Divergent effects of the catalytic and bridging functions of hepatic lipase on atherosclerosis.
OBJECTIVE
Increased expression of human hepatic lipase (HL) or a catalytically inactive (ci) HL clears plasma cholesterol in mice deficient in low-density lipoprotein receptors (LDLr) and murine HL. We hypothesized that increased expression of both HL and ciHL reduces atherosclerosis in these mice.


RESULTS
Mice deficient in both LDLr and murine HL, alone or transgenically expressing similar levels of either human HL or ciHL, were fed a high-fat, cholesterol-enriched "Western" diet for 3 months to accelerate the development of atherosclerosis. Levels of plasma lipids, insulin, glucose, and liver enzymes were measured monthly, and aortic atherosclerosis was quantitated after 3 months. Plasma insulin, glucose, and liver enzyme levels did not differ significantly from controls. After 3 months, expression of HL reduced plasma cholesterol by 55% to 65% and reduced atherosclerosis by 40%. Surprisingly, expression of ciHL did not reduce plasma cholesterol or atherosclerosis.


CONCLUSIONS
High levels of HL, but not ciHL, delay the development of atherosclerosis in mice deficient in LDLr and mHL. These studies demonstrate that high levels of catalytically active human hepatic lipase (HL) reduce atherosclerosis, whereas high levels of a catalytically inactive HL do not affect atherosclerosis in mice genetically deficient in low-density lipoprotein receptor and mouse HL.
Dichek
Helén L
HL
Department of Pediatrics, Box 356320, University of Washington, 1959 NE Pacific Street, Seattle WA 98195, USA. hdichek@u.washington.edu
Qian
Kun
K
Agrawal
Nalini
N
D000818:Animals; D001053:Apolipoproteins / Q000097:blood; D001161:Arteriosclerosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D001786:Blood Glucose / Q000032:analysis; D002384:Catalysis; D002784:Cholesterol / Q000097:blood; D003433:Crosses, Genetic; D004036:Diet, Atherogenic; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D008049:Lipase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000201:enzymology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014280:Triglycerides / Q000032:analysis
D001053:Apolipoproteins; D001786:Blood Glucose; D007328:Insulin; C504173:LIPC protein, human; D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D008049:Lipase