Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Impact of SCP-2/SCP-x gene ablation and dietary cholesterol on hepatic lipid accumulation. 2611 98

Liver fatty acid binding protein (Fabp1) and sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) genes encode proteins that enhance hepatic uptake, cytosolic transport, and peroxisomal oxidation of toxic branched-chain fatty acids derived from dietary phytol. Since male wild-type (WT) mice express markedly higher levels of these proteins than females, the impact of ablating both genes (TKO) was examined in phytol-fed males. In WT males, high phytol diet alone had little impact on whole body weight and did not alter the proportion of lean tissue mass (LTM) versus fat tissue mass (FTM). TKO conferred on dietary phytol the ability to induce weight loss as well as reduce liver weight, FTM, and even more so LTM. Concomitantly TKO induced hepatic lipid accumulation, preferentially threefold increased phospholipid (PL) at the expense of decreased triacylglycerol (TG) and total cholesterol. Increased PL was associated with upregulation of membrane fatty acid transport/translocase proteins (FATP 2,4), cytosolic fatty acid/fatty acyl-CoA binding proteins (FABP2, ACBP), and the rate limiting enzyme in PL synthesis (Gpam). Decreased TG and cholesterol levels were not attributable to altered levels in respective synthetic enzymes or nuclear receptors. These data suggest that the higher level of Fabp1 and Scp2/Scpx gene products in WT males was protective against deleterious effects of dietary phytol, but TKO significantly exacerbated phytol effects in males.
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PMID:Effect of Fabp1/Scp-2/Scp-x Ablation on Whole Body and Hepatic Phenotype of Phytol-Fed Male Mice. 2838 56