The L-α-Lysophosphatidylinositol/G Protein-Coupled Receptor 55 System Induces the Development of Nonalcoholic Steatosis and Steatohepatitis.
Acetyl-CoA Carboxylase
/ antagonists & inhibitors
Adult
Aged
Animals
Biopsy
Cannabinoid Receptor Agonists
/ pharmacology
Cell Line
Cohort Studies
Diet, High-Fat
/ adverse effects
Disease Models, Animal
Female
Gene Knockdown Techniques
Hepatic Stellate Cells
Hepatocytes
Humans
Lipogenesis
/ drug effects
Liver
/ pathology
Lysophospholipids
/ blood
Male
Mice
Middle Aged
Non-alcoholic Fatty Liver Disease
/ blood
Obesity
/ blood
Receptors, Cannabinoid
/ genetics
Up-Regulation
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
17
12
2019
revised:
24
03
2020
accepted:
05
04
2020
pubmed:
25
4
2020
medline:
10
8
2021
entrez:
25
4
2020
Statut:
ppublish
Résumé
G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing β-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.
Sections du résumé
BACKGROUND AND AIMS
G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown.
APPROACH AND RESULTS
We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing β-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC.
CONCLUSIONS
The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.
Identifiants
pubmed: 32329085
doi: 10.1002/hep.31290
pmc: PMC7894478
pii: 01515467-202102000-00013
doi:
Substances chimiques
Cannabinoid Receptor Agonists
0
GPR55 protein, human
0
GPR55 protein, mouse
0
Lysophospholipids
0
Receptors, Cannabinoid
0
lysophosphatidylinositol
0
ACACA protein, human
EC 6.4.1.2
Acetyl-CoA Carboxylase
EC 6.4.1.2
Types de publication
Journal Article
Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
606-624Informations de copyright
© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
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