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J. Biol. Chem., Vol. 281, Issue 6, 3473-3483, February 10, 2006

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Overexpression of Apolipoprotein A-IV Enhances Lipid Secretion in IPEC-1 Cells by Increasing Chylomicron Size^*

Song Lu, Ying Yao, Xiangying Cheng, Sonya Mitchell, Shuangying Leng, Songmei Meng, James W. Gallagher, Gregory S. Shelness, Gabriel S. Morris, James Mahan^¶||, Sharon Frase^**, Charles M. Mansbach^¶||, Richard B. Weinberg, and Dennis D. Black¹

From the Children's Foundation Research Center at Le Bonheur Children's Medical Center and Department of Pediatrics and the ^||Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38103, the Departments of Internal Medicine, Pathology, Physiology, and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, ^¶Veterans Affairs Medical Center, Memphis, Tennessee 38104, and ^**Integrated Microscopy Center, University of Memphis, Memphis, Tennessee 38152

Intestinal apolipoprotein A-IV expression is highly regulated by dietary lipid in newborn swine, suggesting a role in lipid absorption. Constitutive overexpression of apoA-IV in newborn swine enterocytes enhances basolateral secretion of triacylglycerol (TG) in TG-rich lipoproteins 4.9-fold (Lu, S., Yao, Y., Meng, S., Cheng, X., and Black, D. D. (2002) J. Biol. Chem. 277, 31929-31937). To investigate the mechanism of this enhancement, IPEC-1 cells were transfected with a tetracycline-regulatable expression system (Tet-On). In cells incubated with oleic acid, a dose response relationship was observed between medium doxycycline concentration and basolateral apoA-IV and TG secretion. Similarly regulated expression of apoA-I did not enhance lipid secretion. The mean diameter of TG-rich lipoproteins secreted from doxycycline-treated cells was larger than from untreated cells (87.0 nm versus 53.4 nm). Basolateral apoB secretion decreased. Using the same expression system, full-length human apoA-IV (376 amino acids); a "pig-like" human apoA-IV, lacking the C-terminal EQQQ repeats (361 amino acids); and a "chicken-like" apoA-IV, further truncated to 343 amino acids, were expressed in IPEC-1 cells. With increasing protein secretion, cells expressing the full-length human apoA-IV displayed a 2-fold increase in TG secretion; in sharp contrast, cells expressing the pig-like human apoA-IV displayed a 25-fold increase in TG secretion and a 27-fold increase in lipoprotein diameter. When human apoA-IV was further truncated to yield a chicken-like protein, TG secretion was inhibited. We conclude that overexpression of swine apoA-IV enhances basolateral TG secretion in a dose-dependent manner by increasing the size of secreted lipoproteins. These data suggest that the region in the human apoA-IV protein from residues 344 to 354 is critical to its ability to enhance lipid secretion, perhaps by enabling the packaging of additional core TG into chylomicron particles. The EQQQ-rich region may play an inhibitory or modulatory role in chylomicron packaging in humans.

Received for publication, March 7, 2005 , and in revised form, December 6, 2005.

^* This work was supported by National Institutes of Health Grants HL49373 (to G. S. S.), HD22551 (to D. D. B.), DK38760 (to C. M. M.), and HL30897 (to R. B. W.), the Children's Foundation Research Center of Memphis at Le Bonheur Children's Medical Center (to D. D. B), the Office of Research and Development, Medical Research Services, Department of Veterans Affairs (to C. M. M.), and a predoctoral fellowship from the American Heart Association, Mid-Atlantic Affiliate (to J. W. G.). 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: Children's Foundation Research Center of Memphis, Le Bonheur Children's Medical Center, Rm. 401, W. Patient Tower, 50 N. Dunlap, Memphis, TN 38103, Tel.: 901-572-5355; Fax: 901-572-4478; E-mail: dblack{at}utmem.edu.

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