Tenofovir alafenamide alleviates nonalcoholic steatohepatitis in mice by blocking the phosphorylation of AKT in intrahepatic mononuclear phagocytes.

Autor: Roh PR; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: shvn4564@catholic.ac.kr., Kim SM; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: ring704@nate.com., Kang BY; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: kby2132@catholic.ac.kr., Mun KD; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: haruneum31@catholic.ac.kr., Park JG; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: whdrms1230@catholic.ac.kr., Kang MW; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: rkdalsdn9625@catholic.ac.kr., Hur W; Division of Viral Disease Research, Center for Infectious Disease Research, Korea National Institute of Health, Chungbuk 28159, Republic of Korea. Electronic address: wendyhur@korea.kr., Han JW; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea; Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: tmznjf@catholic.ac.kr., Nam H; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea; Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbu 11765, Republic of Korea. Electronic address: hcnam128@catholic.ac.kr., Yoon SK; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea; Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: yoonsk@catholic.ac.kr., Sung PS; The Catholic University Liver Research Center, College of Medicine, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea; Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: pssung@catholic.ac.kr.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2022 Dec; Vol. 156, pp. 113952. Date of Electronic Publication: 2022 Nov 03.
DOI: 10.1016/j.biopha.2022.113952
Abstrakt: Background and Purpose: Although the prevalence of nonalcoholic steatohepatitis (NASH) is rapidly increasing, effective therapy is lacking. Tenofovir alafenamide (TAF) is a widely used antiviral drug for hepatitis B. In this study, we investigated the potential pharmacological effects of TAF on NASH.
Experimental Approach: Two different NASH mouse models were established: 1) by subcutaneous injection of streptozotocin (0.2 mg) and feeding the mice a high-fat, high-cholesterol (HFHC) diet, and 2) feeding the mice a choline-deficient, L-amino acid-defined, high-fat (CDAHF) diet.
Key Results: Serum alanine aminotransferase and triglyceride levels in TAF-treated NASH mice were significantly lower than those in the mock-treated ones. The livers from the TAF-treated NASH mice showed attenuated mononuclear phagocyte (MP) infiltration compared to those from the mock-treated ones. TAF-treated NASH mice exhibited decreased liver infiltration of activated MPs (IAIE + /PD-L1 + /MerTK + ). In ex vivo experiments using sorted human CD14 + monocytes treated with lipopolysaccharide (LPS) and/or TAF, we confirmed the decreased level of phosphorylated AKT in TAF-treated LPS-stimulated monocytes compared to that in the mock-treated ones. Mouse liver immunoblotting showed that phosphorylation levels of AKT were significantly lower in the TAF-treated NASH group than in the mock-treated group.
Conclusion and Implications: TAF exerts anti-inflammatory effects in NASH livers by attenuating AKT phosphorylation in intrahepatic activated MPs. Therefore, TAF may serve as a new therapeutic option for NASH.
(Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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