國家衛生研究院 NHRI:Item 3990099045/12217
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    题名: In vivo efficacy of cannabinoid receptor 1 antagonist, CPD1, in treating non-alcoholic fatty liver disease
    作者: Hsiao, WC;Shia, KS;Chen, PH;Chen, ZR;Chen, BH;Yeh, YN;Hung, MS
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease now, and it is comprised of non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH). When NASH is present, it can progress to fibrosis, cirrhosis and hepatocellular carcinoma and result in liverrelated death . Currently, no FDA-approved pharmacotherapy for this disease is available . Cannabinoid receptor 1 (CB1) is highly induced in human cirrhotic samples and activated hepatic stellate cells, and it contributes to the pathogenesis of acute phase liver injury, fibrogenesis, alcoholic-induced liver disease, NAFLD and cardiovascular associated cirrhosis . Besides, endocannabinoids and CB1 receptors are also highly activated in obesity and type 2 diabetes (T2D), which are risk factors associated with NAFLD . Genetic or pharmacological blockade of CB1 receptors decrease fibrogenesis by suppressing pro-fibrogenic and inflammator y mediators, and have beneficial effects in reducing lipogenesis. These findings suggest that CB1 antagonism may be a potential therapeutic strategy for NASH . The purpose of this study was to evaluate the effects of a highly selective and potent CB1 antagonist, CPD1 on NAFLD/NASH . Methods: The effects of chronic CPD1 treatment were examined in highfat diet (HFD) and choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-fed mice . Alterations to body weight and tissue weights were determined, and blood biochemical parameters were analyzed . Livers tissues were collected and analyzed by histology, immunoblots, quantitative PCR, immunohistochemistry and biochemistry . Results: In HFD-fed mice, chronic administration of CPD1 (0 .01, 0 .03 and 0 .1 mg/kg) showed substantial anti-obesity effect dosedependently . Other than the reduction in body weight, several blood biochemical parameters, such as glucose, insulin and triglycerides (TG) all improved remarkably . In addition, the expression of genes involved in lipogenesis, gluconeogenesis, lipid oxidation, insulin sensitivity was improved . CDAHFD-fed mice increased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) compared with control mice . CDAHFD feeding also enhanced steatohepatitis, hepatic inflammation and level of TG and hydroxyproline, and there is an improvement trend after CPD1 (0 .03 mg/kg) treatment . Conclusion: These results suggest that CPD1 may be a promising candidate for preventing and treating the progression of NAFLD/NASH .
    日期: 2019-10
    關聯: Hepatology. 2019 Oct;70:1333A.
    Link to: https://doi.org/10.1002/hep.30941
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0270-9139&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000488653505020
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