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J. Biol. Chem., Vol. 279, Issue 43, 44938-44944, October 22, 2004

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Overexpression of Human Diacylglycerol Acyltransferase 1, Acyl-CoA:Cholesterol Acyltransferase 1, or Acyl-CoA:Cholesterol Acyltransferase 2 Stimulates Secretion of Apolipoprotein B-containing Lipoproteins in McA-RH7777 Cells^*

John J. Liang, Peter Oelkers¶, Cuiying Guo, Pi-Chun Chu, Joseph L. Dixon||**, Henry N. Ginsberg, and Stephen L. Sturley¶¶

From the Departments of Medicine, Pediatrics, and the Institute of Human Nutrition, Columbia University Medical Center, New York, New York 10032 and the ^||Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri

The relative importance of each core lipid in the assembly and secretion of very low density lipoproteins (VLDL) has been of interest over the past decade. The isolation of genes encoding diacylglycerol acyltransferase (DGAT) and acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) provided the opportunity to investigate the effects of isolated increases in triglycerides (TG) or cholesteryl esters (CE) on apolipoprotein B (apoB) lipoprotein biogenesis. Overexpression of human DGAT1 in rat hepatoma McA-RH7777 cells resulted in increased synthesis, cellular accumulation, and secretion of TG. These effects were associated with decreased intracellular degradation and increased secretion of newly synthesized apoB as VLDL. Similarly, overexpression of human ACAT1 or ACAT2 in McA-RH7777 cells resulted in increased synthesis, cellular accumulation, and secretion of CE. This led to decreased intracellular degradation and increased secretion of VLDL apoB. Overexpression of ACAT2 had a significantly greater impact upon assembly and secretion of VLDL from liver cells than did overexpression of ACAT1. The addition of oleic acid (OA) to media resulted in a further increase in VLDL secretion from cells expressing DGAT1, ACAT1, or ACAT2. VLDL secreted from DGAT1-expressing cells incubated in OA had a higher TG:CE ratio than VLDL secreted from ACAT1- and ACAT2-expressing cells treated with OA. These studies indicate that increasing DGAT1, ACAT1, or ACAT2 expression in McA-RH7777 cells stimulates the assembly and secretion of VLDL from liver cells and that the core composition of the secreted VLDL reflects the enzymatic activity that is elevated.

Received for publication, July 27, 2004

^* This work was supported by National Institutes of Health Grants HL 55368 (to H. N. G.), T32HL07343 (to H. N. G), DK54320 (to S. L. S.), and HL-47586 (to J. L. D.) and by a grant-in-aid and Established Investigator award from American Heart Association (to S. L. S.). 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.

^¶ Present address: Dept. of Bioscience and Biotechnology, Drexel University, 3141 Chestnut St., Philadelphia, PA 19104.

^** Present address: Dept. of Nutritional Sciences, Rutgers, The State University of New Jersey, 96 Lipman Dr., New Brunswick, NJ 08901-8525.

To whom correspondence may be addressed: Dept. of Medicine, Columbia University, 630 W. 168th St., New York, NY 10032. E-mail: hng1{at}columbia.edu. ¶¶ To whom correspondence may be addressed: Dept. of Pediatrics, Columbia University, 630 W. 168th St., New York, NY 10032. E-mail: sls37{at}columbia.edu.

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