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. 2024 Oct 22;43(10):114746.
doi: 10.1016/j.celrep.2024.114746. Epub 2024 Sep 19.

Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway

Weiwei Xu  1 , Dongyan Zhang  2 , Yumin Ma  3 , Rafael C Gaspar  2 , Mario Kahn  2 , Ali Nasiri  2 , Sue Murray  4 , Varman T Samuel  5 , Gerald I Shulman  6
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Free article

Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway

Weiwei Xu et al. Cell Rep. .
Free article

Abstract

Inhibition of the ceramide synthetic pathway with myriocin or an antisense oligonucleotide (ASO) targeting dihydroceramide desaturase (DES1) both improved hepatic insulin sensitivity in rats fed either a saturated or unsaturated fat diet and was associated with reductions in both hepatic ceramide and plasma membrane (PM)-sn-1,2-diacylglycerol (DAG) content. The insulin sensitizing effects of myriocin and Des1 ASO were abrogated by acute treatment with an ASO against DGAT2, which increased hepatic PM-sn-1,2-DAG but not hepatic C16 ceramide content. Increased PM-sn-1,2-DAG content was associated with protein kinase C (PKC)ε activation, increased insulin receptor (INSR)T1150 phosphorylation leading to reduced insulin-stimulated INSRY1152/AktS473 phosphorylation, and impaired insulin-mediated suppression of endogenous glucose production. These results demonstrate that inhibition of de novo ceramide synthesis by either myriocin treatment or DES1 knockdown protects against lipid-induced hepatic insulin resistance through a C16 ceramide-independent mechanism and that they mediate their effects to protect from lipid-induced hepatic insulin resistance via the PM-sn-1,2-DAG-PKCε-INSRT1150 phosphorylation pathway.

Keywords: CP: Metabolism; CP: Molecular biology; antisense oligonucleotides; ceramides; diacylglycerols (DAG); fatty acids; insulin resistance; lipid metabolism; metabolic dysfunction-associated steatotic disease (MASLD); protein kinase C epsilon.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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