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Tenofovir alafenamide alleviates nonalcoholic steatohepatitis in mice by blocking the phosphorylation of AKT in intrahepatic mononuclear phagocytes
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  • Pu Reun Roh,
  • Sung Min Kim,
  • Byung-Yoon Kang,
  • Kyoung Do Mun,
  • Jong Geun Park,
  • Min Woo Kang,
  • Ji Won Han,
  • Heechul Nam,
  • seung kew yoon,
  • Pil Soo Sung
Pu Reun Roh
Catholic University of Korea College of Medicine
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Sung Min Kim
Catholic University of Korea College of Medicine
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Byung-Yoon Kang
Catholic University of Korea College of Medicine
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Kyoung Do Mun
Catholic University of Korea College of Medicine
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Jong Geun Park
Catholic University of Korea College of Medicine
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Min Woo Kang
Catholic University of Korea College of Medicine
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Ji Won Han
Catholic University of Korea College of Medicine
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Heechul Nam
Catholic University of Korea College of Medicine
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seung kew yoon
Catholic University of Korea College of Medicine
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Pil Soo Sung
The Catholic University of Korea
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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.