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Papers In Press, published online ahead of print July 16, 2004
J. Lipid Res., doi:10.1194/jlr.M300403-JLR200
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Department of Atherosclerosis Research Center, University of California, Irvine, Long Beach, CA 90822
Corresponding Author: moti.kashyap{at}med.va.gov
Niacin is a widely used lipid regulating agent in dyslipidemic patients. Previously, we have shown that niacin inhibits triacylglycerol synthesis from fatty acids and glycerol. In this report, using Hep G2 cells, we have examined the effect of niacin on the mRNA expression and microsomal activity of diacylglycerol acyltransferase 1 and 2 (DGAT1 and DGAT2), the last committed but distinctly different enzymes for triglyceride synthesis. Addition of niacin to the DGAT assay reaction mixture dose-dependently (0-3 mM) inhibited microsomal DGAT activity by 35-50%, and the IC50 was found to be 0.1 mM . Enzyme kinetic studies showed a Km value of 8.3 mM and 100 mM using [14C]oleoyl CoA and dioleoyl sn-glycerol as a substrates respectively. The nature of DGAT inhibition by niacin was assessed by measuring the reaction velocity of DGAT at varied oleoyl CoA or dioleoyl sn-glycerol concentrations. A decrease in Vmax was observed with niacin while the Km remained constant. Lineweaver Burk plot of DGAT inhibition by niacin showed a non-competitive type of inhibition. Examination of DGAT1 and DGAT2 showed that niacin selectively inhibited DGAT2 but not DGAT1 activity. Additionally, niacin inhibited overt DGAT activity. Semi-quantitative reverse transcriptase-polymerase chain reaction showed no significant changes in the expression of DGAT1 and DGAT2 mRNA levels by niacin. These data suggest that niacin directly and non-competitively inhibits DGAT2 but not DGAT1, resulting in decreased triglyceride synthesis and hepatic atherogenic lipoprotein secretion, thus indicating a major target site for its mechanism of action.
Revised on July 6, 2004
Accepted on July 16, 2004
Niacin non-competitively inhibits diacylglycerol acyltransferase-2 (DGAT2) but not DGAT1 activity in HepG2 cells
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