iPLA2beta Deficiency in mice fed methionine-choline-deficient diet does not protect hepatic steatosis but still attenuates hepatic fatty acids, cholesterol esters, and liver enzymes

Background and Aims:

Group VIA calcium-independent phospholipase A2 or iPLA2β is among modifier genes of non-alcoholic fatty liver disease (NAFLD). Consistently, iPLA2β deletion protects fatty liver in genetically obese ob/ob mice by replenishing the loss of hepatic phospholipids (PL) (BBAlipids 1861, 449, 2016). Our recent results also show that iPLA2β-null mice are protected from chronic feeding with high-fat-diet only when hepatic PL contents are depleted. As mouse feeding with methionine- and choline-deficient (MCD) diet is a model of lean NAFLD, we hypothesized that iPLA2β-null mice may not be protected from hepatic steatosis since PL syntheses are disturbed.

Methods:

feeding of female wild-type and iPLA2β-null mice MCD-diet for 5 weeks. Serum and livers were subjected to phenotyping by RT-PCR, Western blot, histology, immunohistochemistry, and the analyses of phospholipid profiles by liquid-chromatography mass spectrometry.

Results:

MCD feeding of WT mice induced hepatic steatosis with a severe reduction of body and visceral fat weights concomitant with decreased contents of hepatic phosphatidylcholine and phosphatidylinositol. iPLA2β deficiency under MCD did not modulate these parameters. Notably, iPLA2β deficiency attenuated MCD-induced elevation of serum transaminase activities as well as hepatic expression of fatty-acid translocase CD36 and HDL-uptake scavenger receptor B type 1. The contents of hepatic fatty acids and cholesterol esters were concomitantly attenuated. iPLA2β deficiency under MCD however did not modulate elevated expression of hepatic caspase 1, IL-1b, and pro-inflammatory cytokines, but it further increased hepatic expression of myofibroblast α-smooth muscle actin and vimentin.

Conclusions:

Unlike obese NAFLD models, methionine and choline deficiency did not render hepatic steatosis protection in iPLA2β-null mice due to the lack of PL replenishment. iPLA2β may play a role on cholesterol metabolism during MCD-induced lean NAFLD possibly through PE hydrolysis to generate fatty acids for cholesterol esterification. An attenuation of cholesterol esters by iPLA2β inactivation resulted in an improvement of liver enzymes in MCD-induced NAFLD.