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Journal of Lipid Research, Vol. 45, 1835-1845, October 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells¹

Shobha H. Ganji^a,b, S. Tavintharan^a,b, Daming Zhu^a,b, Yiding Xing^a,b, Vaijinath S. Kamanna^2,a,b and Moti L. Kashyap^2,3,a,b

^a Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, CA
^b Department of Medicine, University of California, Irvine, CA

³ To whom correspondence should be addressed. e-mail: 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. In this report, using HepG2 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 DGAT activity by 35–50%, and the IC₅₀ was found to be 0.1 mM. Enzyme kinetic studies showed apparent K_m values of 8.3 µM and 100 µM using [¹⁴C]oleoyl-CoA and sn-1,2-dioleoylglycerol as substrates, respectively. A decrease in apparent V_max was observed with niacin, whereas the apparent K_m remained constant. A Lineweaver-Burk plot of DGAT inhibition by niacin showed a noncompetitive type of inhibition. Niacin selectively inhibited DGAT2 but not DGAT1 activity. Niacin inhibited overt DGAT activity. Niacin had no effect on the expression of DGAT1 and DGAT2 mRNA.

These data suggest that niacin directly and noncompetitively 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.

Supplementary key words triglyceride • lipoproteins • hepatocytes • diacylglycerol acyltransferase

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