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Summary: The aging liver is affected by several disorders, including steatosis, that can lead to a decline of liver functions. Here, we present evidence that the cdk4-C/EBPα-p300 axis is a critical regulator of age-associated disorders, including steatosis. We found that patients with non-alcoholic fatty liver disease (NAFLD) have increased levels of cdk4 and that cdk4-resistant C/EBPα-S193A mice do not develop hepatic steatosis with advancing age. Underlying mechanisms include a block in C/EBPα activation and subsequent failure in activation of enzymes involved in the development of NAFLD. Inhibition of cdk4 in aged wild-type (WT) mice by a specific cdk4 inhibitor, PD-0332991, reduces C/EBPα-p300 complexes and eliminates hepatic steatosis. Moreover, the inhibition of cdk4 in aged mice reverses many age-related disorders. Mechanisms of correction include elimination of cellular senescence and alterations in the chromatin structure of hepatocytes. Thus, the inhibition of cdk4 might be considered as a therapeutic approach to correct age-associated liver disorders. : Nguyen et al. show that nuclear elevation of cdk4 leads to age-associated disorders, such as hepatic steatosis, and to age-dependent decline of liver functions and morphology. Elevation of cdk4 changes multiple molecular aspects of liver biology. Inhibition of cdk4 in old mice eliminates hepatic steatosis and corrects age-associated liver disorders. Keywords: cdk4, C/EBPα, p300, NAFLD, liver, steatosis, cellular senescence