Disruption of Hepatic Insulin Signaling Causes Phospholipid Dysregulation in Mice.

Abstract

Phospholipids are important components of the bilayer of biological membranes. Alterations of phospholipids are associated with metabolic disorders, including insulin resistance. However, how impaired insulin signaling impacts phospholipids has not been well established. Disruption of hepatic insulin signaling is achieved by insulin receptor substrate 1 (IRS1) and IRS2 double deletion (DKO) in the liver. Further deletion of TGF-β1 or Foxo1 in the liver of DKO mice was used to examine the role of TGF-β1 or Foxo1 in contributing to the alterations of phospholipid metabolism in DKO mice. Disruption of hepatic insulin signaling led to the dysregulation of phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), sphingomyelin (SM), cardiolipin (CL), and lysophospholipids in the liver. Mechanistically, disruption of hepatic insulin signaling dysregulated the expression of genes related to phospholipid metabolism. Interestingly, further deletion of Tgfb1 in the liver of DKO mice (TKObeta1) attenuated the alterations of phospholipids and rescued the abnormal expression of genes related to phospholipid metabolism. Moreover, deletion of transcription factor Foxo1, a key mediator of insulin signaling, achieved similar beneficial effects as Tgfb1 deletion in DKO mice. Our study suggests that insulin signaling plays a crucial role in maintaining phospholipids balance in the liver via TGF-β1 or Foxo1. Targeting TGF-β1 or Foxo1 could be promising strategies to combat phospholipids alterations and related metabolic dysfunctions.