Effects Of Lp-PLA₂ On Lipid Metabolism Of Hepatocyte

Non-alcoholic fatty liver disease(NAFLD) caused by lipid metabolic disorder is a common liver disease. It is estimated that 1 billion people currently suffer from any form of NAFLD. The prevalence of NAFLD is 20-30% in Western countries, 30-50% in patients with type 2 diabetes, 80-90% in obese adults, and up to 90% in patients with hyperlipidemia. Inflammation is one of the causes of NAFLD and plays a key role in the pathogenic process of NAFLD. Lipoprotein-associated phospholipase A2(Lp-PLA2) has been proposed to be a significant predictor of cardiovascular events in recent years and could predict risk complementary to CRP. It has been reported in 2012 that plasma Lp-PLA2 level is positively associated with the degree of liver steatosis in patients with NAFLD, indicating that Lp-PLA2 might be involved in hepatic lipid metabolism. Statins(3-hydroxy-3-methyl-glutaryl-Co A reductase inhibitors) are lipid-lowering drugs that are widely used for the treatment of hyperlipidemia, coronary syndrome and atherosclerosis. There are lots of evidences that suggests statins are safe and effective in the treatment of NAFLD. In addition, statins have been shown to have anti-inflammatory effects and could inhibit the expression and acitivity of Lp-PLA2 in vitro and in vivo.In the present study, influences of inflammation and statins in the expression of Lp-PLA2 and effects of Lp-PLA2 on lipid metabolism of hepatocyte are investigated in vitro and in vivo. Our results suggested that LPS and TNF-α increased the m RNA and protein expression levels of Lp-PLA2 in a dose-dependent manner in Huh7 cells. The expression of lipid metabolism-related genes was increased following LPS and TNF-α treatment. Oil red O staining revealed that LPS and TNF-α induced lipid accumulation in Huh7 cells which was suppressed by pretreatment with 1-linoleoyl glycerol(1-LG), an inhibitor of Lp-PLA2. Lp-PLA2 expression was inhibited by simvastatin and lovastatin in a variety of cell types. Furthermore, simvastatin inhibited the expression of Lp-PLA2 and lipid metabolism-related genes in LPS-induced Huh7 cells and reduced LPS- or TNF-α-induced intracellular lipid accumulation in Huh7 cells in a dose-dependent manner in the presence of OA. In vivo, the m RNA and protein levels Lp-PLA2 were increased in the liver of mice with inflammation induced by a high-fat diet plus casein injection(HC) and these influences were abrogated by simvastatin treatment(HC+Simva). Hep G2 cells stably overexpressing Lp-PLA2 were established to further determine the relationship between Lp-PLA2 and hepatic lipid accumulation. Our results suggested that Lp-PLA2 overexpression promoted the expression of lipid metabolism-related genes and increased intracellular lipid content in vitro, and this change was inhibited by treatment with 1-LG. Besides, Lp-PLA2 disturbed the lipid-lowering effect of simvastatin on OA-induced lipid accumulation in vitro. In the over-expressed Lp-PLA2 transgenic swine which developed previously, the triglyceride(TG) level in liver homogenate was increased compared with that of wildtype.Our results suggest that increased levels of Lp-PLA2 disturb the normal expression of lipid metabolism-related genes and the lipid-lowering effect of statins in vitro and promote hepatic lipid accumulation in vitro and in vivo.