title: Impact of SCP-2/SCP-x gene ablation and dietary cholesterol on hepatic lipid accumulation.
abstract: While a high-cholesterol diet induces hepatic steatosis, the role of intracellular sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) proteins is unknown. We hypothesized that ablating SCP-2/SCP-x [double knockout (DKO)] would impact hepatic lipids (cholesterol and cholesteryl ester), especially in high-cholesterol-fed mice. DKO did not alter food consumption, and body weight (BW) gain decreased especially in females, concomitant with hepatic steatosis in females and less so in males. DKO-induced steatosis in control-fed wild-type (WT) mice was associated with 1) loss of SCP-2; 2) upregulation of liver fatty acid binding protein (L-FABP); 3) increased mRNA and/or protein levels of sterol regulatory element binding proteins (SREBP1 and SREBP2) as well as increased expression of target genes of cholesterol synthesis (Hmgcs1 and Hmgcr) and fatty acid synthesis (Acc1 and Fas); and 4) cholesteryl ester accumulation was also associated with increased acyl-CoA cholesterol acyltransferase-2 (ACAT2) in males. DKO exacerbated the high-cholesterol diet-induced hepatic cholesterol and glyceride accumulation, without further increasing SREBP1, SREBP2, or target genes. This exacerbation was associated both with loss of SCP-2 and concomitant downregulation of Ceh/Hsl, apolipoprotein B (ApoB), MTP, and/or L-FABP protein expression. DKO diminished the ability to secrete excess cholesterol into bile and oxidize cholesterol to bile acid for biliary excretion, especially in females. This suggested that SCP-2/SCP-x affects cholesterol transport to particular intracellular compartments, with ablation resulting in less to the endoplasmic reticulum for SREBP regulation, making more available for cholesteryl ester synthesis, for cholesteryl-ester storage in lipid droplets, and for bile salt synthesis and/or secretion. These alterations are significant findings, since they affect key processes in regulation of sterol metabolism.
authors.affiliation: Department of Pathobiology, Texas A&M University, College Station, Texas; and.
authors.forename: Devon
authors.initials: D
authors.lastname: Klipsic
authors.affiliation: Department of Pathobiology, Texas A&M University, College Station, Texas; and.
authors.forename: Danilo
authors.initials: D
authors.lastname: Landrock
authors.affiliation: Department of Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Martin
authors.affiliation: Department of Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Avery L
authors.initials: AL
authors.lastname: McIntosh
authors.affiliation: Department of Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Kerstin K
authors.initials: KK
authors.lastname: Landrock
authors.affiliation: Department of Pathobiology, Texas A&M University, College Station, Texas; and.
authors.forename: John T
authors.initials: JT
authors.lastname: Mackie
authors.affiliation: Department of Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Schroeder
authors.affiliation: Department of Pathobiology, Texas A&M University, College Station, Texas; and akier@cvm.tamu.edu.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Kier
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000378:metabolism / Q000494:pharmacology*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000123:Acetyltransferases; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002352:Carrier Proteins; D002791:Cholesterol, Dietary; D050556:Fatty Acid-Binding Proteins; D006903:Hydroxymethylglutaryl CoA Reductases; D012333:RNA, Messenger; D002785:Sterol O-Acyltransferase; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D019014:fas Receptor; D000097587:Sterol O-Acyltransferase 2; C415826:Apob protein, mouse; C491899:Fas protein, mouse; C072087:sterol carrier proteins; C055210:aminoglycoside N1-acetyltransferase
keywords: cholesterol; gene ablation; liver; mouse; sterol carrier protein