Abstract
p53 family members control several metabolic and cellular functions. The p53 ortholog p63 modulates cellular adaptations to stress and has a major role in cell maintenance and proliferation. Here we show that p63 regulates hepatic lipid metabolism. Mice with liver-specific p53 deletion develop steatosis and show increased levels of p63. Down-regulation of p63 attenuates liver steatosis in p53 knockout mice and in diet-induced obese mice, whereas the activation of p63 induces lipid accumulation. Hepatic overexpression of N-terminal transactivation domain TAp63 induces liver steatosis through IKKβ activation and the induction of ER stress, the inhibition of which rescues the liver functions. Expression of TAp63, IKKβ and XBP1s is also increased in livers of obese patients with NAFLD. In cultured human hepatocytes, TAp63 inhibition protects against oleic acid-induced lipid accumulation, whereas TAp63 overexpression promotes lipid storage, an effect reversible by IKKβ silencing. Our findings indicate an unexpected role of the p63/IKKβ/ER stress pathway in lipid metabolism and liver disease.
Highlights
P53 family members control several metabolic and cellular functions
The link between p53 and hepatic lipid metabolism is currently not fully understood, as some reports indicate that p53 is an essential player in the pathogenesis of alcoholic fatty liver disease[7,8,9] and NAFLD10–14, whereas others suggest that it attenuates liver steatosis[15,16]
We found a significant increase in the TG content (Fig. 7a,b) and protein levels of XBP1s in the liver of mice over-expressing TAp63a, while no changes were detected in Fatty Acid Synthase (FAS) (Fig. 7b), indicating that changes in hepatic ER stress precedes the stimulation of FAS protein levels
Summary
P53 family members control several metabolic and cellular functions. The p53 ortholog p63 modulates cellular adaptations to stress and has a major role in cell maintenance and proliferation. The link between p53 and hepatic lipid metabolism is currently not fully understood, as some reports indicate that p53 is an essential player in the pathogenesis of alcoholic fatty liver disease[7,8,9] and NAFLD10–14, whereas others suggest that it attenuates liver steatosis[15,16]. The conclusions of those studies should be interpreted with caution since they have not evaluated the role of p53 through its manipulation in the liver but rather based on gene expression results, the use of pharmacological compounds, mice lacking p53 globally or in vitro assays. In the present paper we aim to explore this possibility as well as to acquire knowledge on the role of hepatic p63 on NAFLD, and the possible involvement of ER stress in the molecular pathways altered after gain- and loss-of-function of liver p63
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 call
