Regulation of bile-acid synthesis. Role of sterol carrier protein2 in the biosynthesis of 7α-hydroxycholesterol

Abstract

Sterol carrier protein2 (SCP2) is known to stimulate utilization of cholesterol in enzymic reactions in which cholesterol is the substrate. Substantial recent experimental evidence indicates that SCP2: activates enzymic conversion of intermediates between lanosterol and cholesterol; stimulates the microsomal conversion of cholesterol into cholesterol ester in rat liver; and enhances mitochondrial utilization of cholesterol for pregnenolone formation in the adrenals. The conversion of cholesterol into 7 alpha-hydroxycholesterol is the rate-limiting step in bile-acid synthesis. We therefore investigated the effect of SCP2 on this physiologically critical reaction by using a gas-chromatography-mass-spectrometry procedure that measures the mass of 7 alpha-hydroxycholesterol formed. The results show that SCP2 enhances 7 alpha-hydroxycholesterol formation by rat liver microsomes (microsomal fractions), utilizing either endogenous membrane cholesterol, cholesterol supplied exogenously in serum or in the form of cholesterol/phospholipid liposomes. Microsomes immunotitrated with anti-SCP2 antibody exhibited considerably less capacity to synthesize 7 alpha-hydroxycholesterol, which was restored to control levels on addition of purified SCP2. These data are consistent with the suggestion that SCP2 may be of physiological significance in the overall metabolism of cholesterol.

Increased bile lithogenicity by SCP2 via HMGCR and CYP7A1 regulation in human hepatocytes

“…Animal experiments confirm that SCP2 plays an essential role in the transportation of newly synthesized cholesterol into bile, and that SCP2 can rapidly transfer cholesterol from the endoplasmic reticulum directly into the bile without the involvement of the cellular microtubule system and the Golgi (22). Fuchs et al (14,23) observed the phenomenon in the stone-susceptible mice, and noted that the SCP2 protein and mRNA levels rose at the same time and concluded that the transcriptional upregulation of SCP2 led to the higher levels of SCP2 in hepatocytes, thus increasing bile cholesterol and promoting gallstone formation.…”

“…In its role as a transporter, this protein participates in the transportation of cholesterol inside the cell and through the cytoplasm membrane, (8,9) as well as in the rapid transportation of newly synthesized cholesterol from the endoplasmic reticulum into bile without the intervention of the cytomicrotubule system and Golgi bodies (10). Additionally, some researchers indicate that it may have a role in the biosynthesis of cholesterol, (11)(12)(13) and in the transformation of cholesterol to bile acids (14,15), cholesterol esters (16) and sterols (17). Our former findings indicated that SCP2 was overexpressed in patients with hereditary cholesterol gallstones when compared to patients with non-hereditary cholesterol gallstones, and that SCP2 may be a potential genetic factor that contributes to the formation of cholesterol gallstones (18).…”

Shape and lipid-binding site of the nonspecific lipid-transfer protein (sterol carrier protein 2): A steady-state and time-resolved fluorescence study

“…NsL-TP stimulates, in vitro Van Amerongen et al, 1989), phospholipids (Crain & Zilversmit, 1980; Nichols, 1988; Van Amerongen et al, 1989), sphingomyelin (Crain & Zilversmit, 1980), gangliosides (Bloj & Zilversmit, 1981), and neutral glycosphingolipids (Bloj & Zilversmit, 1981). As a consequence of nsL-TP-mediated transfer of cholesterol, nsL-TP was shown to stimulate microsomal conversion of (Seltman et al, 1985;Lidstrom-Olssen & Wikvall, 1986), and steroid hormone synthesis (Chanderbhan et al, 1982; Vahouny et al, 1983; Van Noort et al, 1986, 1988a. Although many studies have focused on the role of nsL-TP in lipid metabolism, the exact mechanism by which nsL-TP mediates the transfer of cholesterol and of phospholipids is not yet fully understood.…”

Molecular cloning and deduced amino acid sequence of nonspecific lipid transfer protein (sterol carrier protein 2) of rat liver: a higher molecular mass (60 kDa) protein contains the primary sequence of nonspecific lipid transfer protein as its C-terminal part.

“…1). This protein, identical to sterol carrier protein 2 (SCP2), stimulates the enzymatic conversion of lanosterol to cholesterol during the biosynthesis of cholesterol and enhances the synthesis of bile acids (2,3). It has recently been shown that nsLTP, first thought to be a cytosolic protein (4), is localized mostly in peroxisomes, where it is concentrated in the matrix (5-7), in both rat liver and adrenal gland.…”