Deficiencies of iPLA2beta

Calcium-independent phospholipaseA2beta (iPLA2beta), which is one of the patatin-like phospholipase domain-containing genes, catalyzes the hydrolysis of phospholipids providing lipids for cell membrane remodeling. It is known that iPLA2beta mediates monocyte chemotaxis to remove apoptotic cells in inflamed tissues. While iPLA2 has been shown to mediate an assembly of very low density lipoprotein (VLDL) in hepatocyte cell line in vitro, it is not known if iPLA2beta could modulate systemic lipids, lipoprotein secretion and hepatocellular apoptosis in vivo. We aim to investigate these events by using iPLA2beta knockout (iPLA2beta-/-) mice. iPLA2beta-/- mice exhibited reduced body, liver and visceral fat weight concomitatnt with reduced hepatic and visceral triglyceride and cholesterol levels. No changes in serum transaminases were detected in mutant mice. mRNA expression of de novo lipogenic SREBP1c, fatty acid synthase and Elovl6 as well as lipid transport CD36 was decreased in livers of iPLA2beta-/- mice. Upon induction of lipoprotein secretion by tyloxapol, serum chylomicron, VLDL, and LDL levels in triglyceride and cholesterol fractions as well as serum apoB protein levels were significantly decreased in mutant mice. Hepatocytes isolated from iPLA2beta-/- mice were more apoptotic and exhibited increased sensitivity towards palmitate-induced apoptosis. Compared to wild-type, livers of iPLA2beta-/- mice increased expression of inflammatory and fibrogenesis markers. Conclusions: Whole body deficiencies of iPLA2beta caused reduced body and liver weight as well as adiposity. Reduced serum and hepatic lipids and lipoprotein secretion in the mutant mice was associated with increased hepatic apoptosis and inflammation. Since the reduction of serum lipids and lipoproteins have been noted in patients undergoing liver failure, chronic aggressive hepatitis and liver cirrhosis, iPLA2beta may be a predisposed gene for development of liver disease.