Hepatic PPAR alpha Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice

The nutrient sensing nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR alpha) regulates the host response to short-term fasting by inducing hepatic transcriptional programming of ketogenesis, fatty acid oxidation and transport, and autophagy. This adaptation is ineffective in chronically undernourished individuals, among whom dyslipidemia and hepatic steatosis are common. We recently reported that hepatic PPAR alpha protein is profoundly depleted in male mice undernourished by a low-protein, low-fat diet. Here, we identify PPAR alpha as a deacetylation target of the NAD-dependent deacetylase sirtuin-1 (SIRT1) and link this to the decrease in PPAR alpha protein levels in undernourished liver. Livers from undernourished male mice expressed high levels of SIRT1, with decreased PPAR alpha acetylation and strongly decreased hepatic PPAR alpha protein. In cultured hepatocytes, PPAR alpha protein levels were decreased by transiently transfecting constitutively active SIRT1 or by treating cells with the potent SIRT1 activator resveratrol, while silencing SIRT1 increased PPAR alpha protein levels. SIRT1 expression is correlated with increased PPAR alpha ubiquitination, suggesting that protein loss is due to proteasomal degradation. In accord with these findings, the dramatic loss of hepatic PPAR alpha in undernourished male mice was completely restored by treating mice with the proteasome inhibitor bortezomib. Similarly, treating undernourished mice with the SIRT1 inhibitor selisistat/EX-527 completely restored hepatic PPAR alpha protein. These data suggest that induction of SIRT1 in undernutrition results in hepatic PPAR alpha deacetylation, ubiquitination, and degradation, highlighting a new mechanism that mediates the liver's failed adaptive metabolic responses in chronic undernutrition.