Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Attia Y.M.; Tawfiq R.A.; Gibriel A.A.; Ali A.A.; Kassem D.H.; Hammam O.A.; Elmazar M.M.

Journal: Biochemical Pharmacology

Publisher: Elsevier Inc.

Publication Date: April 2021

Volume / Issue: Volume 186

Article No.: 114497

ISSN: 62952

DOI: 10.1016/j.bcp.2021.114497

Scopus: View on Scopus

PubMed: 33675775

Document Type: Article

Access: All Open Access; Hybrid Gold Open Access

Authors and Affiliations

Attia Y.M., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Tawfiq R.A., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Gibriel A.A., The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, Biochemistry & Molecular Biology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Ali A.A., The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Kassem D.H., Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Hammam O.A., Pathology Department, Theodor Bilharz Research Institute, Cairo, Egypt; Elmazar M.M., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt

Abstract

Despite the recent substantial progress in the treatment of hepatocellular carcinoma (HCC) from viral etiology, non-alcoholic steatohepatitis (NASH) is on a trajectory to become the fastest growing indication for HCC-related liver transplantation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily with multifaceted roles in several metabolic disorders, particularly NASH. Its role as a tumor suppressor was also highlighted. Herein, we investigated the effect of obeticholic acid (OCA), as an FXR agonist, on NASH-associated HCC (NASH-HCC) animal model induced by diethylnitrosamine and high fat choline-deficient diet, exploring the potential impact on the suppressor of cytokine signaling 3 (SOCS3)/Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway. Results indicated that OCA treatment upregulated FXR and its key mediator, small heterodimer partner (SHP), with remarkable amelioration in the dysplastic foci observed in the NASH-HCC group. This was paralleled with noticeable downregulation of alpha fetoprotein along with reduction in interferon gamma and transforming growth factor beta-1 hepatic levels besides caspase-3 and p53 upregulation. Moreover, sirtuin-1 (SIRT-1), a key regulator of FXR that controls the regenerative response of the liver, was elevated following OCA treatment. Modulation in the SOCS3/Jak2/STAT3 signaling axis was also reported. In conclusion, OCA attenuated the development and progression of NASH-dependent HCC possibly by interfering with SOCS3/Jak2/STAT3 pathway suggesting the potential use of FXR activators in NASH-related disorders, even at later stages of the disease, to impede its progression to the more deteriorating condition of HCC. © 2021 Elsevier Inc.

Keywords

FXR; Hepatocellular carcinoma; Non-alcoholic steatohepatitis; SOCS3; STAT3; Animals; Carcinoma, Hepatocellular; Chenodeoxycholic Acid; Janus Kinase 2; Liver Neoplasms; Male; Mice; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; alpha fetoprotein; caspase 3; diethylnitrosamine; farnesoid X receptor; gamma interferon; obeticholic acid; protein p53; sirtuin 1; STAT3 protein; suppressor of cytokine signaling 3; transforming growth factor beta1; cell receptor; farnesoid X-activated receptor; Jak2 protein, mouse; Socs3 protein, mouse; Stat3 protein, mouse; animal experiment; animal model; animal tissue; Article; cancer growth; cancer model; cancer staging; controlled study; down regulation; drug mechanism; histopathology; lipid diet; liver cell carcinoma; methionine/choline deficient diet; mouse; nonalcoholic steatohepatitis; nonhuman; nutritional deficiency; pilot study; priority journal; upregulation; animal; liver tumor; metabolism; nonalcoholic fatty liver; pathology; physiology

Citation Information

Scopus Citations: 40

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