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