Tenofovir alafenamide alleviates nonalcoholic steatohepatitis in mice by blocking the phosphorylation of AKT in intrahepatic mononuclear phagocytes - 15/11/22

Doi : 10.1016/j.biopha.2022.113952

Pu Reun Roh ^a , Sung Min Kim ^a,^{^{1
Present address: GeneOne Life Science, Seoul, Republic of Korea.}} , Byung-Yoon Kang ^a , Kyoung Do Mun ^a , Jong Geun Park ^a , Min Woo Kang ^a , Wonhee Hur ^d , Ji Won Han ^a,^b , Heechul Nam ^a,^c , Seung Kew Yoon ^a,^b , Pil Soo Sung ^a,^b,^⁎,^{^{2
ORCID ID: 0000-0002-5780-9607}}
^a 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
^b 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
^c 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
^d Division of Viral Disease Research, Center for Infectious Disease Research, Korea National Institute of Health, Chungbuk 28159, Republic of Korea

^⁎Corresponding author at: 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.Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of KoreaSeoul06591Republic of Korea

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.

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Abbreviations : NASH, TAF, LPS, HFHC, HSCs, KCs, MoMFs, TDF, HLA-DR, CHO, PD-L1, STZ, ALT, AST, TRIG, TLR4, CDAHFD, MerTK, CCL2, IL, TAA, TNF, NAFLD, MP, NAS

Keywords : NASH mouse model, Pharmacological effect, AKT, Tenofovir alafenamide, Mononuclear phagocyte

Plan

Introduction

Experimental procedures

Isolation of peripheral human CD14⁺ monocytes and in vitro experiments

Establishment of in vivo streptozotocin (STZ)-injected, high-fat, high-cholesterol (HFHC)-fed NASH mouse model

Establishment of in vivo choline-deficient, L-amino acid-defined, high-fat (CDAHF)-fed NASH mouse model

Establishment of thioacetamide (TAA)-treated liver injury mouse model

RNA extraction and quantitative real-time polymerase chain reaction (qRT-PCR)

Immunoblotting

Histological analysis

Intracellular protein staining

Statistical analysis

Results

TAF treatment ameliorates liver injury in the NASH mouse model

The number of PD-L1⁺/IAIE⁺/MerTK⁺ intrahepatic MPs is lower in TAF-treated STZ, HFHC diet-fed NASH mice

The number of PD-L1⁺/IAIE⁺/MerTK⁺ intrahepatic MPs is lower in TAF-treated CDAHF diet-fed NASH mice

Cell surface PD-L1 expression of activated intrahepatic MPs decreased by ex vivo TAF treatment

TAF blocks phosphorylation of AKT in MPs

Discussion

Conclusion

Financial support

CRediT authorship contribution statement

Conflict of interest

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Article 113952- décembre 2022 Retour au numéro

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Tenofovir alafenamide alleviates nonalcoholic steatohepatitis in mice by blocking the phosphorylation of AKT in intrahepatic mononuclear phagocytes - 15/11/22

Abstract

Background and purpose

Experimental approach

Key results

Conclusion and implications

Plan

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