Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1864, Issue 12, Pages 3655-3667Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2018.09.027
Keywords
GRK2; NAFLD; NASH; MCD; Hepatic steatosis; NAS
Funding
- Ministerio de Economia y Competitividad (MINECO/FEDER), Spain [SAF2014-55511-R, SAF2017-84125-R, SAF2015-65267-R, SAF2016-76028R, SAF2017-87301-R]
- Comunidad de Madrid [B2017/BMD-3671-INFLAMUNE]
- Gobierno Vasco-Departamento de Salud [2013111114, EITB Maratoia BIO15/CA/014]
- European Foundation for the Study of Diabetes (EFSD) Novo Nordisk Partnership for Diabetes Research in Europe Grant
- Asociacion Espanola contra el Cancer
- Fundacion Ramon Areces
- Instituto de Salud Carlos III
- (European FEDER contribution) funds CIBERCV [CB16/11/00278, 13/01299, 17/00535, 16/00823, PIE/00031]
- Contrato para la Formacion Postdoctoral from MINECO
- Contratos Predoctorales para Formacion de Personal Investigador
- Juan de la Cierva [IJCI-2014-19,381]
- MINECO [SEV-2016-0644]
- CBMSO from Fundacion Ramon Areces
- Fundacion Banco de Santander
Ask authors/readers for more resources
Insulin resistance (IR) and obesity are important risk factors for non-alcoholic fatty liver disease (NAFLD). G protein-coupled receptor kinase 2 (GRK2) is involved in the development of IR and obesity in vivo. However, its possible contribution to NAFLD and/or non-alcoholic steatohepatitis (NASH) independently of its role on IR or fat mass accretion has not been explored. Here, we used wild-type (WT) or GRK2 hemizygous (GRK2 +/-) mice fed a high-fat diet (HFD) or a methionine and choline-deficient diet (MCD) as a model of NASH independent of adiposity and IR. GRK2 +/- mice were protected from HFD-induced NAFLD. Moreover, MCD feeding caused an increased in triglyceride content and liver-to-body weight ratio in WT mice, features that were attenuated in GRK2 +/- mice. According to their NAFLD activity score, MCD-fed GRK2 +/- mice were diagnosed with simple steatosis and not overt NASH. They also showed reduced expression of lipogenic and lipid-uptake markers and less signs of inflammation in the liver. GRK2 +/- mice preserved hepatic protective mechanisms as enhanced autophagy and mitochondrial fusion and biogenesis, together with reduced endoplasmic reticulum stress. GRK2 protein was increased in MCD-fed WT but not in GRK2 +/- mice, and enhanced GRK2 expression potentiated palmitic acid-triggered lipid accumulation in human hepatocytes directly relating GRK2 levels to steatosis. GRK2 protein and mRNA levels were increased in human liver biopsies from simple steatosis or NASH patients in two different human cohorts. Our results describe a functional relationship between GRK2 levels and hepatic lipid accumulation and implicate GRK2 in the establishment and/or development of NASH.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available