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Girisa S, Aswani BS, Manickasamy MK, Hegde M, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Restoring FXR expression as a novel treatment strategy in liver cancer and other liver disorders. Expert Opin Ther Targets 2025; 29:193-221. [PMID: 40169227 DOI: 10.1080/14728222.2025.2487465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
INTRODUCTION Liver cancer is a leading cause of cancer-associated mortality and is often linked to preexisting liver conditions. Emerging research demonstrates FXR dysregulation, particularly its reduced expression, in the pathogenesis of liver diseases, including inflammation, fibrosis, cholestatic disorders, metabolic dysregulation, and liver cancer. Therefore, this review explores the role of FXR and its agonists in mitigating these conditions. AREAS COVERED This article summarizes FXR's involvement in liver disorders, primarily emphasizing on hepatic neoplasms, and examines the potential of FXR agonists in restoring FXR activity in liver diseases, thereby preventing their progression to liver cancer. The information presented is drawn from existing preclinical and clinical studies specific to each liver disorder, sourced from PubMed. EXPERT OPINION It is well established that FXR expression is downregulated in liver disorders, contributing to disease progression. Notably, FXR agonists have demonstrated therapeutic potential in ameliorating liver diseases, including hepatocellular carcinoma. We believe that activating or restoring FXR expression with agonists offers significant promise for the treatment of liver cancer and other liver conditions. Therefore, FXR modulation by agonists, particularly in combination with other therapeutic agents, could lead to more targeted treatments, improving efficacy while reducing side effects.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Leicester, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
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Di Veroli B, Bentanachs R, Roglans N, Alegret M, Giona L, Profumo E, Berry A, Saso L, Laguna JC, Buttari B. Sex Differences Affect the NRF2 Signaling Pathway in the Early Phase of Liver Steatosis: A High-Fat-Diet-Fed Rat Model Supplemented with Liquid Fructose. Cells 2024; 13:1247. [PMID: 39120278 PMCID: PMC11312139 DOI: 10.3390/cells13151247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/18/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis. The KEAP1/NRF2 signaling pathway, autophagy process (LC3B and LAMP2), and endoplasmic reticulum stress response (XBP1) were analyzed in liver homogenates in male and female rats that were fed a 12-week HFHFr diet. In females, the HFHFr diet resulted in the initial activation of the KEAP1/NRF2 pathway, which was not followed by the modulation of downstream molecular targets; this was possibly due to the increase in KEAP1 levels preventing the nuclear translocation of NRF2 despite its cytosolic increase. Interestingly, while in both sexes the HFHFr diet resulted in an increase in the levels of LC3BII/LC3BI, a marker of autophagosome formation, only males showed a significant upregulation of LAMP2 and XBP1s; this did not occur in females, suggesting impaired autophagic flux in this sex. Overall, our results suggest that males are characterized by a greater ability to cope with an HFHFr metabolic stimulus mainly through an autophagic-mediated proteostatic process while in females, this is impaired. This might depend at least in part upon the fine modulation of the cytoprotective and antioxidant KEAP1/NRF2 pathway resulting in sex differences in the occurrence and severity of MASLD. These results should be considered to design effective therapeutics for MASLD.
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Affiliation(s)
- Benedetta Di Veroli
- Department of Cardiovascular and Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità, 00161 Rome, Italy; (B.D.V.); (E.P.)
| | - Roger Bentanachs
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain; (R.B.); (N.R.); (J.C.L.)
- Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain
| | - Núria Roglans
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain; (R.B.); (N.R.); (J.C.L.)
- Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Marta Alegret
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain; (R.B.); (N.R.); (J.C.L.)
- Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Letizia Giona
- Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (L.G.); (A.B.)
| | - Elisabetta Profumo
- Department of Cardiovascular and Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità, 00161 Rome, Italy; (B.D.V.); (E.P.)
| | - Alessandra Berry
- Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (L.G.); (A.B.)
