Seminar

Unraveling the role of p53 and p63 in liver metabolism

Prof. Ruben Nogueiras

p53 and p63 are intensively studied proteins, primarily as a tumour suppressor. Besides cell proliferation, p53 and p63 also play an important role in different biological functions including longevity, stress, ageing, and obesity-associated disorders such as hepatic steatosis and insulin resistance. In this talk we will go through some of the lately results on their metabolic role in the brain and liver. Our lab has investigated some of these metabolic roles manipulating these tumour suppressors in different tissues. The most relevant findings indicate that the lack of p53 in specific neurons of the hypothalamus increases the susceptibility of mice fed a high fat diet to gain more weight, an effect explained by the lower thermogenic activity in the brown adipose tissue. On the other hand, the global or hepatic lack of p53 causes an increased lipid accumulation in the liver, while the over-expression of hepatic p53 ameliorates diet-induced steatosis and the rescue of p53 in the liver of p53 null mice normalizes lipid levels. The effects of p53 are mediated via p63, which down-regulation alleviates liver steatosis in p53-null and diet-induced obese mice. Subsequently, p63 regulates inflammation, endoplasmic reticulum stress and lipogenesis that ultimately alter lipid content in the liver. In addition to the actions of p53 and p63 on lipid metabolism we are now exploring its potential role in glucose homeostasis, and deciphering the molecular mechanisms implicated in the metabolic actions of both tumour suppressors.