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.

Background:The adaptor protein cerebral cavernous malformation 3 (CCM3) is involved in cell death. Results: Ezrin/radixin/moesin (ERM) proteins are phosphorylated after oxidative stress, and this requires CCM3 and the ERM kinase Mst4. Conclusion: CCM3 is necessary for ERM protein phosphorylation after stress, which enhances survival. Significance: This is a novel, functionally significant pathway that protects cells from death.

BaCKgRoUND aND aIMS: G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-αlysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. appRoaCH aND ReSUltS: We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing β-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CoNClUSIoNS: The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC. (Hepatology 2020;0:1-19). N onalcoholic fatty liver (NAFL) disease (NAFLD) is a major global health threat because of its growing incidence and prevalence. It is becoming the leading cause of liver disease and despite the many efforts to find therapeutic targets for this disease, there is no established therapy yet.