Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Open accessAbstract
Insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD) and is a major factor in the pathogenesis of type 2 diabetes. The development of hepatic insulin resistance has been ascribed to multiple causes, including inflammation, endoplasmic reticulum (ER) stress, and accumulation of hepatocellular lipids in animal models of NAFLD. However, it is unknown whether these same cellular mechanisms link insulin resistance to hepatic steatosis in humans. To examine the cellular mechanisms that link hepatic steatosis to insulin resistance, we comprehensively assessed each of these pathways by using flash-frozen liver biopsies obtained from 37 obese, nondiabetic individuals and correlating key hepatic and plasma markers of inflammation, ER stress, and lipids with the homeostatic model assessment of insulin resistance index. We found that hepatic diacylglycerol (DAG) content in cytoplasmic lipid droplets was the best predictor of insulin resistance ( R = 0.80, P < 0.001), and it was responsible for 64% of the variability in insulin sensitivity. Hepatic DAG content was also strongly correlated with activation of hepatic PKCε ( R = 0.67, P < 0.001), which impairs insulin signaling. In contrast, there was no significant association between insulin resistance and other putative lipid metabolites or plasma or hepatic markers of inflammation. ER stress markers were only partly correlated with insulin resistance. In conclusion, these data show that hepatic DAG content in lipid droplets is the best predictor of insulin resistance in humans, and they support the hypothesis that NAFLD-associated hepatic insulin resistance is caused by an increase in hepatic DAG content, which results in activation of PKCε.
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Insulin resistance may promote ectopic fat deposition in the liver and muscle.
“Subsequently, it may promote ectopic fat deposition in the liver and muscle.98 99”
From Dietary sugar consumption and health: umbrella review (2023) · cites this paper as [98]
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Aging- and obesity-related peri-muscular adipose tissue accelerates muscle atrophy
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Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease
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Self-citationHepatokines and non-alcoholic fatty liver disease
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“The data obtained by Kumashiro et al. (2011) in humans confirmed the role of DAG accumulation in the liver and activation of PKCε in pathogenesis of hepatic insulin resistance.”
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- Authors
- Kumashiro, N., Erion, D. M., Zhang, D., Kahn, M., Beddow, S. A., Chu, X., Still, C. D., Gerhard, G. S., Han, X., Dziura, J., Petersen, K. F., Samuel, V. T., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Departments of bInternal Medicine and
- Geisinger Medical Center (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- United States Department of Veterans Affairs (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-09-19
- Volume
- 108
- Issue
- 39
- Pages
- 16381-16385
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3182681
- OpenAlex
- W2020799782
- Cited by
- 585
- References
- 57
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 34 · 2023: 28 · 2022: 33 · 2021: 43 · 2020: 46 · 2019: 55 · 2018: 46 · 2017: 40 · 2016: 45 · 2015: 44 · 2014: 40 · 2013: 55 · 2012: 36
- FWCI
- 31.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Diabetes Association (DK-49230, DK-085638)
- U.S. Department of Veterans Affairs
- Manpei Suzuki Diabetes Foundation
- National Institute on Aging (R01-AG-23686, R01AG023686)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK049230, R01 DK-49230, R01DK088231, R24DK085638)
- National Center for Research Resources (UL1RR024139)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin resistance, non-alcoholic fatty liver disease, hepatic steatosis, diacylglycerol, lipid droplets, protein kinase C epsilon, endoplasmic reticulum stress, liver inflammation, insulin signaling, type 2 diabetes, obesity, liver biopsy
- MeSH terms
- Adult, Diglycerides, Enzyme Activation, Fatty Liver, Female, Humans, Insulin Resistance, Male, Middle Aged, Protein Kinase C-epsilon
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