Downregulation of PPARs and SREBP by acyl-CoA-binding protein overexpression in transgenic rats

• Published in: Pflügers Archiv 2008-05, Vol.456 (2), p.369-377
• Main Authors: Oikari, Sanna, Ahtialansaari, Tiia, Heinonen, Miika V., Mauriala, Timo, Auriola, Seppo, Kiehne, Karlheinz, Fölsch, Ulrich R., Jänne, Juhani, Alhonen, Leena, Herzig, Karl-Heinz
• Format: Article
• Language: English
• Subjects: Adipose Tissue - metabolism; Animals; Animals, Genetically Modified; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cholesterol - blood; Diazepam Binding Inhibitor - metabolism; Fatty Acids, Nonesterified - metabolism; Human Physiology; Integrative Physiology; Kinases; Lipid Metabolism - physiology; Liver - metabolism; Male; Molecular Medicine; Neurosciences; PPAR delta - metabolism; PPAR gamma - metabolism; Protein Kinases - metabolism; Rats; Rats, Wistar; Receptors; RNA, Messenger - metabolism; Rodents; Sterol Regulatory Element Binding Protein 1 - metabolism; Triglycerides - blood
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-007-0416-y

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 (PPARγ, PPARδ) 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.