Fy. Jin et al., Niacin accelerates intracellular apoB degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (HepG2) cells, ART THROM V, 19(4), 1999, pp. 1051-1059
The mechanism by which the potent drug niacin decreases apoB-containing ath
erogenic lipoproteins and prevents coronary disease is unclear. Utilizing h
uman hepatoblastoma (HepG2) cells as an in vitro model, we have examined th
e 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 in
hibitor of certain protease-mediated apoB degradation], did not alter niaci
n-induced apoB degradation. Niacin decreased inhibition of oleate-mediated
apoB degradation. Niacin dose-dependently inhibited the synthesis of both f
atty acids and triacylglycerol (TG) by 20% to 40% as determined by the inco
rporation of C-14-acetate and H-3-glycerol into fatty acids and TC, respect
ively. Incubation of HepG2 cells with niacin significantly inhibited (by 12
% to 15%) fatty acid esterification to produce TG as assessed by the incorp
oration of H-3-oleic acid into TG. C-14-acetate incorporation into choleste
rol and phospholipids was unchanged. The activity of microsomal triglycerid
e transfer protein (MTP), a carrier protein for lipids, was not altered by
pretreatment of cells with niacin. ApoB mRNA expression and I-125-LDL prote
in 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 synthe
sis and fatty acid esterification to produce TG) without affecting ALLN-inh
ibitable protease- or MTP-mediated intracellular apoB processing, resulting
in decreased apoB secretion and hence lower circulating levels of the athe
rogenic lipoproteins.