Liver-specific overexpression of LPCAT3 reduces postprandial hyperglycemia and improves lipoprotein metabolic profile in mice

Abstract

Previous studies have shown that group 1B phospholipase A2-mediated absorption of lysophospholipids inhibits hepatic fatty acid β-oxidation and contributes directly to postprandial hyperglycemia and hyperlipidemia, leading to increased risk of cardiometabolic disease. The current study tested the possibility that increased expression of lysophosphatidylcholine acyltransferase-3 (LPCAT3), an enzyme that converts lysophosphatidylcholine to phosphatidylcholine in the liver, may alleviate the adverse effects of lysophospholipids absorbed after a lipid-glucose mixed meal. The injection of an adenovirus vector harboring the human LPCAT3 gene into C57BL/6 mice increased hepatic LPCAT3 expression fivefold compared with mice injected with a control LacZ adenovirus. Postprandial glucose tolerance tests after feeding these animals with a bolus lipid-glucose mixed meal revealed that LPCAT3 overexpression improved postprandial hyperglycemia and glucose tolerance compared with control mice with LacZ adenovirus injection. Mice with LPCAT3 overexpression also showed reduced very low density lipoprotein production and displayed elevated levels of the metabolic- and cardiovascular-protective large apoE-rich high density lipoproteins in plasma. The mechanism underlying the metabolic benefits of LPCAT3 overexpression was shown to be due to the alleviation of lysophospholipid inhibition of fatty acid β-oxidation in hepatocytes. Taken together, these results suggest that specific LPCAT3 induction in the liver may be a viable strategy for cardiometabolic disease intervention.

Biglycan gene connects metabolic dysfunction with brain disorder

“…Acox1 is the first enzyme of the fatty acid beta-oxidation pathway [35] while Lpcat3 catalyzes the reacylation of lysophospholipids to phospholipids to modulate lysophospholipid availability and metabolism in the liver. It has been shown that LPCAT3 is an important mediator of liver X receptor effects on metabolism [36,37]. The overall results support a strong regulatory role of Bgn in peripheral metabolism.…”

Metabolites as regulators of insulin sensitivity and metabolism

“…Lysophosphatidylcholine acyltransferase-3 (LPCAT3) preferentially synthesizes unsaturated fatty acid-containing PCs and is induced by liver X receptors (LXRs) and PPARδ in liver 139,140 . Hepatic knockdown of LPCAT3 induces ER stress and inflammation 139 , while its overexpression improves insulin sensitivity and glucose tolerance in wild-type and ob / ob mice 139,141 . Future studies identifying the intracellular signals generated by specific phospholipid species will help clarify their role in insulin sensitivity.…”

Phospholipid Remodeling in Physiology and Disease

“…This is likely caused by the accumulation of lysoPC, which in turn increases microsomal triglyceride transfer protein (MTP) expression and facilitates apoB-containing very low-density lipoprotein (VLDL) assembly and secretion (35). Conversely, mice acutely over-expressing human LPCAT3 in liver for several days show reduced VLDL secretion and lowered hepatic triglyceride levels, perhaps due to the fact that, at reduced levels, lysoPC no longer suppresses fatty acid β-oxidation in hepatocytes (37). These mice also displayed beneficial lipoprotein profiles with increased levels of protective ApoE-rich high-density lipoprotein (HDL) in plasma.…”