Background: G-protein coupled receptors (GPCRs) are recognized as attractive targets for drug therapy. However, it remains poorly understood how GPCRs, except for a few chemokine receptors, regulate the progression of liver fibrosis. Here, we aimed to reveal the role of GPR65, a proton-sensing receptor, in liver fibrosis and to elucidate the underlying mechanism.
Methods: The expression level of GPR65 was evaluated in both human and mouse fibrotic livers. Furthermore, Gpr65-deficient mice were treated with either bile duct ligation (BDL) for 21 d or carbon tetrachloride (CCl) for 8 weeks to investigate the role of GPR65 in liver fibrosis. A combination of experimental approaches, including Western blotting, quantitative real-time reverse transcription‑polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and rescue studies, were used to explore the underlying mechanisms of GPR65's action in liver fibrosis. Additionally, the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated.
Results: We found that hepatic macrophages (HMs)-enriched GPR65 was upregulated in both human and mouse fibrotic livers. Moreover, knockout of Gpr65 significantly alleviated BDL- and CCl-induced liver inflammation, injury and fibrosis in vivo, and mouse bone marrow transplantation (BMT) experiments further demonstrated that the protective effect of Gpr65 knockout is primarily mediated by bone marrow-derived macrophages (BMMs). Additionally, in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited, while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-β (TGF-β), all of which subsequently promoted the activation of hepatic stellate cells (HSCs) and the damage of hepatocytes (HCs). Mechanistically, GPR65 overexpression, the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-α and IL-6 via the Gαq-Ca-JNK/NF-κB pathways, while promoted the expression of TGF-β through the Gαq-Ca-MLK3-MKK7-JNK pathway. Notably, pharmacological GPR65 inhibition retarded the development of inflammation, HCs injury and fibrosis in vivo.
Conclusions: GPR65 is a major regulator that modulates the progression of liver fibrosis. Thus, targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis.
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http://dx.doi.org/10.1186/s40779-023-00494-4 | DOI Listing |
Biochem Pharmacol
December 2024
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address:
With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis.
View Article and Find Full Text PDFJ Vasc Interv Radiol
December 2024
Department of Interventional Radiology, Zhongshan Hospital, Fudan University; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University; Shanghai Institution of Medical Imaging, Fudan University. Electronic address:
Purpose: To evaluate the consistency and agreement between portal venous pressure measured by fine-needle (F), portal vein catheterization (D), and hepatic vein balloon-occlusion (W) in decompensated cirrhotic patients with intrahepatic venovenous shunts (IHVS).
Materials And Methods: 156 consecutive patients planning to receive transjugular intrahepatic portosystemic shunt in our center were screened for study participation. The F/D/W were assessed for consistency by Pearson coefficient (r), linear regression coefficient (R), and intraclass correlation coefficient (ICC), and for disagreement (error exceeding 20% of D) by Bland-Altman method.
J Hepatol
December 2024
AP-HP, Hôpital Avicenne, Liver Unit, F-93000 Bobigny, France; University Sorbonne Paris Nord, UFR SMBH, F-93000 Bobigny, France; INSERM UMR-1168, Functional Genomics of Solid Tumours, F-75006 Paris, France.
Alcohol-related liver disease is the third cause of hepatocellular carcinoma worldwide and the leading cause in Europe. Additionally, the recent definition of Metabolic dysfunction-Associated Steatotic Liver Disease with increased alcoholic intake will enrich this population with a more nuanced phenotype, reflecting recent epidemiological trends. In these patients, hepatocellular carcinoma diagnosis is often delayed and less frequently detected through screening programs.
View Article and Find Full Text PDFCell Mol Gastroenterol Hepatol
December 2024
Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Broad Institute, Cambridge, MA. Electronic address:
Background And Aims: Alcohol abuse is the most frequent precipitating factor of acute-on-chronic liver failure (ACLF). We aimed at developing an alcohol-induced ACLF model and dissecting its underlying molecular mechanisms.
Methods: ACLF was triggered by a single alcohol binge (5g/Kg) in a bile duct ligation (BDL) liver fibrosis murine model.
Metabolism
December 2024
Department of Pathology, School of Basic Medical Sciences, Wannan Medical College, Wuhu, China; Postdoctoral Research Station of Clinical Medicine, Jinan University, Guangzhou, China. Electronic address:
Background & Aims: Abnormal expression of long noncoding RNAs is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise molecular mechanisms remain unclear. This study explores the roles of noncoding RNA activated by DNA damage (NORAD)/miR-511-3p/Rho-associated protein kinase 2 (Rock2) axis and the NORAD/ROCK2 interaction in the development of MASLD.
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