Novel regulation of insulin action in the liver

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PROJECT SUMMARY Insulin resistance and type 2 diabetes mellitus (T2DM) have presented an enormous burden to public health and economy with increasing prevalence. T2DM is characterized by relative insulin deficiency caused by pancreas β cells dysfunction and insulin resistance in metabolic organs. The liver plays a central role in regulating systemic glucose and lipid homeostasis. Aberrant hepatic insulin action is believed to be a primary driver of insulin resistance, in which insulin fails to adequately suppress hepatic glucose production (HGP), while enhances lipogenesis and triglyceride secretion, a phenomenon referred to as selective insulin resistance. Although downstream signaling cascades mediating insulin's control of glucose and lipid metabolism have been extensively studied, the molecular mechanisms underlying the development of insulin resistance and its differential effect on glucose and lipid metabolism are not well understood. We previously have identified critical functions of lysophosphatidylcholine acyltransferase 3 (Lpcat3), a phospholipid (PL) remodeling enzyme, in lipid metabolism in liver. Loss of Lpcat3 selectively reduces polyunsaturated PL in membranes, leading to decreased membrane fluidity and curvature. Changes in membrane dynamics result in impaired SREBP-1c processing and lipogenesis, and reduced triglyceride secretion in liver. The overall goal of this proposal is to define the roles of hepatic Lpcat3 and PL composition in insulin signaling and systemic lipid and glucose metabolism, and their contribution to the development of insulin resistance. In Aim 1, we will elucidate the mechanisms by which PL composition regulates insulin sensitivity. In Aim 2, we will investigate whether dysregulation of Lpcat3 expression mediates selective insulin resistance in T2DM. In Aim 3, we will test the therapeutic potential of targeting Lpcat3 for hyperglycemia and hypertriglyceridemia in T2DM. The results of this work will advance our understanding of how membrane composition modulates insulin sensitivity and glucose metabolism in liver, and how changes in membrane biophysical properties contribute to the pathogenesis of insulin resistance.