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Journal of Lipid Research, Vol. 43, 1035-1045, July 2002
Copyright © 2002 by Lipid Research, Inc.

Inhibition of phosphatidylcholine synthesis via the phosphatidylethanolamine methylation pathway impairs incorporation of bulk lipids into VLDL in cultured rat hepatocytes

Tomoko Nishimaki-Mogami^1,*, Zemin Yao and Kannosuke Fujimori^*

^* National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan
Lipoprotein and Atherosclerosis Group, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada, K1Y 4W7

¹ To whom correspondence should be addressed. e-mail: mogami{at}nihs.go.jp

Inhibition of phosphatidylcholine (PC) synthesis via the phosphatidylethanolamine (PE) methylation pathway was shown to decrease the secretion of VLDL from primary rat hepatocytes (Nishimaki-Mogami et al. 1996. Biochim. Biophys. Acta. 1304: 21–31). To understand further the role of PE methylation, we determined the effect of bezafibrate, an inhibitor of PE methylation, on VLDL assembly within the microsomal lumen. Bezafibrate was shown to decrease VLDL (triacylglycerol) secretion only when cellular PE methylation was active in the presence of methionine. Pulse-chase experiments showed that bezafibrate treatment did not impair the movement of [³⁵S]apolipoprotein (apo)B-48 from microsomal membranes into the lumen. However, bezafibrate treatment resulted in reduced VLDL-[³⁵S]apoB-48 and increased [³⁵S]apoB-48-containing particles in the HDL density range (HDL-[³⁵S]apoB-48) within the lumen. Inhibition of PE methylation by bezafibrate or 3-deazaadenosine after the completion of HDL-[³⁵S]apoB-48 assembly effectively decreased VLDL-[³⁵S]apoB-48 secretion with a concomitant increase in HDL-[³⁵S]apoB-48 secretion.

These findings suggest that inhibition of PC synthesis via the PE methylation pathway impairs the stage of bulk triacylglycerol incorporation during the assembly of VLDL.

Abbreviations: APMSF, (p-amidinophenyl) methanesulfonyl fluoride-HCl; apo, apolipoprotein; DZA, 3-deazaadenosine; ER, endoplasmic reticulum; HDL-apoB, immunoaffinity purified HDL containing apoB; MTP, microsomal triglyceride transfer protein; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEMT, PE N-methyltransferase; PMME, phosphatidylmonomethylethanolamine; PPAR, peroxisome proliferator-activated receptor; RIPA, radio-immunoprecipitation assay; TG, triacylglycerol; VLDL-apoB, immunoaffinity purified VLDL containing apoB

Supplementary key words bezafibrate • 3-deazaadenosine • apolipoprotein B

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