[Approaches to the Treatment of Lifestyle-related Diseases Through the Regulation of Phospholipid Biosynthesis in the Liver].

Abstract

The incidence of type 2 diabetes mellitus (T2DM), a major lifestyle-related disease, is increasing worldwide. T2DM, which accounts for approximately 90-95% of all diabetes mellitus cases, is caused by deficient insulin secretion, tissue insulin resistance, or both. Many therapeutic drugs for T2DM have been developed that target the pancreas, which secretes insulin. The liver is the central organ for glucose and lipid metabolism, and failure of hepatic regulatory mechanisms leads to hyperglycemia, insulin resistance, and lipid accumulation. Here, we focused on the liver as a novel therapeutic target for T2DM. The fatty acid composition of phospholipids, a major component of biological membranes, has received considerable research attention owing to their involvement in T2DM onset and progression. Fatty acids in phospholipids are cleaved by phospholipase A to form lysophospholipids, which are subsequently remodeled back into phospholipids by lysophospholipid acyltransferases (LPLATs). LPLATs play an important role in lipid metabolism and homeostasis by regulating the abundance of various phospholipid species in multiple cell and tissue types. We investigated whether overexpression of LPLAT10, also called LPCAT4 and LPEAT2, in the liver could improve abnormalities in glucose metabolism and help treat T2DM. For overexpression, we generated an LPLAT10-expressing adenovirus (Ad) vector using an improved Ad vector named Ad-E4-122aT, which exhibited higher and longer-term transgene expression and lower hepatotoxicity than conventional Ad vectors. In this article, we review the current findings that changes in hepatic phospholipid species due to liver-specific LPLAT10 overexpression affect the pancreas and suppress postprandial hyperglycemia by increasing postprandial insulin secretion.