Modulation of Membrane Phospholipids by Hepatic Deficiency of iPLA2beta Renders Hepatitis Susceptibility in Non-obese but Protects against Steatosis in Obese Mice

• Applicant: Dr. Walee Chamulitrat, Ph.D.
• Subject Area: Gastroenterology ; Animal Physiology and Biochemistry
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249280891

Calcium-indepedent phospholipase A2 (PLA2) VIA or iPLA2beta catalyzes the hydrolysis of a phospholipid to lysophospholipid which is thought to play a role in macrophage signalling and PL remodeling of epithelial cells. Our work in the first DFG period has shown that whole-body iPLA2beta deficiency induces hypometabolism in decreasing hepatic lipids, and this in turn elicits protection against obesity and fatty liver. However, in non-obese mice iPLA2beta deficiency represents a 'sensitized' state rendering susceptibility for fulminant hepatitis as well as microbial- and age-dependent development of fibrosis and hepatocellular carcinoma. In this renewal application, we hypothesize that these pathological events may be related to the preferential hydrolysis by iPLA2beta towards aminophospholipids, namely, phosphatidylethanolamine (PE) and phosphatidylserine (PS), since their levels are accumulated in iPLA2beta-deficient livers. By using isolated hepatocytes, we will determine whether this accumulation would lead to an increase in PE and PS externalized to the membrane outer leaflets, thus being prone for oxidation to PE/PS aldehydes. Externalization of PE and PS is an early event in apoptosis, we will determine if iPLA2beta deficiency sensitizes TNF-alpha-induced apoptosis with a mechanism involving PE/PS externalization. Since PE (but not PS) is known as a lipid receptor for the binding of gram-negative bacteria in host cells, we will also determine whether externalized PE binds to Helicobacter Hepaticus, as these bacteria can induce hepatitis and sensitize HCC in susceptible mouse strains. By using hepatocyte-specific iPLA2beta-knockout mice with the deletion of exons 6-8, we will further determine the changes in hepatic PL profiles, PE/PS aldehydes, and externalized PE and PS upon in vivo administration with H. Hepaticus LPS, diethylnitrosamine, and high-fat diet as a model of hepatitis, hepatocellular carcinoma, and obesity, respectively.Our research highlights iPLA2beta as a gene that modulates membrane PL whereby its deficiency increases inflammation susceptibility in non-obese but protects fatty liver in obese mice. The understanding of this contrasting scenario in the modulation of membrane PL may be used as a therapeutic basis for treatment of hepatitis and fatty liver in humans.

• DFG Programme: Research Grants