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University, 00185 Rome, Italy;
| | - Juan Carlos Laguna
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain; (R.B.); (N.R.); (J.C.L.)
- Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Brigitta Buttari
- Department of Cardiovascular and Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità, 00161 Rome, Italy; (B.D.V.); (E.P.)
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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Billig S, Hein M, Kirchner C, Schumacher D, Habigt MA, Mechelinck M, Fuchs D, Klinge U, Theißen A, Beckers C, Bleilevens C, Kramann R, Uhlig M. Coronary Microvascular Dysfunction in Acute Cholestasis-Induced Liver Injury. Biomedicines 2024; 12:876. [PMID: 38672230 PMCID: PMC11048529 DOI: 10.3390/biomedicines12040876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/08/2024] [Accepted: 04/14/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Previous studies have shown cardiac abnormalities in acute liver injury, suggesting a potential role in the associated high mortality. METHODS We designed an experimental study exploring the short-term effects of acute cholestasis-induced liver injury on cardiac function and structure in a rodent bile duct ligation (BDL) model to elucidate the potential interplay. Thirty-seven male Sprague-Dawley rats were subjected to BDL surgery (n = 28) or served as sham-operated (n = 9) controls. Transthoracic echocardiography, Doppler evaluation of the left anterior descending coronary artery, and myocardial contrast echocardiography were performed at rest and during adenosine and dobutamine stress 5 days after BDL. Immunohistochemical staining of myocardial tissue samples for hypoxia and inflammation as well as serum analysis were performed. RESULTS BDL animals exhibited acute liver injury with elevated transaminases, bilirubin, and total circulating bile acids (TBA) 5 days after BDL (TBA control: 0.81 ± 2.54 µmol/L vs. BDL: 127.52 ± 57.03 µmol/L; p < 0.001). Concurrently, cardiac function was significantly impaired, characterized by reduced cardiac output (CO) and global longitudinal strain (GLS) in the echocardiography at rest and under pharmacological stress (CO rest control: 120.6 ± 24.3 mL/min vs. BDL 102.5 ± 16.6 mL/min, p = 0.041; GLS rest control: -24.05 ± 3.8% vs. BDL: -18.5 ± 5.1%, p = 0.01). Myocardial perfusion analysis revealed a reduced myocardial blood flow at rest and a decreased coronary flow velocity reserve (CFVR) under dobutamine stress in the BDL animals (CFVR control: 2.1 ± 0.6 vs. BDL: 1.7 ± 0.5 p = 0.047). Immunofluorescence staining indicated myocardial hypoxia and increased neutrophil infiltration. CONCLUSIONS In summary, acute cholestasis-induced liver injury can lead to impaired cardiac function mediated by coronary microvascular dysfunction, suggesting that major adverse cardiac events may contribute to the mortality of acute liver failure. This may be due to endothelial dysfunction and direct bile acid signaling.
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Affiliation(s)
- Sebastian Billig
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
| | - Marc Hein
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
| | - Celine Kirchner
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
| | - David Schumacher
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
- Department of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Moriz Aljoscha Habigt
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
| | - Mare Mechelinck
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
| | - Dieter Fuchs
- FUJIFILM VisualSonics, Inc., Joop Geesinkweg 140, 1114 AB Amsterdam, The Netherlands
| | - Uwe Klinge
- Department of General, Visceral and Transplantation Surgery, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Alexander Theißen
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
| | - Christian Beckers
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
| | - Christian Bleilevens
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
| | - Rafael Kramann
- Department of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Moritz Uhlig
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany (C.B.)
