Abstract
Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC.
Highlights
The term “liver disease’ encompasses a spectrum of pathologies that includes, but is not limited to, hepatosteatosis, hepatic insulin resistance, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma (HCC) [1]
While failure of liver function can occur at several stages, HCC is often regarded as the end stage of the progression of alcoholic liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD), with varying incidences [2]
Whereas some models suggest a defined, successive cascade in the etiology of liver disease, other reports paint a less clear picture
Summary
The term “liver disease’ encompasses a spectrum of pathologies that includes, but is not limited to, hepatosteatosis, hepatic insulin resistance, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma (HCC) [1]. Increased fatty acid oxidation, decreased de novo fatty acid synthesis, reduced inflammation and lowered ER stress were found to be correlated with the attenuation of liver injury [39] This argues for a positive effect of moderate p53 activation on liver lipid metabolism and the prevention of NASH-associated liver pathology. Since plasma levels of miRNA-34a were upregulated and associated with disease severity in NAFLD mouse models, it was suggested as a biomarker for susceptibility to liver injury in fatty liver disease [91] Establishing another link of miRNA-34a and p53 to liver lipid metabolism, data from Xu et al suggest that in NASH patients, p53, free fatty acids and cholesterol may act synergistically via different pathways to inactivate the hepatocyte nuclear factor 4α (HNFα) via miRNA-34a, leading to reduced lipoprotein secretion and subsequent steatosis [89]. These opposing findings reflect the complexity of p53-dependent regulation in NASH
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