This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rinninger, F. Articles by Tall, A. R. Search for Related Content PubMed PubMed Citation Articles by Rinninger, F. Articles by Tall, A. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Antioxidants Related Collections Cardiovascular Pharmacology Animal models of human disease Lipid and lipoprotein metabolism

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1325-1332.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Probucol Enhances Selective Uptake of HDL-Associated Cholesteryl Esters In Vitro by a Scavenger Receptor B-I–Dependent Mechanism

Franz Rinninger; Nan Wang; Rajasekhar Ramakrishnan; Xian Cheng Jiang; Alan R. Tall

From the College of Physicians and Surgeons of Columbia University, Department of Medicine, Division of Molecular Medicine, New York, NY. Dr Rinninger is presently at the Universität Hamburg, Krankenhaus Eppendorf, Medizinische Kernklinik und Poliklinik, Hamburg, Germany.

Abstract—Recently, the class B, type I scavenger receptor (SR-BI) has been shown to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl esters (CEs), ie, lipid uptake independent of HDL holoparticle uptake. In vivo, this selective uptake delivers CEs to the liver for excretion and to steroidogenic tissues for hormone synthesis. Probucol, a hydrophobic antioxidant drug, lowers plasma cholesterol in humans and rodents and may inhibit progression of atherosclerosis and postangioplasty restenosis. In this study, the effect of probucol on HDL selective CE uptake was investigated in mice and in cells expressing SR-BI. Probucol feeding lowered plasma HDL cholesterol and markedly increased selective CE uptake from HDL in the liver and adrenal glands. However, probucol did not alter SR-BI protein levels in membranes from these organs. When incubated with control Chinese hamster ovary (CHO) cells, HDL isolated from probucol-treated mice (P-HDL) and HDL from control mice (C-HDL) showed similar low selective uptake of CEs. However, when incubated with SR-BI–transfected CHO cells, P-HDL showed a 2-fold increase in selective uptake compared with C-HDL. In an adrenal cell line (Y1-BS1), which expresses SR-BI in an adrenocorticotropic hormone–inducible manner, P-HDL showed significantly greater selective CE uptake than did C-HDL, and the differential response was amplified by adrenocorticotropic hormone treatment. In contrast to P-HDL, incorporation of this compound into HDL in vitro did not result in stimulation of selective CE uptake by SR-BI–transfected CHO cells, even though a significant mass of probucol could be detected in the HDL preparation. The specific interaction of P-HDL with SR-BI in cell culture could be observed after only 24 hours of probucol feeding, when there were minimal changes in HDL size and composition. Thus, probucol or one of its metabolites increases selective CE uptake in vivo by modifying HDL in a way that causes enhanced interaction with SR-BI. The increased interaction of P-HDL with SR-BI in the liver and arterial wall may be partly responsible for the effects of probucol on atherosclerosis and restenosis.

Key Words: HDL • selective uptake • scavenger receptor BI • probucol

This article has been cited by other articles:

				R. Arakawa, M. Tsujita, N. Iwamoto, C. Ito-Ohsumi, R. Lu, C.-A. Wu, K. Shimizu, T. Aotsuka, H. Kanazawa, S. Abe-Dohmae, et al. Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis J. Lipid Res., November 1, 2009; 50(11): 2299 - 2305. [Abstract] [Full Text] [PDF]

				T. C. Rideout, Z. Yuan, M. Bakovic, Q. Liu, R.-K. Li, Y. Mine, and M. Z. Fan Guar Gum Consumption Increases Hepatic Nuclear SREBP2 and LDL Receptor Expression in Pigs Fed an Atherogenic Diet J. Nutr., March 1, 2007; 137(3): 568 - 572. [Abstract] [Full Text] [PDF]

				K.-i. Hirano, C. Ikegami, K.-i. Tsujii, Z. Zhang, F. Matsuura, Y. Nakagawa-Toyama, M. Koseki, D. Masuda, T. Maruyama, I. Shimomura, et al. Probucol Enhances the Expression of Human Hepatic Scavenger Receptor Class B Type I, Possibly Through a Species-Specific Mechanism Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2422 - 2427. [Abstract] [Full Text] [PDF]

				E. Favari, I. Zanotti, F. Zimetti, N. Ronda, F. Bernini, and G. H. Rothblat Probucol Inhibits ABCA1-Mediated Cellular Lipid Efflux Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2345 - 2350. [Abstract] [Full Text] [PDF]

				B. G. Brown, M. C. Cheung, A. C. Lee, X.-Q. Zhao, and A. Chait Antioxidant Vitamins and Lipid Therapy: End of a Long Romance? Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1535 - 1546. [Abstract] [Full Text] [PDF]

				S. Qin, K. Kawano, C. Bruce, M. Lin, C. Bisgaier, A. R. Tall, and X.-c. Jiang Phospholipid transfer protein gene knock-out mice have low high density lipoprotein levels, due to hypercatabolism, and accumulate apoA-IV-rich lamellar lipoproteins J. Lipid Res., February 1, 2000; 41(2): 269 - 276. [Abstract] [Full Text]