Abstract
BackgroundPeroxisome Proliferator-Activated receptor α (PPARα) 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 PPARα and CREB3L3 in regulating hepatic gene expression. Male wild-type, PPARα−/−, CREB3L3−/− and combined PPARα/CREB3L3−/− mice were subjected to a 16-h fast or 4 days of ketogenic diet. Whole genome expression analysis was performed on liver samples.ResultsUnder conditions of overnight fasting, the effects of PPARα ablation and CREB3L3 ablation on plasma triglyceride, plasma β-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 PPARα as master regulator of intracellular lipid metabolism. A small number of genes, including Fgf21 and Mfsd2a, were under dual control of PPARα and CREB3L3. By contrast, a strong interaction between PPARα 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 PPARα. Loss of CREB3L3 influenced PPARα signalling in two major ways. Firstly, it reduced expression of PPARα and its target genes involved in fatty acid oxidation and ketogenesis. In stark contrast, the hepatoproliferative function of PPARα was markedly activated by loss of CREB3L3.ConclusionsThese data indicate that CREB3L3 ablation uncouples the hepatoproliferative and lipid metabolic effects of PPARα. Overall, except for the shared regulation of a very limited number of genes, the roles of PPARα and CREB3L3 in hepatic lipid metabolism are clearly distinct and are highly dependent on dietary status.
Highlights
Peroxisome Proliferator-Activated receptor α (PPARα) and cAMP-Responsive Element Binding Protein 3-Like 3 (CREB3L3) are transcription factors involved in the regulation of lipid metabolism in the liver
Effect of PPARα and/or CREB3L3 ablation on fasting plasma metabolites To study the potential interaction between PPARα and CREB3L3 in metabolic regulation in the fasted state, we first performed basic metabolic measurements in wild-type, PPARα−/−, CREB3L3−/−, and combined PPARα/CREB3L3−/− mice after 16 h of fasting
In agreement with our previous report [19], non-esterified fatty acid (NEFA) and β-hydroxybutyrate levels were elevated in CREB3L3−/− mice, while levels in PPARα/CREB3L3−/− mice were similar to those in PPARα−/− mice (Fig. 1b and c), suggesting a dominant effect of PPARα ablation
Summary
Peroxisome Proliferator-Activated receptor α (PPARα) and cAMP-Responsive Element Binding Protein 3-Like 3 (CREB3L3) are transcription factors involved in the regulation of lipid metabolism in the liver. PPARα can be aptly described as the master regulator of hepatic lipid metabolism, especially under conditions of elevated hepatic lipid load, as occurs during fasting, high fat feeding, and a ketogenic diet. In line with this notion, the absence of PPARα during fasting leads to a host of metabolic disturbances, including a fatty liver, elevated plasma non-esterified fatty acids, hypoglycemia and hypoketonemia [8,9,10,11,12]
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