Rescue of Hepatic Phospholipid Remodeling Defectin iPLA2β-Null Mice Attenuates Obese but Not Non-Obese Fatty Liver.

Walee Chamulitrat,Huili Li,Gerhard Liebisch,Chutima Jansakun

doi:10.3390/biom10091332

Abstract

Polymorphisms of group VIA calcium-independent phospholipase A2 (iPLA2β or PLA2G6) are positively associated with adiposity, blood lipids, and Type-2 diabetes. The ubiquitously expressed iPLA2β catalyzes the hydrolysis of phospholipids (PLs) to generate a fatty acid and a lysoPL. We studied the role of iPLA2β on PL metabolism in non-alcoholic fatty liver disease (NAFLD). By using global deletion iPLA2β-null mice, we investigated three NAFLD mouse models; genetic Ob/Ob and long-term high-fat-diet (HFD) feeding (representing obese NAFLD) as well as feeding with methionine- and choline-deficient (MCD) diet (representing non-obese NAFLD). A decrease of hepatic PLs containing monounsaturated- and polyunsaturated fatty acids and a decrease of the ratio between PLs and cholesterol esters were observed in all three NAFLD models. iPLA2β deficiency rescued these decreases in obese, but not in non-obese, NAFLD models. iPLA2β deficiency elicited protection against fatty liver and obesity in the order of Ob/Ob › HFD » MCD. Liver inflammation was not protected in HFD NAFLD, and that liver fibrosis was even exaggerated in non-obese MCD model. Thus, the rescue of hepatic PL remodeling defect observed in iPLA2β-null mice was critical for the protection against NAFLD and obesity. However, iPLA2β deletion in specific cell types such as macrophages may render liver inflammation and fibrosis, independent of steatosis protection.

Highlights

Obesity is an epidemic with a prevalence rate of 13% of the world’s population [1] and has become a major public health problem resulting in decreased quality of life, reduced working ability, and early death
We studied the role of iPLA2β on PL metabolism in non-alcoholic fatty liver disease (NAFLD)
We investigated the extent of hepatic fatty acid (FA) and PL metabolism in livers of male Ob/Ob mice at six months old [39], male C57BL/6 mice at six months old fed with HFD (60 kcal % fat, Research Diet, USA) for six months [40], and female C57BL/6 mice at 12 months old fed with methionine- and choline-deficient (MCD) diet for four weeks [41]

Summary

Obesity and NAFLD

Obesity is an epidemic with a prevalence rate of 13% of the world’s population [1] and has become a major public health problem resulting in decreased quality of life, reduced working ability, and early death. A study in mouse GWAS has identified 11 genome-wide significant loci to be associated with obesity traits, and a PL-metabolizing enzyme lysophospholipase-like 1 (LYPLAL1) was among these loci identified in the epididymal adipose tissues of diet-induced obese mice [13] These results are consistent with association of this gene with human NAFLD [77]. We showed that protection was observed in iPLA2β KO mice with an attenuation of HFD-induced body and liver-weight gains, liver enzymes, serum-free FAs, as well as hepatic TGs and steatosis scores. This deficiency did not attenuate hepatic ER stress, fibrosis, and inflammation markers. Our data emphasize the contributions and involvement of hepatic PL, TG, and CE metabolism in the development of NAFLD

13.1. Consideration of Cell-Type Specificity of iPLA2β

Findings

14. Conclusions