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Bekheit M, Grundy L, Salih AK, Bucur P, Vibert E, Ghazanfar M. Post-hepatectomy liver failure: A timeline centered review. Hepatobiliary Pancreat Dis Int 2023; 22:554-569. [PMID: 36973111 DOI: 10.1016/j.hbpd.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 03/10/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Post-hepatectomy liver failure (PHLF) is a leading cause of postoperative mortality after liver surgery. Due to its significant impact, it is imperative to understand the risk stratification and preventative strategies for PHLF. The main objective of this review is to highlight the role of these strategies in a timeline centered way around curative resection. DATA SOURCES This review includes studies on both humans and animals, where they addressed PHLF. A literature search was conducted across the Cochrane Library, Embase, MEDLINE/PubMed, and Web of Knowledge electronic databases for English language studies published between July 1997 and June 2020. Studies presented in other languages were equally considered. The quality of included publications was assessed using Downs and Black's checklist. The results were presented in qualitative summaries owing to the lack of studies qualifying for quantitative analysis. RESULTS This systematic review with 245 studies, provides insight into the current prediction, prevention, diagnosis, and management options for PHLF. This review highlighted that liver volume manipulation is the most frequently studied preventive measure against PHLF in clinical practice, with modest improvement in the treatment strategies over the past decade. CONCLUSIONS Remnant liver volume manipulation is the most consistent preventive measure against PHLF.
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Affiliation(s)
- Mohamed Bekheit
- Department of Surgery, NHS Grampian, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK; Institute of Medical Sciences, Medical School, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK; Hépatica, Integrated Center of HPB Care, Elite Hospital, Agriculture Road, Alexandria, Egypt.
| | - Lisa Grundy
- Department of Surgery, NHS Grampian, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK
| | - Ahmed Ka Salih
- Department of Surgery, NHS Grampian, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK; Institute of Medical Sciences, Medical School, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK
| | - Petru Bucur
- Department of Surgery, University Hospital Tours, Val de la Loire 37000, France
| | - Eric Vibert
- Centre Hépatobiliaire, Paul Brousse Hospital, 12 Paul Valliant Couturier, 94804 Villejuif, France
| | - Mudassar Ghazanfar
- Department of Surgery, NHS Grampian, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK
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Tang HX, Yi FZ, Huang ZS, Huang GL. Role of Hippo signaling pathway in occurrence, development, and treatment of primary hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2022; 30:34-42. [DOI: 10.11569/wcjd.v30.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The Hippo signal transduction pathway, first discovered in drosophila, is a highly conserved signaling pathway that inhibits cell growth. Its core molecules include Hpo, Sav, Wts, Mats, and downstream effector factor YAP/TAZ. Corresponding homologous analogs in humans are STE20 protein-like kinase 1/2, Salvatore family 1, large tumor suppressor gene 1/2 kinase, and MOB kinase activator 1A/1B. Inactivation of this pathway promotes the survival, proliferation, invasive migration, and metastasis of cancer cells. This process can be seen in liver cancer, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, melanoma, glioma, and other cancers, which can lead to the occurrence of resistance to chemotherapy, radiotherapy, or immunotherapy. This paper aims to review the role of the Hippo signaling pathway in the occurrence, development, and treatment of liver cancer, in order to provide reference for new targeted therapies for liver cancer.
