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 approximately 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 approximately 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.