1. Tenofovir alafenamide alleviates nonalcoholic steatohepatitis in mice by blocking the phosphorylation of AKT in intrahepatic mononuclear phagocytes
- Author
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Pu Reun Roh, Sung Min Kim, Byung-Yoon Kang, Kyoung Do Mun, Jong Geun Park, Min Woo Kang, Wonhee Hur, Ji Won Han, Heechul Nam, Seung Kew Yoon, and Pil Soo Sung
- Subjects
NASH mouse model ,Pharmacological effect ,AKT ,Tenofovir alafenamide ,Mononuclear phagocyte ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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.
- Published
- 2022
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