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Affiliation(s)
- Hui-Xian Tang
- Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Fu-Zhen Yi
- Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Zan-Song Huang
- Department of Gastroenter-ology, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China,Guangxi Clinical Research Center for Hepatobiliary Diseases, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Gui-Liu Huang
- Department of Gastroenter-ology, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
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Bayat G, Hashemi SA, Karim H, Fallah P, Hedayatyanfard K, Bayat M, Khalili A. Biliary cirrhosis-induced cardiac abnormality in rats: Interaction between Farnesoid-X-activated receptors and the cardiac uncoupling proteins 2 and 3. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:126-133. [PMID: 35656450 PMCID: PMC9118280 DOI: 10.22038/ijbms.2022.60888.13485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 01/03/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVES This study aimed to evaluate the relationship between Farnesoid-X-activated receptors (FXR) as nuclear regulators of the antioxidant defense system as well as cardiac mitochondrial carrier proteins of UCP2 and UCP3 in cardiac damage induced by cirrhosis. MATERIALS AND METHODS Twenty-two male Wistar rats (200-250 g) were randomly divided into 3 experimental groups, including a control group (n=6), a sham-operated group (n=8), and a bile duct ligated (BDL) group (n=8). Four weeks after surgical intervention, biochemical assessment (AST, ALT, GGT, LDH, and ALP), histological observation, and molecular evaluation (FXR, UCP2, UCP3, BNP, Caspase3, and GAPDH) using real-time RT-PCR were performed. RESULTS Compared with the sham-operation group, the BDL group showed a significant rise in liver enzymes of AST, ALT, GGT, LDH, and ALP. Defined fibrotic and necrotic bundles and thick reticulin fibers were also found in BDL liver tissue. Besides liver morphological alterations, left ventricles of BDL ones were also associated with defined cardiomyocyte hypertrophy, myofiber vacuolization, and clear pigmentation. Findings showed a significant up-regulation of cardiac Brain Natriuretic Peptide (BNP) along with marked down-regulation in hepatic FXR, cardiac FXR, and cardiac UCP2 and UCP3. However, the expression of caspase 3 in the cardiac tissue was not affected by BDL operation during 4 weeks. CONCLUSION Expression of FXR as an upstream regulator of cellular redox status, besides the non-enzymatic ROS buffering defense system of cardiac UCPs, has a pivotal role in the pathogenesis of cirrhotic-induced cardiac abnormality in rats.
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Affiliation(s)
- Gholamreza Bayat
- Department of Physiology-Pharmacology-Medical Physic, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Seyed Ali Hashemi
- Department of Pathology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Hosein Karim
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Department of Cardiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Parviz Fallah
- Department of Medical Laboratory Sciences, Faculty of Para-Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Keshvad Hedayatyanfard
- Department of Physiology-Pharmacology-Medical Physic, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Mahnaz Bayat
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Azadeh Khalili
- Department of Physiology-Pharmacology-Medical Physic, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
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Sen A, Anakk S. Jekyll and Hyde: nuclear receptors ignite and extinguish hepatic oxidative milieu. Trends Endocrinol Metab 2021; 32:790-802. [PMID: 34481730 PMCID: PMC8464172 DOI: 10.1016/j.tem.2021.07.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/21/2022]
Abstract
Nuclear receptors (NRs) are ligand-binding transcription factors that regulate gene networks and physiological responses. Often oxidative stress precedes the onset of liver diseases, and Nrf2 is a key regulator of antioxidant pathways. NRs crosstalk with Nrf2, since NR activation can influence the oxidative milieu by modulating reductive cellular processes. Diet and xenobiotics also regulate NR expression and activity, suggesting a feedback loop. Depending on the tissue context and cues, NRs either increase or decrease toxicity and oxidative damage. Many FDA-approved drugs target NRs, and one could potentially repurpose them to ameliorate reactive oxygen species (ROS). Here, we discuss how several NRs modulate oxidative stress subsequent to diet, organic pollutants, and drug-induced injury to the liver.
