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

This Article Full Text Full Text (PDF) All Versions of this Article: M800248-JLR200v1 49/9/2038    most recent Alert me when this article is cited 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 Minehira, K. Articles by Tappy, L. Search for Related Content PubMed PubMed Citation Articles by Minehira, K. Articles by Tappy, L. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 49, 2038-2044, September 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice

Kaori Minehira^1,*,, Stephen G. Young, Claudio J. Villanueva^*, Laxman Yetukuri, Matej Oresic, Mark K. Hellerstein^**, Robert V. Farese, Jr.^*, Jay D. Horton, Frederic Preitner, Bernard Thorens and Luc Tappy

^* Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158
Department of Medicine, University of California, Los Angeles, CA 90095
VTT Technical Research Centre of Finland, Tietotie 2, FIN-02044, Espoo, Finland
^** Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390
Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland

Published, JLR Papers in Press, June 1, 2008.

This work was supported by the Swiss National Science Foundation, by a fellowship award from the American Heart Association, Western States Affiliate, and by l'association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques (ALFEDIAM).

¹ To whom correspondence should be addressed. e-mail: kaori.minehira{at}unil.ch

The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity.

Supplementary key words microsomal triglyceride transfer protein • triglyceride-rich lipoprotein • fatty liver • insulin resistance • obesity • de novo lipogenesis • ceramide • diacylglycerol

Abbreviations: apo, apolipoprotein; DGAT2, acyl-CoA:diacylglycerol acyltransferase 2; FPLC, fast protein liquid chromatography; Mttp, the gene for microsomal triglyceride transfer protein; PEPCK, phosphoenolpyruvate carboxykinase; pI-pC, polyinosinic-polycytidylic ribonucleic acid

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

This article has been cited by other articles:

				E. Xu, M.-J. Dubois, N. Leung, A. Charbonneau, C. Turbide, R. K. Avramoglu, L. DeMarte, M. Elchebly, T. Streichert, E. Levy, et al. Targeted Disruption of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Promotes Diet-Induced Hepatic Steatosis and Insulin Resistance Endocrinology, August 1, 2009; 150(8): 3503 - 3512. [Abstract] [Full Text] [PDF]

				A. Grefhorst and E. J. Parks Reduced insulin-mediated inhibition of VLDL secretion upon pharmacological activation of the liver X receptor in mice J. Lipid Res., July 1, 2009; 50(7): 1374 - 1383. [Abstract] [Full Text] [PDF]

				C. A. Nagle, E. L. Klett, and R. A. Coleman Hepatic triacylglycerol accumulation and insulin resistance J. Lipid Res., April 1, 2009; 50(Supplement): S74 - S79. [Abstract] [Full Text] [PDF]