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标题：Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells
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作者：Shobha H. Ganji ; S. Tavintharan ; Daming Zhu 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2004
卷号：45
期号：10
页码：1835-1845
DOI：10.1194/jlr.M300403-JLR200
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：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.