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J. Biol. Chem., Vol. 283, Issue 10, 6449-6458, March 7, 2008

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Conversion of Low Density Lipoprotein-associated Phosphatidylcholine to Triacylglycerol by Primary Hepatocytes^*

Carlos Minahk¹, Kyung-Wook Kim, Randy Nelson, Bernardo Trigatti, Richard Lehner^¶2, and Dennis E. Vance³

From the Department of Biochemistry and the Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, and the ^¶Department of Pediatrics, Department of Cell Biology and the Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

We have studied the uptake and metabolism of phosphatidylcholine (PC), the major phospholipid of low density lipoproteins (LDL), by cultures of primary hepatocytes. Strikingly, in the absence of the LDL receptor, PC incorporation into hepatocytes was inhibited by only 30%, whereas cholesteryl ether uptake was inhibited by 60-70%. On the other hand, scavenger receptor class B, type I, the other important receptor for LDL in the liver, was found to be responsible for the uptake of the remaining 30-40% of LDL-cholesteryl ether. PC uptake was, however, only partially inhibited (30%) in scavenger receptor class B, type I, knock-out hepatocytes. Once LDL-PC was taken up by hepatocytes, 50% of LDL-[³H]oleate-PC was converted to triacylglycerol rather than degraded in lysosomes as occurs for LDL-derived cholesteryl esters. The remainder of the LDL-derived PC was not significantly metabolized to other products. Triacylglycerol synthesis from LDL-PC requires a PC-phospholipase C activity as demonstrated by inhibition with the phospholipase C inhibitor D609 or activation with rattlesnake venom. Small interfering RNA-mediated suppression of acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), but not DGAT1, decreased the acylation of the LDL-derived diacylglycerol. These findings show that PC in LDL particles is taken up not only by the classical receptors but also by additional mechanism(s) followed by metabolism that is completely different from the cholesteryl esters or apoB100, the other main components of LDL.

Received for publication, August 21, 2007 , and in revised form, January 5, 2008.

^* This work was supported in part by Canadian Institutes of Health Research Grant MOP-62935 (to D. E. V.) and the Heart and Stroke Foundation of Ontario Grant T5470 (to B. L. T.). 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 Recipient of a postdoctoral fellowship from the Alberta Heritage Foundation for Medical Research.

² Senior Scholar of the Alberta Heritage Foundation for Medical Research.

³ Holder of the Canada Research Chair in Molecular and Cell Biology of Lipids and Scientist of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: 328 HMRC, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-8286; Fax: 780-492-3393; E-mail: dennis.vance{at}ualberta.ca.

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