Abstract
Although in vitro studies suggest a role for sterol carrier protein-2 (SCP-2) in cholesterol trafficking and metabolism, the physiological significance of these observations remains unclear. This issue was addressed by examining the response of mice overexpressing physiologically relevant levels of SCP-2 to a cholesterol-rich diet. While neither SCP-2 overexpression nor cholesterol-rich diet altered food consumption, increased weight gain, hepatic lipid, and bile acid accumulation were observed in wild-type mice fed the cholesterol-rich diet. SCP-2 overexpression further exacerbated hepatic lipid accumulation in cholesterol-fed females (cholesterol/cholesteryl esters) and males (cholesterol/cholesteryl esters and triacyglycerol). Primarily in female mice, hepatic cholesterol accumulation induced by SCP-2 overexpression was associated with increased levels of LDL-receptor, HDL-receptor scavenger receptor-B1 (SR-B1) (as well as PDZK1 and/or membrane-associated protein 17 kDa), SCP-2, liver fatty acid binding protein (L-FABP), and 3alpha-hydroxysteroid dehydrogenase, without alteration of other proteins involved in cholesterol uptake (caveolin), esterification (ACAT2), efflux (ATP binding cassette A-1 receptor, ABCG5/8, and apolipoprotein A1), or oxidation/transport of bile salts (cholesterol 7alpha-hydroxylase, sterol 27alpha-hydroxylase, Na(+)/taurocholate cotransporter, Oatp1a1, and Oatp1a4). The effects of SCP-2 overexpression and cholesterol-rich diet was downregulation of proteins involved in cholesterol transport (L-FABP and SR-B1), cholesterol synthesis (related to sterol regulatory element binding protein 2 and HMG-CoA reductase), and bile acid oxidation/transport (via Oapt1a1, Oatp1a4, and SCP-x). Levels of serum and hepatic bile acids were decreased in cholesterol-fed SCP-2 overexpression mice, especially in females, while the total bile acid pool was minimally affected. Taken together, these findings support an important role for SCP-2 in hepatic cholesterol homeostasis.
Highlights
In vitro studies suggest a role for sterol carrier protein-2 (SCP-2) in cholesterol trafficking and metabolism, the physiological significance of these observations remains unclear
The effects of a cholesterol-rich diet on male and female mice were examined to show that, depending on sex and diet, SCP-2 overexpression significantly i) potentiated the effect of cholesterol on increased body weight gain, especially in female mice; ii) increased hepatic mass and lipid accumulation, more so in females; and iii) increased hepatic expression of proteins involved in cholesterol uptake and intracellular trafficking, especially those proteins involved in the reverse cholesterol transport (RCT) pathway. These results indicate a significant role for SCP-2 in hepatic cholesterol metabolism
SCP-2 is a ubiquitous protein expressed in all mammalian tissues but at highest levels in tissues active in cholesterol metabolism, including liver, steroidogenic cells, and intestine
Summary
In vitro studies suggest a role for sterol carrier protein-2 (SCP-2) in cholesterol trafficking and metabolism, the physiological significance of these observations remains unclear This issue was addressed by examining the response of mice overexpressing physiologically relevant levels of SCP-2 to a cholesterol-rich diet. While the ability of cytoplasmic cholesterol binding protein(s), such as sterol carrier protein-2 (SCP-2), to facilitate cholesterol uptake and transhepatocyte transfer has been shown, this work was undertaken to study the process of cholesterol homeostasis in transgenic mice stably overexpressing physiologically relevant levels of SCP-2 in response to a cholesterol-rich diet. SCP-2 overexpression enhanced cholesterol uptake, stimulated cholesterol intracellular retention by increasing esterification and decreasing efflux, facilitated intracellular cholesterol cycling, and altered the properties of plasma membrane lipid cholesterol-rich microdomains wherein the SR-B1 and several ABC transporters are localized SCP-2 overexpression enhanced cholesterol uptake, stimulated cholesterol intracellular retention by increasing esterification and decreasing efflux, facilitated intracellular cholesterol cycling, and altered the properties of plasma membrane lipid cholesterol-rich microdomains wherein the SR-B1 and several ABC transporters are localized (reviewed in Refs. 8, 15, and 18)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
