Reduced atherosclerosis in chow-fed mice expressing high levels of a catalytically inactive human hepatic lipase

Abstract 

Increased expression of catalytically inactive hepatic lipase (ciHL) lowers remnants and low-density lipoproteins (LDL) and may reduce atherosclerosis in mice lacking both LDLreceptors (LDLR) and murine (m) HL. However, in a previous study, ciHL expression failed to reduce atherosclerosis but increased liver fat accumulation after a 3-month high-fat diet, suggesting that diet-induced metabolic changes compromised the antiatherogenic effects of ciHL. Therefore, we hypothesized that reduced dietary fat would reduce atherosclerosis in ciHL expressing mice. Mice lacking both LDLR and mHL, alone, or expressing ciHL were fed a low-fat (chow) diet for 9 months to match the cumulative cholesterol exposure resulting from a 3-month high-fat diet. Plasma lipids and lipoproteins as well as atherosclerosis were determined at sacrifice. Also, liver expression of receptors and proteins contributing to cholesterol delivery including the LDLreceptor related protein (LRP), scavenger receptor (SR)-B1 and apoE were determined. At 9 months, ciHL expression reduced plasma cholesterol by ∼20% and atherosclerosis by 79% (from 2.67±0.61% of aortic surface, Ldlr−/−hl−/−, n=9, to 0.55±0.32% of aortic surface, Ldlr−/−hl−/−ciHL, n=7, P=0.01). Also, LRP-expression increased ∼4-fold, whereas SR-B1 and apoE remained unchanged.

These results demonstrate that ciHL expression reduces atherosclerosis. Also, these results demonstrate that ciHL increases LRP expression and suggest increased LRP-mediated lipoprotein clearance as a pathway for ciHL-mediated atherosclerosis reduction.

Abbreviations: HL, Hepatic lipase, LDL, Low density lipoprotein, HDL, High density lipoprotein, LDLR, LDLreceptor, LRP, LDLreceptor related protein, SR-B1, Scavenger receptor B1, ORO, Oil Red O, TBS, Tris buffered saline, HRP, Horse radish peroxidase

Keywords: Atherosclerosis, Genetically modified mice, Catalytically inactive hepatic lipase, LRP, Liver lipid accumulation, Heparan sulfate proteoglycans (HSPG)