Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway
Weiwei Xu,
Dongyan Zhang,
Yumin Ma,
Rafael C. Gaspar,
Mario Kahn,
Ali Nasiri,
Sue Murray,
Varman T. Samuel,
Gerald I. Shulman
Affiliations
Weiwei Xu
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Endocrinology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, China
Dongyan Zhang
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
Yumin Ma
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Endocrinology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225009, China
Rafael C. Gaspar
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
Mario Kahn
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
Ali Nasiri
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
Sue Murray
Ionis Pharmaceuticals, Carlsbad, CA 92010, USA
Varman T. Samuel
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; VA Connecticut Healthcare System, West Haven, CT 06516, USA; Corresponding author
Gerald I. Shulman
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Corresponding author
Summary: 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.
