Abstract
The liver plays a central role in the regulation of fatty acid metabolism, which is highly sensitive to transcriptional responses to nutrients and hormones. Transcription factors involved in this process include nuclear hormone receptors. One such receptor, PPARα, which is highly expressed in the liver and activated by a variety of fatty acids, is a critical regulator of hepatic fatty acid catabolism during fasting. The present study compared the influence of dietary fatty acids and fasting on hepatic PPARα-dependent responses. Pparα−/− male mice and their wild-type controls were fed diets containing different fatty acids for 10 weeks prior to being subjected to fasting or normal feeding. In line with the role of PPARα in sensing dietary fatty acids, changes in chronic dietary fat consumption influenced liver damage during fasting. The changes were particularly marked in mice fed diets lacking essential fatty acids. However, fasting, rather than specific dietary fatty acids, induced acute PPARα activity in the liver. Taken together, the data imply that the potent signalling involved in triggering PPARα activity during fasting does not rely on essential fatty acid-derived ligand.
Highlights
In mammals, the liver plays a critical role in controlling fatty acid homeostasis, which is under tight transcriptional control
We recently reported that hepatocyte PPARα acts as a transcriptional sensor for free fatty acids released from adipocytes during fasting and controls the expression of hundreds of genes involved in fatty acid uptake, transport, and catabolism in hepatocytes [14]
Whatever the diet, the absence of PPARα led to a major shift in the hepatic fatty acid profile (Figure 1d), providing further in vivo evidence that this nuclear receptor is a major regulator of hepatic fatty acid homeostasis in response to changes in fatty acid intake
Summary
The liver plays a critical role in controlling fatty acid homeostasis, which is under tight transcriptional control. A broad catabolic response occurs in hepatocytes using free fatty acids released from adipocytes and involving several transcriptional regulators in the liver [4]. Among these molecules, Peroxisome Proliferator-Activated Receptor alpha (PPARα) is a major player, as deletion of the gene in mice leads to steatosis, hypoglycaemia, hypothermia, and reduced ketone bodies in response to fasting [5,6]. The PPARs regulate gene expression as heterodimers with the Retinoid X Receptors (RXRs), binding to response elements in the regulatory regions of target genes Fatty acids and their derivatives act as ligands that activate PPARα by promoting the recruitment of co-activator proteins, such as CBP/p300 and SRC/p160 [7,8]. We recently reported that hepatocyte PPARα acts as a transcriptional sensor for free fatty acids released from adipocytes during fasting and controls the expression of hundreds of genes involved in fatty acid uptake, transport, and catabolism in hepatocytes [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
