CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway

• Published in: The Journal of biological chemistry Vol. 295; no. 50; pp. 17310 - 17322
• Main Authors: Deleye, Yann, Cotte, Alexia Karen, Hannou, Sarah Anissa, Hennuyer, Nathalie, Bernard, Lucie, Derudas, Bruno, Caron, Sandrine, Legry, Vanessa, Vallez, Emmanuelle, Dorchies, Emilie, Martin, Nathalie, Lancel, Steve, Annicotte, Jean Sébastien, Bantubungi, Kadiombo, Pourtier, Albin, Raverdy, Violeta, Pattou, François, Lefebvre, Philippe, Abbadie, Corinne, Staels, Bart, Haas, Joel T., Paumelle, Réjane
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.12.2020; American Society for Biochemistry and Molecular Biology
• Subjects: AMP-activated kinase (AMPK); AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPKα; Animals; CDKN2A; cell cycle; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; fatty acid oxidation; Fatty Acids - genetics; Fatty Acids - metabolism; Genome-Wide Association Study; Humans; Life Sciences; Lipid Droplets - metabolism; lipid metabolism; liver; Liver - metabolism; Metabolism; Mice; Mice, Knockout; Mitochondria, Liver - genetics; Mitochondria, Liver - metabolism; Obesity - genetics; Obesity - metabolism; Oxidation-Reduction; peroxisome proliferator-activated receptor (PPAR); PPAR alpha - genetics; PPAR alpha - metabolism; PPARα; Signal Transduction; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; steatosis; peroxisome proliferator-activated receptor (PPAR); AMPKα; CDKN2A; liver; cell cycle; lipid metabolism; AMP-activated kinase (AMPK); fatty acid oxidation; PPARα; steatosis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA120.012543

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.