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

ABSTRACT: 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.

SUBMITTER: Deleye Y

PROVIDER: S-EPMC7863903 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Deleye Yann Y Cotte Alexia Karen AK Hannou Sarah Anissa SA Hennuyer Nathalie N Bernard Lucie L Derudas Bruno B Caron Sandrine S Legry Vanessa V Vallez Emmanuelle E Dorchies Emilie E Martin Nathalie N Lancel Steve S Annicotte Jean Sébastien JS Bantubungi Kadiombo K Pourtier Albin A Raverdy Violeta V Pattou François F Lefebvre Philippe P Abbadie Corinne C Staels Bart B Haas Joel T JT Paumelle Réjane R

The Journal of biological chemistry 20201009 50

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 <i>CDKN2A</i>, 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 ...[more]

PMID: 33037071

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Project description:Obesity, a major health concern, results from an imbalance between energy intake and expenditure. Leptin-deficient ob/ob mice are paradigmatic of obesity, resulting from excess energy intake and storage. Mice lacking acyl-CoA oxidase 1 (Acox1), the first enzyme of the peroxisomal fatty acid β-oxidation system, are characterized by increased energy expenditure and a lean body phenotype caused by sustained activation of peroxisome proliferator-activated receptor α (PPARα) by endogenous ligands in liver that remain unmetabolized in the absence of Acox1. We generated ob/ob mice deficient in Acox1 (Acox1(-/-)) to determine how the activation of PPARα by endogenous ligands might affect the obesity of ob/ob mice. In contrast to Acox1(-/-) (14.3±1.2 g at 6 mo) and the Acox1-deficient (ob/ob) double-mutant mice (23.8±4.6 g at 6 mo), the ob/ob mice are severely obese (54.3±3.2 g at 6 mo) and had significantly more (P<0.01) epididymal fat content. The resistance of Acox1(-/-)/ob/ob mice to obesity is due to increased PPARα-mediated up-regulation of genes involved in fatty acid oxidation in liver. Activation of PPARα in Acox1-deficient ob/ob mice also reduces serum glucose and insulin (P<0.05) and improves glucose tolerance and insulin sensitivity. Further, PPARα activation reduces hepatic steatosis and increases hepatocellular regenerative response in Acox1(-/-)/ob/ob mice at a more accelerated pace than in mice lacking only Acox1. However, Acox1(-/-)/ob/ob mice manifest hepatic endoplasmic reticulum (ER) stress and also develop hepatocellular carcinomas (8 of 8 mice) similar to those observed in Acox1(-/-) mice (10 of 10 mice), but unlike in ob/ob (0 of 14 mice) and OB/OB (0 of 6 mice) mice, suggesting that superimposed ER stress and PPARα activation contribute to carcinogenesis in a fatty liver. Finally, absence of Acox1 in ob/ob mice can impart resistance to high-fat diet (60% fat)-induced obesity, and their liver had significantly (P<0.01) more cell proliferation. These studies with Acox1(-/-)/ob/ob mice indicate that sustained activation of lipid-sensing nuclear receptor PPARα attenuates obesity and restores glucose homeostasis by ameliorating insulin resistance but increases the risk for liver cancer development, in part related to excess energy combustion.

Dataset Information

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

Publications

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

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