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Affiliation(s)
- Anushna Sen
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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Kaur I, Tiwari R, Naidu VGM, Ramakrishna S, Tripathi DM, Kaur S. Bile Acids as Metabolic Inducers of Hepatocyte Proliferation and Liver Regeneration. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-021-00221-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Jung K, Kim M, So J, Lee SH, Ko S, Shin D. Farnesoid X Receptor Activation Impairs Liver Progenitor Cell-Mediated Liver Regeneration via the PTEN-PI3K-AKT-mTOR Axis in Zebrafish. Hepatology 2021; 74:397-410. [PMID: 33314176 PMCID: PMC8605479 DOI: 10.1002/hep.31679] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 11/15/2020] [Accepted: 11/29/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Following mild liver injury, pre-existing hepatocytes replicate. However, if hepatocyte proliferation is compromised, such as in chronic liver diseases, biliary epithelial cells (BECs) contribute to hepatocytes through liver progenitor cells (LPCs), thereby restoring hepatic mass and function. Recently, augmenting innate BEC-driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end-stage liver diseases. Despite this attention, the molecular basis of BEC-driven liver regeneration remains poorly understood. APPROACH AND RESULTS By performing a chemical screen with the zebrafish hepatocyte ablation model, in which BECs robustly contribute to hepatocytes, we identified farnesoid X receptor (FXR) agonists as inhibitors of BEC-driven liver regeneration. Here we show that FXR activation blocks the process through the FXR-PTEN (phosphatase and tensin homolog)-PI3K (phosphoinositide 3-kinase)-AKT-mTOR (mammalian target of rapamycin) axis. We found that FXR activation blocked LPC-to-hepatocyte differentiation, but not BEC-to-LPC dedifferentiation. FXR activation also suppressed LPC proliferation and increased its death. These defects were rescued by suppressing PTEN activity with its chemical inhibitor and ptena/b mutants, indicating PTEN as a critical downstream mediator of FXR signaling in BEC-driven liver regeneration. Consistent with the role of PTEN in inhibiting the PI3K-AKT-mTOR pathway, FXR activation reduced the expression of pS6, a marker of mTORC1 activation, in LPCs of regenerating livers. Importantly, suppressing PI3K and mTORC1 activities with their chemical inhibitors blocked BEC-driven liver regeneration, as did FXR activation. CONCLUSIONS FXR activation impairs BEC-driven liver regeneration by enhancing PTEN activity; the PI3K-AKT-mTOR pathway controls the regeneration process. Given the clinical trials and use of FXR agonists for multiple liver diseases due to their beneficial effects on steatosis and fibrosis, the detrimental effects of FXR activation on LPCs suggest a rather personalized use of the agonists in the clinic.
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Affiliation(s)
- Kyounghwa Jung
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
| | - Minwook Kim
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
| | - Juhoon So
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
| | - Seung-Hoon Lee
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
| | - Sungjin Ko
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA;,Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
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11
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Wang H, Wei X, Wei X, Sun X, Huang X, Liang Y, Xu W, Zhu X, Lin X, Lin J. 4-hydroxybenzo[d]oxazol-2(3H)-one ameliorates LPS/D-GalN-induced acute liver injury by inhibiting TLR4/NF-κB and MAPK signaling pathways in mice. Int Immunopharmacol 2020; 83:106445. [PMID: 32272395 DOI: 10.1016/j.intimp.2020.106445] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/16/2020] [Accepted: 03/24/2020] [Indexed: 01/09/2023]
Abstract
The purpose of this study was to synthesize 4-hydroxybenzo[d]oxazol-2(3H)-one (HBO) and to investigate its protective effects on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury. HBO (C7H5O3N) was synthesized based on 2-nitro-resorcinol and identified by physicochemical analysis. In the animal experiment, mice were pretreated with HBO (50, 100, 200 mg/kg) for 10 days. At the end of pretreatment, the animals were injected with LPS (10 µg/kg)/D-GalN (700 mg/kg). The results showed that HBO significantly alleviated liver injury induced by LPS/D-GalN in mice. It remarkably decreased inflammatory response by reducing the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, HBO notably attenuated hepatocyte apoptosis by inhibiting the release of Cytochrome C (Cyt C) from mitochondria into the cytoplasm and regulating the expression of B-cell lymphoma-2 (Bcl-2) family. Furthermore, the result showed that HBO inhibited the expressions of nuclear factor kappa-B p50 (NF-κBp50), toll-like receptor 4 (TLR4), and myeloid differentiation factor 88 (MyD88), as well as the phosphorylation of inhibitor of nuclear factor kappa-B (IκB), inhibitor of nuclear factor kappa-B kinase-α/β (IKK-α/β), nuclear factor kappa-B p65 (NF-κBp65), suggesting that HBO had a certain influence on the TLR4/NF-κB pathway. In addition, the mitogen-activated protein kinase (MAPK) signaling pathway was also affected by HBO, as evidenced by the decrease in the phosphorylation levels of extracellular regulated protein kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38). In conclusion, our study suggested that HBO could protect against LPS/D-GalN-induced liver injury, moreover, treatment with HBO appeared to be capable of further regulating the TLR4/NF-κB and MAPK signaling pathways.
