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

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 INSR^Y1152/Akt^S473 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-INSR^T1150 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.