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J. Biol. Chem., Vol. 282, Issue 45, 33043-33051, November 9, 2007

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Conditional Intestinal Lipotoxicity in Apobec-1^-/- Mttp-IKO Mice

A SURVIVAL ADVANTAGE FOR MAMMALIAN INTESTINAL APOLIPOPROTEIN B mRNA EDITING^*

Yan Xie, Jianyang Luo, Susan Kennedy, and Nicholas O. Davidson¹

From the Departments of Medicine and Pharmacology and Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110

Mammalian small intestinal lipid absorption requires the coordinated interactions of apolipoprotein B (apoB) and the microsomal triglyceride transfer protein (Mttp). The observation that apoB100 displays greater dependence on Mttp availability than does apoB48 prompted us to examine the phenotype of Mttp deletion in an Apobec-1^-/- background (i.e. apoB100 Mttp-IKO). 20% apoB100 Mttp-IKO mice died on a chow diet, and >90% died following high fat feeding (versus 0 and 11% apoB48 Mttp-IKO mice, respectively). Intestinal adaptation occurred in apoB48 Mttp-IKO mice in response to high fat feeding, evidenced by increased bromodeoxyuridine incorporation and villus lengthening, changes that did not occur in apoB100 Mttp-IKO mice. There was an exaggerated unfolded protein response (UPR), which became more pronounced in apoB100 Mttp-IKO mice. To examine the role of endoplasmic reticulum stress and the UPR in the lipotoxic effects of Mttp deletion, we administered tauroursodeoxycholate to apoB100 Mttp-IKO mice upon initiation of high fat feeding. Tauroursodeoxycholate administration abrogated the UPR but produced an unexpected acceleration in the onset of lethality in apoB100 Mttp-IKO mice. The findings demonstrate that there is activation of the UPR with lethal lipotoxicity in conditional intestinal apoB100 Mttp-IKO mice. Together the data provide the first plausible biological evidence for a survival advantage for mammalian intestinal apoB mRNA editing.

Received for publication, June 29, 2007 , and in revised form, September 4, 2007.

^* This work was supported by National Institutes of Health Grants HL-38180 and DK-56260 (to N. O. D.) and by Digestive Disease Research Core Grant DK-52574, particularly the morphology core. 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 To whom correspondence should be addressed: GI Division, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110. Tel.: 314-362-2027; Fax: 314-362-2033; E-mail: nod{at}wustl.edu.

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				Z. Chen, E. P. Newberry, J. Y. Norris, Y. Xie, J. Luo, S. M. Kennedy, and N. O. Davidson ApoB100 is required for increased VLDL-triglyceride secretion by microsomal triglyceride transfer protein in ob/ob mice J. Lipid Res., September 1, 2008; 49(9): 2013 - 2022. [Abstract] [Full Text] [PDF]