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Affiliation(s)
- Hongyuan Wang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China
| | - Xiugui Wei
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China
| | - Xian Wei
- Youjiang Medical University for Nationalities, Youjiang, Guangxi, China
| | - Xuemei Sun
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China
| | - Xiukun Huang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China
| | - Yingqin Liang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China
| | - Wanpeng Xu
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China
| | - Xunshuai Zhu
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China
| | - Xing Lin
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China.
| | - Jun Lin
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, China.
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12
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Tsai MS, Lee HM, Huang SC, Sun CK, Chiu TC, Chen PH, Lin YC, Hung TM, Lee PH, Kao YH. Nerve growth factor induced farnesoid X receptor upregulation modulates autophagy flux and protects hepatocytes in cholestatic livers. Arch Biochem Biophys 2020; 682:108281. [PMID: 32001246 DOI: 10.1016/j.abb.2020.108281] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/20/2020] [Accepted: 01/24/2020] [Indexed: 02/08/2023]
Abstract
Upregulation of nerve growth factor (NGF) in parenchymal hepatocytes has been shown to exert hepatoprotective function during cholestatic liver injury. However, the modulatory role of NGF in regulation of liver autophagy remains unclear. This study aimed to scrutinize the regulatory role of NGF in hepatic expression of farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor, and to determine its cytoprotective effect on BA-induced autophagy and cytotoxicity. Livers of human hepatolithiasis and bile duct ligation (BDL)-induced mouse cholestasis were used for histopathological and molecular detection. The regulatory roles of NGF in autophagy flux and FXR expression, as well as its hepatoprotection against BA cytotoxicity were examined in cultured hepatocytes. FXR downregulation in human hepatolithiasis livers showed positive correlation with hepatic NGF levels. NGF administration upregulated hepatic FXR levels, while neutralization of NGF decreased FXR expression in BDL-induced cholestatic mouse livers. In vitro studies demonstrated that NGF upregulated FXR expression, increased cellular LC3 levels, and exerted hepatoprotective effect in cultured primary rat hepatocytes. Conversely, autophagy inhibition abrogated NGF-driven cytoprotection under BA exposure, suggesting involvement of NGF-modulated auophagy flux. Although FXR agonistic GW4064 stimulation did not affect auophagic LC3 levels, FXR activity inhibition significantly potentiated BA-induced cytotoxicity and increased cellular p62/SQSTM1 and Rab7 protein in SK-Hep1 hepatocytes. Moreover, FXR gene silencing abolished the protective effect of NGF under BA exposure. These findings support that NGF modulates autophagy flux via FXR upregulation and protects hepatocytes against BA-induced cytotoxicity. NGF/FXR axis is a novel therapeutic target for treatment of cholestatic liver diseases.
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Affiliation(s)
- Ming-Shian Tsai
- Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan; Body Health and Beauty Center, Jiann-Ren Hospital, Kaohsiung, Taiwan
| | - Hui-Ming Lee
- Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
| | - Shih-Che Huang
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
| | - Cheuk-Kwan Sun
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | | | - Po-Han Chen
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
| | - Yu-Chun Lin
- Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
| | - Tzu-Min Hung
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan; Committee for Integration and Promotion of Advanced Medicine and Biotechnology, E-Da Healthcare Group, Kaohsiung, Taiwan
| | - Po-Huang Lee
- Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan; Committee for Integration and Promotion of Advanced Medicine and Biotechnology, E-Da Healthcare Group, Kaohsiung, Taiwan.
| | - Ying-Hsien Kao
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.
