Disruption of the Sterol Carrier Protein 2 Gene in Mice Impairs Biliary Lipid and Hepatic Cholesterol Metabolism

Abstract

Hepatic up-regulation of sterol carrier protein 2 (Scp2) in mice promotes hypersecretion of cholesterol into bile and gallstone formation in response to a lithogenic diet. We hypothesized that Scp2 deficiency may alter biliary lipid secretion and hepatic cholesterol metabolism. Male gallstone-susceptible C57BL/6 and C57BL/6 Scp2(؊⁄؊) knockout mice were fed a standard chow or lithogenic diet. Hepatic biles were collected to determine biliary lipid secretion rates, bile flow, and bile salt pool size. Plasma lipoprotein distribution was investigated, and gene expression of cytosolic lipidbinding proteins, lipoprotein receptors, hepatic regulatory enzymes, and intestinal cholesterol absorption was measured. Compared with chow-fed wild-type animals, C57BL/6 Scp2(؊⁄؊) mice had higher bile flow and lower bile salt secretion rates, decreased hepatic apolipoprotein expression, increased hepatic cholesterol synthesis, and up-regulation of liver fatty acid-binding protein. In addition, the bile salt pool size was reduced and intestinal cholesterol absorption was unaltered in C57BL/6 Scp2(؊⁄؊) mice. When C57BL/6Scp2(؊⁄؊) mice were challenged with a lithogenic diet, a smaller increase of hepatic free cholesterol failed to suppress cholesterol synthesis and biliary cholesterol secretion increased to a much smaller extent than phospholipid and bile salt secretion. Scp2 deficiency did not prevent gallstone formation and may be compensated in part by hepatic up-regulation of liver fatty acid-binding protein. These results support a role of Scp2 in hepatic cholesterol metabolism, biliary lipid secretion, and intracellular cholesterol distribution.Cholesterol gallstone disease is characterized by a perturbation of the physical-chemical balance of cholesterol solubility in bile with an unphysiological cholesterol saturation. Hypersecretion of unesterified cholesterol into bile appears to represent the key molecular mechanism in the gallstone-susceptible C57L/J mouse (1, 2) and in humans (3). The plasma membrane contains up to 90% of total cell cholesterol (4), which implies that sterol trafficking in the cell is tightly controlled. Efforts to elucidate the complex molecular mechanisms of intracellular cholesterol transport suggested the contribution of vesicles (5) and carrier proteins such as sterol carrier protein 2 (Scp2) 1 (6) and the Niemann Pick type C1 (Npc1) protein (7).Scp2 is a soluble lipid transfer protein, which is capable of cholesterol transport in vitro (6,8,9). Although localized predominantly to peroxisomes, substantial amounts of Scp2 are present in cytosol (10, 11), suggesting that Scp2 may be involved in intracellular cholesterol transport in vivo. Indeed, several lines of evidence support this notion: (i) Scp2 antisense treatment of rats reduced and delayed biliary cholesterol secretion (6); (ii) diosgenin-induced hypersecretion of cholesterol into bile in rats was associated with increased hepatic Scp2 expression (6); (iii) adenovirus-mediated overexpression of Scp2 in mice led to increased biliary cholestero...

Decreased Liver Fatty Acid Binding Capacity and Altered Liver Lipid Distribution in Mice Lacking the Liver Fatty Acid-binding Protein Gene

“…Overexpression of SCP-2 in L cells inhibited cholesterol efflux and increased the intracellular cholesterol pool (53), and adenoviral overexpression of SCP-2 was previously found to increase hepatic cholesterol contents (54). Conversely, liver cholesterol ester levels are reduced by 50% in SCP-2/SCP-x null mice (49) along with hypersecretion of cholesterol in bile (17,50,51). The findings in the latter two models are especially relevant, because they were obtained in vivo, although at least the second model (SCP null mice) is complicated by the concomitant alteration of L-FABP gene expression (49) mentioned above.…”

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

“…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).…”

A New N-Terminal Recognition Domain in Caveolin-1 Interacts with Sterol Carrier Protein-2 (SCP-2)

“…At least three cholesterol binding proteins may be involved in protein-mediated cholesterol trafficking through the cytoplasm: caveolin-1, sterol carrier protein-2 (SCP-2), and liver fatty acid binding protein (L-FABP) (4,35,36). Bidirectional flux of free cholesterol and unidirectional uptake of cholesterol ester is thought to be mediated by cytoplasmic transport complexes of caveolin-1, cholesterol (or cholesterol ester), and one or more chaperone proteins (cyclophilin A, cyclophilin 40, heat shock protein 56, and/or annexin II).…”