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The L‐α‐Lysophosphatidylinositol/G Protein–Coupled Receptor 55 System Induces the Development of Nonalcoholic Steatosis and Steatohepatitis
Hepatology (Baltimore, Md.), 2021-02, Vol.73 (2), p.606-624
2021

Details

Autor(en) / Beteiligte
Titel
The L‐α‐Lysophosphatidylinositol/G Protein–Coupled Receptor 55 System Induces the Development of Nonalcoholic Steatosis and Steatohepatitis
Ist Teil von
  • Hepatology (Baltimore, Md.), 2021-02, Vol.73 (2), p.606-624
Ort / Verlag
United States: Wiley Subscription Services, Inc
Erscheinungsjahr
2021
Link zum Volltext
Quelle
Wiley-Blackwell Journals
Beschreibungen/Notizen
  • 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.
Sprache
Englisch
Identifikatoren
ISSN: 0270-9139
eISSN: 1527-3350
DOI: 10.1002/hep.31290
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7894478
Format
–
Schlagworte
Acetyl-CoA Carboxylase - antagonists & inhibitors, Acetyl-CoA Carboxylase - metabolism, Adenosine kinase, Adult, Aged, AMP, Animal models, Animals, Biopsy, Cannabinoid Receptor Agonists - pharmacology, Cannabinoid receptors, Cannabinoids, Cell activation, Cell Line, Choline, Coenzyme A, Cohort Studies, Diet, High-Fat - adverse effects, Disease Models, Animal, Energy balance, Fatty liver, Female, Gene Knockdown Techniques, Hepatic Stellate Cells, Hepatocytes, Hepatology, High fat diet, Homeostasis, Humans, Kinases, Lipid metabolism, Lipogenesis, Lipogenesis - drug effects, Liver - pathology, Liver diseases, Lysophospholipids - blood, Lysophospholipids - metabolism, Male, Methionine, Mice, Middle Aged, Non-alcoholic Fatty Liver Disease - blood, Non-alcoholic Fatty Liver Disease - etiology, Non-alcoholic Fatty Liver Disease - metabolism, Non-alcoholic Fatty Liver Disease - pathology, Nutrient deficiency, Obesity - blood, Obesity - complications, Obesity - metabolism, Original, Oxidation, Protein kinase, Proteins, Receptors, Cannabinoid - genetics, Receptors, Cannabinoid - metabolism, Steatosis, Stellate cells, Up-Regulation

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