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J. Biol. Chem., Vol. 281, Issue 7, 4075-4086, February 17, 2006

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Compensatory Increase in Hepatic Lipogenesis in Mice with Conditional Intestine-specific Mttp Deficiency^*

Yan Xie, Elizabeth P. Newberry, Stephen G. Young, Sylvie Robine^¶1, Robert L. Hamilton^||, Jinny S. Wong^||, Jianyang Luo, Susan Kennedy, and Nicholas O. Davidson^**2

From the Division of Gastroenterology, Department of Medicine, and the ^**Department of Pharmacology and Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110, the Department of Medicine, University of California, Los Angeles, California 90095, the ^¶Institut Curie, 25 rue d'Ulm, 75248 Paris Cedex 05, France, and the ^||Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, California 94143

Microsomal TG transfer protein (MTTP) is required for the assembly and secretion of TG (TG)-rich lipoproteins from both enterocytes and hepatocytes. Liver-specific deletion of Mttp produced a dramatic reduction in plasma very low density lipoprotein-TG and virtually eliminated apolipoprotein B100 (apoB100) secretion yet caused only modest reductions in plasma apoB48 and apoB48 secretion from primary hepatocytes. These observations prompted us to examine the phenotype following intestine-specific Mttp deletion because murine, like human enterocytes, secrete virtually exclusively apoB48. We generated mice with conditional Mttp deletion in villus enterocytes (Mttp-IKO), using a tamoxifen-inducible, intestine-specific Cre transgene. Villus enterocytes from chow-fed Mttp-IKO mice contained large cytoplasmic TG droplets and no chylomicron-sized particles within the secretory pathway. Chow-fed, Mttp-IKO mice manifested steatorrhea, growth arrest, and decreased cholesterol absorption, features that collectively recapitulate the phenotype associated with abetalipoproteinemia. Chylomicron secretion was reduced dramatically in vivo, in conjunction with an 80% decrease in apoB48 secretion from primary enterocytes. Additionally, although plasma and hepatic cholesterol and TG content were decreased, Mttp-IKO mice demonstrated a paradoxical increase in both hepatic lipogenesis and very low density lipoprotein secretion. These findings establish distinctive features for MTTP involvement in intestinal chylomicron assembly and secretion and suggest that hepatic lipogenesis undergoes compensatory induction in the face of defective intestinal TG secretion.

Received for publication, September 28, 2005 , and in revised form, November 15, 2005.

^* This work was supported in part by National Institutes of Health Grants HL-38180, DK-56260, and DDRCC DK-52574 (to N. O. D.) and CA103999, CA099506, and AR050200 (to S. G. Y.). The electron microscopic work was funded by University of California Tobacco-related Diseases Grant 9RT-0227 (to R. L. H.). 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.

¹ Supported by the Association pour la Recherche sur le Cancer and Biologie du development et physiologie integrative.

² To whom correspondence should be addressed: Box 8124, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail: nod{at}wustl.edu.

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