Impact of SCP-2/SCP-x gene ablation and dietary cholesterol on hepatic lipid accumulation

Am J Physiol Gastrointest Liver Physiol. 2015 Sep 1;309(5):G387-99. doi: 10.1152/ajpgi.00460.2014. Epub 2015 Jun 25.

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.

Keywords: cholesterol; gene ablation; liver; mouse; sterol carrier protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism
  • Animals
  • Apolipoprotein B-100
  • Apolipoproteins B / genetics
  • Apolipoproteins B / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cholesterol, Dietary / metabolism
  • Cholesterol, Dietary / pharmacology*
  • Fatty Acid-Binding Proteins / genetics
  • Fatty Acid-Binding Proteins / metabolism
  • Female
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Lipid Metabolism*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sterol O-Acyltransferase / genetics
  • Sterol O-Acyltransferase / metabolism
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Apob protein, mouse
  • Apolipoprotein B-100
  • Apolipoproteins B
  • Carrier Proteins
  • Cholesterol, Dietary
  • Fas protein, mouse
  • Fatty Acid-Binding Proteins
  • RNA, Messenger
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • fas Receptor
  • sterol carrier proteins
  • Hydroxymethylglutaryl CoA Reductases
  • Acetyltransferases
  • aminoglycoside N1-acetyltransferase
  • Sterol O-Acyltransferase
  • sterol O-acyltransferase 2