Combined hyperlipidemia/hyperalphalipoproteinemia associated with premature spontaneous atherosclerosis in mice lacking hepatic lipase and low density lipoprotein receptor.
METHODS
Hepatic lipase (HL) is an enzyme which hydrolyzes triglycerides from plasma lipoproteins and thus takes part in the metabolism of triglyceride-rich lipoprotein remnants and high density lipoproteins. The search described here concentrated on the description of the double invalidation of the HL and LDL receptor genes in mice in order to better understand the possible role of HL in combined hyperlipidemia/hyperalphalipoproteinemia and development of atherosclerosis.


RESULTS
We show here that mice lacking both endogenous HL and LDL receptor (HL-/-:LDLR-/-) dramatically increased their plasma triglyceride-rich lipoproteins and their remnants as a consequence of reduced liver uptake. This result is strenghthened by the fact that HL-/-:LDLR-/- were found to overexpress LRP, LSR, and apoE genes. Interestingly, HL-/-:LDLR-/- mice showed premature spontaneous atherosclerosis and aortic lesions from 1-year-old animals were two-fold larger than those of LDLR-/- single mutants. We confirmed that HL-/- and wild-type mice did not develop atherosclerosis lesion even 1 year after birth.


CONCLUSIONS
Analysis of this double HL-LDLR knockout mouse model provides in vivo evidence that HL has a major role in the clearance of TRL remnants when LDLR is deficient and in the reduction of the development of atherosclerosis.
Barcat
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Laboratoire de Biochimie et de Biologie Moléculaire, EA no. 3670, Centre Hospitalier Universitaire de Bordeaux, Université Victor Ségalen Bordeaux 2, 146 rue Léo-Saignat, 33076 Bordeaux, France.
Amadio
A
A
Palos-Pinto
A
A
Daret
D
D
Benlian
P
P
Darmon
M
M
Bérard
A M
AM
D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D006949:Hyperlipidemias / Q000235:genetics* / Q000473:pathology; D008072:Hyperlipoproteinemia Type I / Q000235:genetics* / Q000473:pathology; D008049:Lipase / Q000172:deficiency* / Q000235:genetics; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D008049:Lipase; C495700:Lipc protein, mouse