Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells.

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Ganji SH, Tavintharan S, Zhu D, Xing Y, Kamanna VS, Kashyap ML

Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells.

J Lipid Res. 2004 Oct;45(10):1835-45. Epub 2004 Jul 16.

PubMed ID

15258194 [ View in PubMed

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Abstract

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 IC(50) was found to be 0.1 mM. Enzyme kinetic studies showed apparent K(m) values of 8.3 microM and 100 microM using [(14)C]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.

DrugBank Data that Cites this Article

Drugs

Inositol nicotinate

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Inositol nicotinate	Diacylglycerol O-acyltransferase 2	Protein	Humans	No	Inhibitor	Details