p53 Involvement in the Pathogenesis of Fatty Liver Disease

Abstract

Obesity is a major health problem in industrialized societies, and fatty liver disease (hepatic steatosis) is common in obese individuals. Oxidative stress originating from increased intracellular levels of fatty acids has been implicated as a cause of hepatocellular injury in steatosis, although the precise mechanisms remain to be elucidated. p53, widely known as a tumor suppressor, has been shown often to be activated in stressed cells, inducing cell cycle arrest or death. Here we demonstrate that p53 is involved in the molecular mechanisms of hepatocellular injury associated with steatosis. We found that p53 in the nucleus is induced in the liver from two mouse models of fatty liver disease, ob/ob and a transgenic mouse model that overexpresses an active form of sterol regulatory element-binding protein-1 in the liver (TgSREBP-1), the one with obesity and the other without obesity. This activation of the p53 pathway leads to the elevation of p21 mRNA expression, which can be considered an indicator of p53 activity, because ob/ob mice lacking p53 generated by targeting gene disruption exhibited the complete restoration of the p21 elevation to wild type levels. Consistent with these results, the amelioration of hepatic steatosis caused by Srebp-1 gene disruption in ob/ob mice lowered the p21 expression in a triglyceride content-dependent manner. Moreover, p53 deficiency in ob/ob mice resulted in a marked improvement of plasma alanine aminotransferase levels, demonstrating that p53 is involved in the mechanisms of hepatocellular injury. In conclusion, we revealed that p53 plays an important role in the pathogenesis of fatty liver disease.

Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4α (HNF4α) gene

“…In response to this stress, p53 protein levels are increased, resulting in the classical blockage of the cell cycle and cell death via apoptosis. It is also known that p53 itself causes liver injury [51][52][53][54]. Since HNF4α function is known to be critical for the differentiated liver phenotype [55][56][57], the down-regulation of HNF4α by activated p53 that we demonstrate in the present study could, in the chronic situation, lead to decreased liver differentiation and hence decreased liver function.…”

Hepatocyte CYP2E1 Overexpression and Steatohepatitis Lead to Impaired Hepatic Insulin Signaling

“…Western blot analysis revealed no effect of CYP2E1 overexpression on levels of PKC isoforms and suppressor of cytokine signaling-3 (data not shown). Expression of p53 is induced by oxidative stress and has recently been demonstrated to have a critical role in the development of steatohepatitis (61). However, p53 up-regulation was also not observed in CYP2E1 overexpressing RALA hepatocytes (data not shown).…”

High Dietary Selenium Intake Alters Lipid Metabolism and Protein Synthesis in Liver and Muscle of Pigs

“…Dietary selenium and/or GPX1 production (9) affected the functional expression of important proteins involved in gluconeogenesis [phosphoenolpyruvate carboxykinase (PEPCK)] and glycolysis [glucokinase (GK)] (10), insulin signaling [insulin receptor (INSR), insulin receptor substrate 1 (IRS1), and v-akt murine thymoma viral oncogene homolog 2 (AKT2)], and lipid metabolism (11) [sterol regulatory element binding protein (SREBP) 1 and SREBP2, acetyl-CoA carboxylase 1 (ACC1); cholesterol 7a-hydroxylase (CYP7A1), PPARG, fatty acid synthase (FASN), and tumor suppressor p53 (P53)] (12)(13)(14)(15)(16)(17). Alterations of these factors were associated with expressions of 12 selenoproteins (1,3,5,9,18,19).…”