SCP2 adenovirus

Although high-density lipoprotein (HDL)-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into bile, the fate of HDL-associated cholesterol esters (HDL-CE), which account for more than 80% of HDL-cholesterol (HDL-cholesterol), is only beginning to be understood. Here, researchers tested the hypothesis that intracellular cholesterol transporters [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 (FABP1)] not only facilitate CE hydrolase-mediated hydrolysis of HDL-CE but also enhance cholesterol clearance into bile. Adenovirus-mediated overexpression of FABP1 or SCP2 in primary hepatocytes significantly increased the hydrolysis of HDL-[³H]CE, reduced the resecretion of HDL-CE-derived FC as nascent HDL, and increased its secretion as bile acids. Consistently, in vivo overexpression of SCP2 or FABP1 increased the flux of [³H]cholesterol from HDL-[³H]CE to bile acids, whereas this was reduced in SCP2-/- mice. Increased flux of HDL-[³H]CE to bile bile acids was observed in both FABP1 overexpressing and SCP2-/- mice with increased FABP1 expression. In FABP1-/- mice, flux of HDL-[³H]CE to bile bile acids or bile acids was not significantly reduced, suggesting that its function may be compensated by an as yet undetermined mechanism. These studies suggest that FABP1 and SCP2 promote the preferential transport of HDL-CE to bile and its eventual elimination.

Previously, the laboratory-identified hepatocyte CEH binds to CE delivered to hepatocytes by HDL and catalyzes the hydrolysis of HDL-CE. In addition, the expression of SR-BI is essential for this process, and the CEH-dependent increase in HDL-CE hydrolysis is attenuated in SR-BI-/- mice or hepatocytes. Because product accumulation inhibits CEH activity, effective removal of the product (i.e., unesterified or FC) is a prerequisite for sustained hydrolysis. The researchers speculated that intracellular FC-binding proteins may promote the removal of FC, thereby enhancing CEH-mediated HDL-CE hydrolysis. Adenovirus-mediated overexpression of human SCP2 or FABP1 consistently enhanced the hydrolysis of HDL-CE in primary mouse hepatocytes (Figure 1). Of note, fold increases in SCP2 or FABP1 expression could not be calculated because species-specific TaqMan assays were used, and no Ct values were obtained in control Ad-LacZ-transduced mouse hepatocytes, whereas Ct values for hepatocytes transduced with human Ad-SCP2 or Ad-FABP1 viruses ranged from 23 to 25, indicating increased expression.

Figure 1. Overexpression of FABP1 and SCP2 increases intracellular hydrolysis of HDL-CE. (Wang J, et al., 2016)