Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice

Authors

Ji Ho Suh
Kang Ho Kim
Margaret E Conner
David D Moore
Geoffrey A Preidis

Publication Date

1-1-2022

Journal

Frontiers in Nutrition

DOI

10.3389/fnut.2022.831879

PMID

35419389

PMCID

PMC8997242

PubMedCentral® Posted Date

3-28-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

undernutrition, PPARα (peroxisome proliferator-activated receptor alpha), sirtuin-1 (SIRT1), post-translational modification of proteins, mouse models, sex differences

Abstract

The nutrient sensing nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) 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 PPARα protein is profoundly depleted in male mice undernourished by a low-protein, low-fat diet. Here, we identify PPARα as a deacetylation target of the NAD-dependent deacetylase sirtuin-1 (SIRT1) and link this to the decrease in PPARα protein levels in undernourished liver. Livers from undernourished male mice expressed high levels of SIRT1, with decreased PPARα acetylation and strongly decreased hepatic PPARα protein. In cultured hepatocytes, PPARα protein levels were decreased by transiently transfecting constitutively active SIRT1 or by treating cells with the potent SIRT1 activator resveratrol, while silencing SIRT1 increased PPARα protein levels. SIRT1 expression is correlated with increased PPARα ubiquitination, suggesting that protein loss is due to proteasomal degradation. In accord with these findings, the dramatic loss of hepatic PPARα 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 PPARα protein. These data suggest that induction of SIRT1 in undernutrition results in hepatic PPARα deacetylation, ubiquitination, and degradation, highlighting a new mechanism that mediates the liver's failed adaptive metabolic responses in chronic undernutrition.