Downregulation of PPARs and SREBP by acyl-CoA-binding protein overexpression in transgenic rats.
Acyl-CoA-binding protein (ACBP) acts as an acyl-CoA pool former, transporter, and regulator of gene transcription in vitro. We created a transgenic rat line overexpressing ACBP, as the physiological relevance of ACBP in lipid metabolism is unclear. Transgenic rats revealed increased levels of ACBP and significantly elevated acyl-CoA tissue levels while there was no effect on plasma triglyceride, cholesterol, or serum-free fatty acid levels. Metabolic regulators like peroxisome proliferator-activated receptors (PPARgamma, PPARdelta) and sterol regulatory element-binding protein-1 (SREBP-1) messenger RNA levels were significantly reduced (by 23-82%) in liver and adipose tissue of fed transgenic rats, whereas adenosine monophosphate-activated protein kinase (AMPK) protein levels were increased (by 60%). Fasting abolished PPAR downregulation in liver and caused an upregulation in adipose tissue. Administration of AMPK inhibitor reversed SREBP-1 but did not affect PPAR regulation. In conclusion, ACBP acts as an acyl-CoA pool former in transgenic rats and regulates lipid metabolism via SREBP-1 and PPAR regulation. Reduction of SREBP-1 is mediated via increased AMPK levels, whereas regulation of PPARs seems to be mediated by an AMPK-independent mechanism. ACBP itself is a target gene for both transcription factors demonstrating important feedback loops.
D000091162:AMP-Activated Protein Kinase Kinases; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002784:Cholesterol / Q000097:blood; D026261:Diazepam Binding Inhibitor / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D047494:PPAR delta / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
D026261:Diazepam Binding Inhibitor; D005230:Fatty Acids, Nonesterified; D047494:PPAR delta; D047495:PPAR gamma; D012333:RNA, Messenger; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D002784:Cholesterol; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases