Cited by 49Liver Disease Diagnosis and TreatmentMetabolism, Diabetes, and CancerLipid metabolism and biosynthesis

Insulin Regulation of Hepatic Lipid Homeostasis

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Uehara, Kahealani, Santoleri, Dominic, Whitlock, Anna E. Garcia, Titchenell, Paul M.·2023·Comprehensive Physiology

Abstract

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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  1. [22]Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARa and is a key mediator of hepatic lipid metabolism in Ketotic States. Cell Metab 5: 426– 437, 2007. 17550778
  2. [27]Bennett MJ, Santani AB. Carnitine palmitoyltransferase 1A deficiency. GeneReviews, Bookshelf ID: NBK1527, 2005. 20301700

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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)
OpenAlex
W4382011091
Cited by
49
References
362
Citations by year
2026: 8 · 2025: 19 · 2024: 19 · 2023: 3
Type
other
Language
en
Open access
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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