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Journal of Lipid Research, Vol. 45, 551-560, March 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology
The bridging function of hepatic lipase clears plasma cholesterol in LDL receptor-deficient "apoB-48-only" and "apoB-100-only" mice
Department of Pediatrics, University of Washington, Seattle, WA 98195
1 To whom correspondence should be addressed. e-mail: hdichek{at}u.washington.edu
Hepatic lipase clears plasma cholesterol by lipolytic and nonlipolytic processing of lipoproteins. We hypothesized that the nonlipolytic processing (known as the bridging function) clears cholesterol by removing apoB-48- and apoB-100-containing lipoproteins by whole particle uptake. To test our hypotheses, we expressed catalytically inactive human HL (ciHL) in LDL receptor deficient "apoB-48-only" and "apoB-100-only" mice. Expression of ciHL in "apoB-48-only" mice reduced cholesterol by reducing LDL-C (by 54%, 46 ± 6 vs. 19 ± 8 mg/dl, P < 0.001). ApoB-48 was similarly reduced (by 60%). The similar reductions in LDL-C and apoB-48 indicate cholesterol removal by whole particle uptake. Expression of ciHL in "apoB-100-only" mice reduced cholesterol by reducing IDL-C (by 37%, 61 ± 19 vs. 38 ± 12 mg/dl, P < 0.003). Apo-B100 was also reduced (by 27%). The contribution of nutritional influences was examined with a high-fat diet challenge in the "apoB-100-only" background. On the high fat diet, ciHL reduced IDL-C (by 30%, 355 ± 72 vs. 257 ± 64 mg/dl, P < 0.04) but did not reduce apoB-100. The reduction in IDL-C in excess of apoB-100 suggests removal either by selective cholesteryl ester uptake, or by selective removal of larger, cholesteryl ester-enriched particles.
Our results demonstrate that the bridging function removes apoB-48- and apoB-100-containing lipoproteins by whole particle uptake and other mechanisms.
Abbreviations: apoB, apolipoprotein B; ciHL, catalytically inactive hepatic lipase; FPLC, fast-protein liquid chromatography; HDL-C, HDL-cholesterol; HL, hepatic lipase; HSPG, heparan sulfate proteoglycan; IDL-C, IDL-cholesterol; LDL-C, LDL-cholesterol; LDLR, LDL receptor; LRP, LDLR-related protein; SR-BI, scavenger receptor BI
Supplementary key words triglyceride • remnants • fast protein liquid chromatography • apolipoprotein A-I • apolipoprotein B • apolipoprotein E • low density lipoprotein
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