Objective Non-alcoholic steatohepatitis (NASH) can progress to fibrosis, cirrhosis and end-stage liver disease. Glucagon-like peptide 1 receptor (GLP-1R) mediates β cell function. Its receptor agonists, currently used to treat type 2 diabetes mellitus, might be effective against NASH. GLP-1R, a G protein-coupled receptor family member, preferentially localises to caveolae. Therefore, we ascertained the cellular localisation of GLP-1R and caveolin (CAV)-1 in NASH liver.
Methods Liver biopsies were obtained from three patients with NASH and were compared with those of four normal patients. Immunohistochemistry (IHC) and immunoelectron microscopy (IEM) were used to compare GLP-1R and CAV-1 expression in the livers of patients with metastatic liver cancer and normal patients.
Results IHC showed that GLP-1R localised to basolateral membranes of hepatocytes with macrovesicular steatosis and was expressed in monocytes infiltrating hepatic sinusoids. CAV-1 was minimally associated with low-electron density lipid droplets (LDs) in hepatocytes. IEM showed small clusters of GLP-1R molecules on the peripheral rims of LDs and on cytoplasmic leaflets of endoplasmic reticulum membranes and vesicles, whereas CAV-1 molecules were found in LD caveolae.
Conclusions GLP-1R is present in the lipid microdomains of hepatocytes with macrovesicular steatosis. These results may help inform future studies about the liver-specific mechanisms of GLP-1 modulation in NASH therapy.
- nonalcoholic steatohepatitis
- liver immunology
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Contributors HY and WA designed the study. HY and WA conducted the experiments. HY, WA and MO wrote the manuscript.
Funding HY received scholarship support from AbbVie GK, Gilead Sciences, Merck Sharp & Dohme, Astellas Pharma, Otsuka Pharmaceutical, Zeria Pharmaceutical, EA Pharma, Shionogi and Co. Ltd. and Chugai Pharmaceutical. None of the study sponsor(s) had any role in the study design, in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data available. All data in this article.
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