Introduction
Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, hepatocellular damage, and liver inflammation, progressing to more severe stages, including cirrhosis or hepatocellular carcinoma (Abdelmalek, 2021; Huby & Gautier, 2021). Although NASH is highly prevalent, there are currently no effective treatments for this disease (Raza, Rajak, Upadhyay, Tewari, & Anthony Sinha, 2021). NASH treatments are currently being developed for various targets, and several clinical trials are underway. Only few drugs are in phase III trials, whereas others remain in phase I or II trials (Yoo et al., 2019). The US Food and Drug Administration has not yet approved any specific drug for NASH treatment; therefore, developing new and improved therapeutic drugs is essential (Kang et al., 2021).
Complex crosstalk between hepatocytes, hepatic stellate cells (HSCs), and diverse immune cells is activated during NASH progression (Huby & Gautier, 2021; H. L. Lee et al., 2022). During the process, inflammatory signals increase the mononuclear phagocyte (MP) pool size in the liver. Single-cell RNA sequencing of NASH mice liver showed increased size of MP clusters compared with normal mice liver (Xiong et al., 2019). Recent studies have focused on the diversity of MP in NASH mouse models (Remmerie et al., 2020; Seidman et al., 2020; Tran et al., 2020). Intrahepatic MPs are traditionally classified into two populations, Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs). KCs are liver-resident phagocytes; MoMFs are recruited from the circulation to the hepatic injury site (Krenkel et al., 2018). Monocytes infiltrate the liver, and recruited monocytes differentiate into intrahepatic MPs, promoting HSC activation in the chronically inflamed liver (Sung, 2021; P. S. Sung et al., 2022). A recent single cell analysis also demonstrated that the recruited and intrahepatic MPs exhibit distinct inflammatory phenotypes during nonalcoholic fatty liver disease (NAFLD) progression (Krenkel et al., 2020).
Two tenofovir prodrugs are currently available for treating human immunodeficiency and hepatitis B virus infections. Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are commonly used antiviral agents with potent antiviral activity, causing liver fibrosis regression (S. W. Lee et al., 2021; Zhao et al., 2020). Another report demonstrated that TDF regulates liver fibrosis by downregulating the PI3K/Akt/mTOR signaling pathway, leading to the activation of HSC apoptosis (S. W. Lee et al., 2021). TAF treatment also resulted in liver fibrosis regression, similar to TDF effects in a fibrosis mouse model (Zhao et al., 2020). However, there are currently no reports showing the effects of TAF treatment on NASH regression. This study investigated the potential therapeutic effects of TAF on NASH in two different in vivo NASH models. Moreover, we examined the effect of TAF on the PI3K/Akt/mTOR signaling pathway in intrahepatic MPs.