| First Author | Ruppert PMM | Year | 2019 |
| Journal | BMC Genomics | Volume | 20 |
| Issue | 1 | Pages | 199 |
| PubMed ID | 30866796 | Mgi Jnum | J:274579 |
| Mgi Id | MGI:6293941 | Doi | 10.1186/s12864-019-5563-y |
| Citation | Ruppert PMM, et al. (2019) Transcriptional profiling of PPARalpha-/- and CREB3L3-/- livers reveals disparate regulation of hepatoproliferative and metabolic functions of PPARalpha. BMC Genomics 20(1):199 |
| abstractText | BACKGROUND: Peroxisome Proliferator-Activated receptor alpha (PPARalpha) and cAMP-Responsive Element Binding Protein 3-Like 3 (CREB3L3) are transcription factors involved in the regulation of lipid metabolism in the liver. The aim of the present study was to characterize the interrelationship between PPARalpha and CREB3L3 in regulating hepatic gene expression. Male wild-type, PPARalpha-/-, CREB3L3-/- and combined PPARalpha/CREB3L3-/- mice were subjected to a 16-h fast or 4 days of ketogenic diet. Whole genome expression analysis was performed on liver samples. RESULTS: Under conditions of overnight fasting, the effects of PPARalpha ablation and CREB3L3 ablation on plasma triglyceride, plasma beta-hydroxybutyrate, and hepatic gene expression were largely disparate, and showed only limited interdependence. Gene and pathway analysis underscored the importance of CREB3L3 in regulating (apo)lipoprotein metabolism, and of PPARalpha as master regulator of intracellular lipid metabolism. A small number of genes, including Fgf21 and Mfsd2a, were under dual control of PPARalpha and CREB3L3. By contrast, a strong interaction between PPARalpha and CREB3L3 ablation was observed during ketogenic diet feeding. Specifically, the pronounced effects of CREB3L3 ablation on liver damage and hepatic gene expression during ketogenic diet were almost completely abolished by the simultaneous ablation of PPARalpha. Loss of CREB3L3 influenced PPARalpha signalling in two major ways. Firstly, it reduced expression of PPARalpha and its target genes involved in fatty acid oxidation and ketogenesis. In stark contrast, the hepatoproliferative function of PPARalpha was markedly activated by loss of CREB3L3. CONCLUSIONS: These data indicate that CREB3L3 ablation uncouples the hepatoproliferative and lipid metabolic effects of PPARalpha. Overall, except for the shared regulation of a very limited number of genes, the roles of PPARalpha and CREB3L3 in hepatic lipid metabolism are clearly distinct and are highly dependent on dietary status. |
