ArticleProceedings of the National Academy of Sciences of the United States of America2018
PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 75 citations in OpenAlex.
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- Insulin Resistance and Inflammation.International journal of molecular sciences · 2026Review
- Unravelling the obesity epidemic among young people in Qatar: a literature review.Frontiers in public health · 2026Review
- Dynamic transcriptomic profiling of dorsal root ganglia reveals stage-specific mechanisms in diabetic neuropathic pain.Frontiers in molecular neuroscience · 2026Article
- Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia.Nature communications · 2025Article
- Metals in the human liver: An underappreciated risk factor of hepatic insulin resistance and associated pathophysiology.Environmental pollution (Barking, Essex : 1987) · 2025Review
- Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model.Molecular medicine reports · 2025Article
- Zapotin mitigates breast cancer progression by targeting PKCε mediated glycolytic pathway regulation.BMC cancer · 2025Article
- Identification of Interactive Genetic Loci Linked to Insulin Resistance in Metabolic Syndrome-An Update.Medicina (Kaunas, Lithuania) · 2025Review
- Comparative proteomics and micro-RNA analysis of skeletal muscle cell small extracellular vesicles - Unique profiles in cells from severely obese individuals with type 2 diabetesFrontiers in physiology · 2025Article
- Diet-induced obesity and aging-induced upregulation of Trib3 interfere with energy homeostasis by downregulating the thermogenic capacity of BAT.Experimental & molecular medicine · 2024Article
- Association Between Ultraprocessed Food Consumption and Metabolic Disorders in Children and Adolescents with Obesity.Nutrients · 2024Article
- Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.The EMBO journal · 2024Article
- Glucosamine substituted sulfonylureas: IRS-PI3K-PKC-AKT-GLUT4 insulin signalling pathway intriguing agent.RSC medicinal chemistry · 2024Article
- From NAFLD to MASLD: Meta-analysis and systematic review of NAFLD patients in Turkiye in terms of metabolic profile and MASLD potential.Hepatology forum · 2024Review
- Inter-organ crosstalk during development and progression of type 2 diabetes mellitus.Nature reviews. Endocrinology · 2024Review
- Review
- Regulation of Insulin Clearance by Non-Esterified Fatty Acids.Biomedicines · 2022Review
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat-fed, and high-fat-fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.
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