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
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Article info
Publication history
Published online: January 20, 2007
Accepted:
December 1,
2006
Received in revised form:
October 11,
2006
Received:
April 17,
2006
Identification
Copyright
© 2006 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