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13
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Ozaki M. Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol 2019; 100:62-73. [PMID: 31669133 DOI: 10.1016/j.semcdb.2019.10.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 01/08/2023]
Abstract
Liver regeneration is an important and necessary process that the liver depends on for recovery from injury. The regeneration process consists of a complex network of cells and organs, including liver cells (parenchymal and non-parenchymal cells) and extrahepatic organs (thyroid, adrenal glands, pancreas, duodenum, spleen, and autonomic nervous system). The regeneration process of a normal, healthy liver depends mainly on hepatocyte proliferation, growth, and programmed cell death. Cell proliferation and growth are regulated in a cooperative manner by interleukin (IL)-6/janus kinase (Jak)/signal transducers and activators of transcription-3 (STAT3), and phosphoinositide 3-kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathways. The IL-6/Jak/STAT3 pathway regulates hepatocyte proliferation and protects against cell death and oxidative stress. The PI3-K/PDK1/Akt pathway is primarily responsible for the regulation of cell size, sending mitotic signals in addition to pro-survival, antiapoptotic and antioxidative signals. Though programmed cell death may interfere with liver regeneration in a pathological situation, it seems to play an important role during the termination phase, even in a normal, healthy liver regeneration. However, further study is needed to fully elucidate the mechanisms regulating the processes of liver regeneration with regard to cell-to-cell and organ-to-organ networks at the molecular and cellular levels.
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Affiliation(s)
- Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
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14
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Haga S, YiMin, Yamaki H, Jin S, Sogon T, Morita N, Ozaki M. Extracts of bilberry ( Vaccinium myrtillus L.) fruits improve liver steatosis and injury in mice by preventing lipid accumulation and cell death. Biosci Biotechnol Biochem 2019; 83:2110-2120. [PMID: 31244392 DOI: 10.1080/09168451.2019.1634514] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Bilberry has been reported to have anti-oxidant and anti-inflammatory properties. We studied the effect of bilberry (Vaccinium myrtillus L.) fruits extracts (BEs) on the pathogenesis caused by lipid accumulation in fatty liver and non-alcoholic steatohepatitis (NASH). 5 μg/ml of BEs was enough to suppress lipid accumulation in the fatty liver model of the mouse hepatic AML12 cells. BEs increased cell viability and anti-oxidant capacity, presumably by activating (phosphorylating) Akt/STAT3 and inducing MnSOD/catalase. BEs also significantly reduced Rubicon and induced p62/SQSTM1, possibly contributing to reduce cellular lipids (lipophagy). When the mice were fed supplemented with BEs (5% or 10%, w/w), hepatic steatosis, injury, and hypercholesterolemia/hyperglycemia were significantly improved. Furthermore, histological and cytokine studies indicated that BEs possibly suppress hepatic inflammation (hepatitis) and fibrosis. Therefore, BEs improved liver steatosis and injury, and potentially suppress fibrosis by suppressing inflammatory response, which therefore may prevent the progression of fatty liver to NASH.
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Affiliation(s)
- Sanae Haga
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University , Sapporo , Hokkaido , Japan
| | - YiMin
- Department of Advanced Medicine, Graduate School of Medicine, Hokkaido University , Sapporo , Hokkaido , Japan
| | - Hikari Yamaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University , Sapporo , Hokkaido , Japan
| | - Shigeki Jin
- Department of Forensic Medicine, Graduate School of Medicine, Hokkaido University , Sapporo , Hokkaido , Japan
| | | | - Naoki Morita
- Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) , Sapporo , Hokkaido , Japan
| | - Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University , Sapporo , Hokkaido , Japan.,Laboratory of Molecular and Functional Bio-imaging, Faculty of Health Sciences, Hokkaido University , Sapporo , Hokkaido , Japan
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15
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Khambu B, Li T, Yan S, Yu C, Chen X, Goheen M, Li Y, Lin J, Cummings OW, Lee YA, Friedman S, Dong Z, Feng GS, Wu S, Yin XM. Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury. Hepatology 2019; 69:2196-2213. [PMID: 30520052 PMCID: PMC6461497 DOI: 10.1002/hep.30407] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 11/27/2018] [Indexed: 12/12/2022]
Abstract
Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagy-related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up-regulated expression of farnesoid X receptor (Fxr) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, codeletion of nuclear factor erythroid 2-related factor 2 (Nrf2) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury.
