HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 22, 22913-22925, May 28, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/22/22913    most recent M402838200v2 M402838200v1 Submit a Letter to Editor 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 Wu, J. E. Articles by Santamarina-Fojo, S. Search for Related Content PubMed PubMed Citation Articles by Wu, J. E. Articles by Santamarina-Fojo, S. Social Bookmarking                      What's this?

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice^*

Justina E. Wu, Federica Basso, Robert D. Shamburek, Marcelo J. A. Amar, Boris Vaisman, Gergely Szakacs, Charles Joyce, Terese Tansey, Lita Freeman, Beverly J. Paigen¶, Fairwell Thomas, H. Bryan Brewer, Jr., and Silvia Santamarina-Fojo||

From the Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the ^¶Jackson Laboratory, Bar Harbor, Maine 04609

The individual roles of hepatic versus intestinal ABCG5 and ABCG8 in sterol transport have not yet been investigated. To determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we generated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5/G8-Tg) in three different genetic backgrounds: C57Bl/6, apoE-KO, and low density lipoprotein receptor (LDLr)-KO. Hepatic overexpression of ABCG5/G8 enhanced hepatobiliary secretion of cholesterol and plant sterols by 1.5–2-fold, increased the amount of intestinal cholesterol available for absorption and fecal excretion by up to 27%, and decreased the accumulation of plant sterols in plasma by 25%. However, it did not alter fractional intestinal cholesterol absorption, fecal neutral sterol excretion, hepatic cholesterol concentrations, or hepatic cholesterol synthesis. Consequently, overexpression of ABCG5/G8 in only the liver had no effect on the plasma lipid profile, including cholesterol, HDL-C, and non-HDL-C, or on the development of proximal aortic atherosclerosis in C57Bl/6, apoE-KO, or LDLr-KO mice. Thus, liver ABCG5/G8 facilitate the secretion of liver sterols into bile and serve as an alternative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of dietary plant sterols in plasma. However, in the absence of changes in fractional intestinal cholesterol absorption, increased secretion of sterols into bile induced by hepatic overexpression of ABCG5/G8 was not sufficient to alter hepatic cholesterol balance, enhance cholesterol removal from the body or to alter atherogenic risk in liver G5/G8-Tg mice. These findings demonstrate that overexpression of ABCG5/G8 in the liver profoundly alters hepatic but not intestinal sterol transport, identifying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism.

Received for publication, March 12, 2004 , and in revised form, March 24, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: MDB, NHLBI, National Institutes of Health, Bldg. 10, Rm. 7N115, Bethesda, MD 20892. Tel.: 301-496-5095; Fax: 301-402-0190; E-mail: silvia{at}mdb.nhlbi.nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. Shelly, L. Royer, T. Sand, H. Jensen, and Y. Luo Phospholipid transfer protein deficiency ameliorates diet-induced hypercholesterolemia and inflammation in mice J. Lipid Res., April 1, 2008; 49(4): 773 - 781. [Abstract] [Full Text] [PDF]

				R. Callaghan, E. Crowley, S. Potter, and I. D. Kerr P-glycoprotein: So Many Ways to Turn It On J. Clin. Pharmacol., March 1, 2008; 48(3): 365 - 378. [Abstract] [Full Text] [PDF]

				F. Basso, L. A. Freeman, C. Ko, C. Joyce, M. J. Amar, R. D. Shamburek, T. Tansey, F. Thomas, J. Wu, B. Paigen, et al. Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited J. Lipid Res., January 1, 2007; 48(1): 114 - 126. [Abstract] [Full Text] [PDF]

				C. W. Joyce, E. M. Wagner, F. Basso, M. J. Amar, L. A. Freeman, R. D. Shamburek, C. L. Knapper, J. Syed, J. Wu, B. L. Vaisman, et al. ABCA1 Overexpression in the Liver of LDLr-KO Mice Leads to Accumulation of Pro-atherogenic Lipoproteins and Enhanced Atherosclerosis J. Biol. Chem., November 3, 2006; 281(44): 33053 - 33065. [Abstract] [Full Text] [PDF]

				B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]