Format

Send to

Choose Destination
Nat Commun. 2017 May 8;8:15111. doi: 10.1038/ncomms15111.

Hepatic p63 regulates steatosis via IKKβ/ER stress.

Author information

1
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain.
2
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
3
CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Derio 48160, Spain.
4
CIC bioGUNE, Centro de Investigación Biomédica en Red de Cáncer (CIBERonc), Technology Park of Bizkaia, Derio 48160, Spain.
5
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
6
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
7
Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Department of Surgery, University of Salamanca, Salamanca, Spain.
8
Department of Internal Medicine, University Hospital of Salamanca-IBSAL, Department of Medicine, University of Salamanca, Salamanca, Spain.
9
Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Hospital Universitario Reina Sofía, Córdoba 14004, Spain.
10
IKERBASQUE, Basque foundation for science, Bilbao 48011, Spain.
11
Department of Biochemistry, University of the Basque Country (UPV/EHU), Spain.
12
Department of Physiology, University of the Basque Country (UPV/EHU), Spain.
13
Biocruces Research Institute, Bilbao 48903, Spain.

Abstract

p53 family members control several metabolic and cellular functions. The p53 ortholog p63 modulates cellular adaptations to stress and has a major role in cell maintenance and proliferation. Here we show that p63 regulates hepatic lipid metabolism. Mice with liver-specific p53 deletion develop steatosis and show increased levels of p63. Down-regulation of p63 attenuates liver steatosis in p53 knockout mice and in diet-induced obese mice, whereas the activation of p63 induces lipid accumulation. Hepatic overexpression of N-terminal transactivation domain TAp63 induces liver steatosis through IKKβ activation and the induction of ER stress, the inhibition of which rescues the liver functions. Expression of TAp63, IKKβ and XBP1s is also increased in livers of obese patients with NAFLD. In cultured human hepatocytes, TAp63 inhibition protects against oleic acid-induced lipid accumulation, whereas TAp63 overexpression promotes lipid storage, an effect reversible by IKKβ silencing. Our findings indicate an unexpected role of the p63/IKKβ/ER stress pathway in lipid metabolism and liver disease.

PMID:
28480888
PMCID:
PMC5424198
DOI:
10.1038/ncomms15111
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center