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Affiliation(s)
- Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Changshun Yu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA,Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiaoyun Chen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Michael Goheen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yong Li
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jingmei Lin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Oscar W. Cummings
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Youngmin A. Lee
- Department of Medicine, Mount Sinai Medical School, New York, NY, USA,Laboratory of RNA Molecular Biology, The Rockefeller University, New York, NY, USA
| | - Scott Friedman
- Department of Medicine, Mount Sinai Medical School, New York, NY, USA
| | - Zheng Dong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China,Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Gen-Sheng Feng
- Department of Pathology, University of California at San Diego, San Diego, CA, USA
| | - Shangwei Wu
- Center of Pathology and Laboratory Medicine, Nankai Hospital, Tianjin, China
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA,Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China,Corresponding Author. Xiao-Ming Yin, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, Phone: 317-274-1779, Fax: 317-491-6639,
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16
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Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol 2017; 23:6549-6570. [PMID: 29085205 PMCID: PMC5643281 DOI: 10.3748/wjg.v23.i36.6549] [Citation(s) in RCA: 176] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/25/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver (simple steatosis), a small percentage develops progressive liver disease. Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available. The treatment for ALD remains as it was 50 years ago: abstinence, nutritional support and corticosteroids (or pentoxifylline as an alternative if steroids are contraindicated). As for NAFLD, the treatment modality is mainly directed toward weight loss and co-morbidity management. Therefore, new pathophysiology directed therapies are urgently needed. However, the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination therapy towards multiple targets would eventually be required. In this review, we delineate the treatment options in ALD and NAFLD, including various new targeted therapies that are currently under investigation. We hope that soon we will be having an effective multi-therapeutic regimen for each disease.
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Affiliation(s)
- Sukhpreet Singh
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, Nebraska Medical Center, Omaha, NE 68198, United States
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17
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Gai Z, Chu L, Xu Z, Song X, Sun D, Kullak-Ublick GA. Farnesoid X receptor activation protects the kidney from ischemia-reperfusion damage. Sci Rep 2017; 7:9815. [PMID: 28852062 PMCID: PMC5575310 DOI: 10.1038/s41598-017-10168-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 06/16/2017] [Indexed: 02/06/2023] Open
Abstract
Farnesoid X receptor (FXR) activation has been reported to reduce inflammation and oxidative stress. Because both inflammation and oxidative stress are critical for tissue destruction during kidney ischemia reperfusion (I/R) injury, we investigated the protective role of FXR against kidney damage induced by I/R in mice. Mice undergoing renal I/R developed the typical features of acute kidney injury (AKI): increased creatinine, albuminuria, tubular necrosis and apoptosis. Inflammatory cytokine production and oxidative stress were also markedly increased. In mice pretreated with 6-ethyl-chenodeoxycholic acid (6-ECDCA), a selective FXR agonist, I/R induced changes were prevented and renal function and structure were improved. Moreover, FXR activation also effectively prevented the subsequent progression of AKI to chronic kidney disease (CKD) by ameliorating glomerulosclerosis and interstitial fibrosis and by suppressing fibrogenic gene expression. FXR mRNA levels were inversely correlated with the progression to CKD in mice and with the degree of interstitial fibrosis in human biopsies. In further experiments administering 6-ECDCA to renal proximal tubular cells cultured under hypoxia, the renoprotective effects of FXR activation were associated with inhibition of oxidative and ER stress and with increased antioxidant activity. In conclusion, FXR agonists may have a therapeutic role in conditions associated with ischemic kidney damage.
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Affiliation(s)
- Zhibo Gai
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Lei Chu
- Department of Urology, Tengzhou Central People's Hospital, Zaozhuang, People's Republic of China
| | - Zhenqiang Xu
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, People's Republic of China
| | - Xiaoming Song
- Department of Thoracic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China
| | - Dongfeng Sun
- Department of Thoracic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China.
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
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