The ACAT2 expression of human leukocytes is responsible for the excretion of lipoproteins containing cholesteryl/steryl esters

Abstract

Acyl-coenzymeA:cholesterol acyltransferase 2 (ACAT2) is abundantly expressed in intestine and fetal liver of healthy human. Our previous studies have shown that in monocytic cells the low-level expression of human ACAT2 gene with specific CpG-hypomethylated promoter is regulated by the CCAAT/enhancer binding protein (C/EBP) transcription factors. In this study, we further report that the ACAT2 gene expression is attributable to the C/EBPs in the human leukocytes and correlated with the excretion of fluorescent lipoproteins containing the ACAT2-catalyzed NBD22-steryl esters. Moreover, this lipoprotein excretion can be inhibited by the ACAT2 isoform-selective inhibitor pyripyropene A (PPPA) in a dose-dependent manner, and employed to determine the half maximum inhibitory concentration (IC 50 ) values of PPPA. Significantly, it is found that the differentiation-inducing factor all-trans retinoic acid, but not the proinflammatory cytokine tumor necrosis factor-α, enhances this ACAT2-dependent lipoprotein excretion. These data demonstrate that the ACAT2 expression of human leukocytes is responsible for the excretion of lipoproteins containing cholesteryl/steryl esters (CE/SE), and suggest that the excretion of lipoproteins containing the ACAT2-catalyzed CS/SE may avoid cytotoxicity through decreasing the excess intracellular cholesterols/sterols (especially various oxysterols), which is essential for the action of the human leukocytes.

Insensitivity to atorvastatin is associated with increased accumulation of intracellular lipid droplets and fatty acid metabolism in breast cancer cells

“…In fact, despite being downregulated by the treatment in all cell lines, ABCA1 expression was still the highest in MDA-MB-231 displaying little or no change in LD content. However, acetyl-CoA acetyltransferase 2 ( ACAT2 ), which is involved in the excretion of lipoproteins containing cholesterol esters from human intestine, fetal liver and leukocytes 35 was found to be selectively upregulated in the less sensitive cells (MCF7, BT474, SKBR3, Fig. 3C ) suggesting the likelihood that attempts to prevent toxic levels of lipid accumulation by increasing efflux channels following statin exposure may still be active in the less sensitive cells.…”

Enhanced acyl-CoA:cholesterol acyltransferase activity increases cholesterol levels on the lipid droplet surface and impairs adipocyte function

“…The cells were grown to desired cell confluency using DMEM supplemented with serum and PSG depending on cell types. Insulin (10 nM) (Sigma-Aldrich), isoproterenol (10 M) (Sigma-Aldrich), mevastatin (10 M) (Sigma-Aldrich), HPCD (1% w/v) (Sigma-Aldrich), Sandoz 58-035 (10 M) (Sigma-Aldrich), and PPPA (10 M) (Cayman Chemical) (60,61) were used in this study. The incubation time for each drug treatment is stated in the figure legends.…”