcoholic Fatty Liver Disease
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