|
| Status |
Public on Oct 09, 2020 |
| Title |
Effect of p16 deficiency on gene expression in primary hepatocytes |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
*Objectives:* 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. Genome wide association studies identified SNPs near the cell cycle regulator CDKN2A/p16INK4a (p16) as strongly associated with risk of developing type 2 diabetes (T2D). T2D is associated with numerous perturbations of hepatic lipid and glucose metabolism. We have recently shown that p16 controls fasting-induced hepatic gluconeogenesis in mice. However, whether p16 may also affect hepatic lipid homeostasis is unknown.
*Results:* In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism and enhanced activation of PPAR. This led to increased mitochondrial fatty acid oxidation (FAO) through a mechanism requiring the catalytic AMPK 2 subunit and SIRT1. 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*. Gene expression analysis of human liver samples revealed a negative correlation between *CDKN2A* expression and *PPARA* and its target genes, suggesting a potential association between hepatic p16 expression and FAO in obese humans.
*Conclusions:* Our findings demonstrate that p16 plays a key role in hepatic lipid metabolism and may thus contribute to the development of metabolic diseases.
|
| |
|
| Overall design |
Primary hepatocytes were isolated by two step collagenase perfusion from p16+/+ and p16-/- littermate mice and RNA was harvested after 24 hours.
|
| |
|
| Contributor(s) |
Haas J, Paumelle R |
| Citation(s) |
33037071 |
| |
| Submission date |
Jul 22, 2019 |
| Last update date |
Jan 08, 2021 |
| Contact name |
Joel Haas |
| Organization name |
Institut Pasteur de Lille
|
| Department |
UMR1011
|
| Street address |
1 Rue du Professeur Calmette
|
| City |
Lille |
| ZIP/Postal code |
59019 |
| Country |
France |
| |
|
| Platforms (1) |
| GPL16570 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [transcript (gene) version] |
|
| Samples (8)
|
|
| Relations |
| BioProject |
PRJNA555876 |
Less...
More...