Overexpression of sterol carrier protein-2 differentially alters hepatic cholesterol accumulation in cholesterol-fed mice.
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.
Atshaves
Barbara P
BP
Department of Physiology and Pharmacology, Texas A&M University, Texas Veterinary Medical Center, College Station, TX 77843-4466, USA.
McIntosh
Avery L
AL
Martin
Gregory G
GG
Landrock
Danilo
D
Payne
H Ross
HR
Bhuvanendran
Shivaprasad
S
Landrock
Kerstin K
KK
Lyuksyutova
Olga I
OI
Johnson
Jeffery D
JD
Macfarlane
Ronald D
RD
Kier
Ann B
AB
Schroeder
Friedhelm
F
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism; D001835:Body Weight; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000008:administration & dosage / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D002791:Cholesterol, Dietary; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010743:Phospholipids / Q000097:blood; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D051242:Caveolin 1; D002791:Cholesterol, Dietary; C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D008055:Lipids; D027361:Organic Anion Transporters; D010743:Phospholipids; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C072087:sterol carrier proteins; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse