Hepatic hypolipidemia in phospholipase A2 VIA-null mice mediates apoptosis, chronic persistent hepatitis, and sensitivity for autoimmune hepatitis

Introduction: Calcium-independent phospholipaseA2 VIA (iPLA2β), which is one of the patatin-like phospholipase domain-containing genes, catalyzes the hydrolysis of phospholipids providing lysophospholipids which have been identified as 'find me' signals for the removal of apoptotic cells by phagocytes. The deletion of iPLA2β may cause accumulation of apoptotic hepatocytes. iPLA2β transcription is known to be regulated by SREBP1c which is a transcription factor for de novo lipogenesis. It is thus postulated that alterations of hepatic lipids by iPLA2β deficiency may lead to apoptosis in vivo. Methods: Whole body iPLA2β-null and wild-type male mice were used. Serum and hepatic lipids were measured by using kits. Gene expression was performed by quantitative TaqMan RT-PCR. Histology (H&E), Sirius red and α-smooth muscle actin (α-SMA) staining was performed. Concanavalin A (10mg/kg) was i.p. injected for 16h. Results: iPLA2β-null mice exhibited reduced body and liver weight concomitant with reduced hepatic triglyceride and cholesterol levels. Mild increases of serum alkaline phosphatase and decreases of albumin and total protein were observed in mutant mice. mRNA expression of SREBP1c, FAS and Elovl6 was decreased in mutant mice, this was accompanied with mild infiltration of immune cells and increases of inflammatory and fibrosis mRNAs including TNF-α, MCP-1, VCAM-1, CCL3, CCL4, CCL5, CCR2, α -SMA, TGF- β1, PAI-1, and CTGF. iPLA2β-null mice were more susceptible towards ConA-induced autoimmune hepatitis with increased liver enzymes, hepatocellular necrosis and fibrosis. Conclusions: Whole body deficiency of iPLA2β was well-tolerated causing reduced liver weight and hepatic hypolipidemia. This was associated with increased hepatic apoptosis and secondarily inflammation/fibrosis. These findings are consistent with altered lipid metabolism seen in patients undergoing liver failure, chronic aggressive hepatitis and liver cirrhosis. Thus, deficiency of iPLA2β may mediate chronic persistent hepatitis by its inability to synthesize lipids.