Niacin accelerates intracellular ApoB degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (HepG2) cells.
The mechanism by which the potent drug niacin decreases apoB-containing atherogenic lipoproteins and prevents coronary disease is unclear. Utilizing human hepatoblastoma (HepG2) cells as an in vitro model, we have examined the effect of niacin on intracellular degradation of apoB and the regulatory mechanisms involved in apoB processing. Niacin significantly increased apoB degradation in a dose- and time-dependent manner. Treatment of HepG2 cells with calpain inhibitor I [N-acetyl-leucyl-leucyl-norleucinal (ALLN), an inhibitor of certain protease-mediated apoB degradation], did not alter niacin-induced apoB degradation. Niacin decreased inhibition of oleate-mediated apoB degradation. Niacin dose-dependently inhibited the synthesis of both fatty acids and triacylglycerol (TG) by 20% to 40% as determined by the incorporation of 14C-acetate and 3H-glycerol into fatty acids and TG, respectively. Incubation of HepG2 cells with niacin significantly inhibited (by 12% to 15%) fatty acid esterification to produce TG as assessed by the incorporation of 3H-oleic acid into TG. 14C-acetate incorporation into cholesterol and phospholipids was unchanged. The activity of microsomal triglyceride transfer protein (MTP), a carrier protein for lipids, was not altered by pretreatment of cells with niacin. ApoB mRNA expression and 125I-LDL protein uptake were also unchanged. These data indicate that niacin accelerates hepatic intracellular post-translational degradation of apoB by selectively reducing triglyceride synthesis (through inhibiting both fatty acid synthesis and fatty acid esterification to produce TG) without affecting ALLN-inhibitable protease- or MTP-mediated intracellular apoB processing, resulting in decreased apoB secretion and hence lower circulating levels of the atherogenic lipoproteins.
Jin
F Y
FY
Cholesterol Center, Medical Service, Department of Veterans Affairs Medical Center, Long Beach, CA, USA.
Kamanna
V S
VS
Kashyap
M L
ML
D001055:Apolipoproteins B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018197:Hepatoblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D009525:Niacin / Q000494:pharmacology*; D014280:Triglycerides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D001055:Apolipoproteins B; D014280:Triglycerides; D009525:Niacin