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Ramachandran P, Brice M, Sutherland EF, Hoy AM, Papachristoforou E, Jia L, Turner F, Kendall TJ, Marwick JA, Carragher NO, Oro D, Feigh M, Leeming DJ, Nielsen MJ, Karsdal MA, Hartmann N, Erickson M, Adorini L, Roth JD, Fallowfield JA. Aberrant basement membrane production by HSCs in MASLD is attenuated by the bile acid analog INT-767. Hepatol Commun 2024; 8:e0574. [PMID: 39585303 PMCID: PMC11596521 DOI: 10.1097/hc9.0000000000000574] [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: 03/13/2024] [Accepted: 09/07/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND The farnesoid X receptor (FXR) is a leading therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis. INT-767, a potent FXR agonist, has shown promise in preclinical models. We aimed to define the mechanisms of INT-767 activity in experimental MASH and dissect cellular and molecular targets of FXR agonism in human disease. METHODS Leptin-deficient ob/ob mice were fed a MASH-inducing diet for 15 weeks before the study started. After baseline liver biopsy and stratification, mice were allocated to INT-767 (10 mg/kg/d) or vehicle treatment for 8 weeks, either alongside an ongoing MASH diet (progression) or following conversion to normal chow (reversal). Effects on extracellular matrix remodeling were analyzed histologically and by RNA-sequencing. Serum fibrosis biomarkers were measured longitudinally. Human liver samples were investigated using bulk and single-cell RNA-sequencing, histology, and cell culture assays. RESULTS INT-767 treatment was antifibrotic during MASH progression but not reversal, attenuating the accumulation of type I collagen and basement membrane proteins (type IV collagen and laminin). Circulating levels of PRO-C4, a type IV collagen formation marker, were reduced by INT-767 treatment and correlated with fibrosis. Expression of basement membrane constituents also correlated with fibrosis severity and adverse clinical outcomes in human MASH. Single-cell RNA-sequencing analysis of mouse and human livers, and immunofluorescence staining colocalized FXR and basement membrane expression to myofibroblasts within the fibrotic niche. Treatment of culture-activated primary human HSCs with INT-767 decreased expression of basement membrane components. CONCLUSIONS These findings highlight the importance of basement membrane remodeling in MASH pathobiology and as a source of circulating biomarkers. Basement membrane deposition by activated HSCs is abrogated by INT-767 treatment and measurement of basement membrane molecules should be included when determining the therapeutic efficacy of FXR agonists.
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Affiliation(s)
- Prakash Ramachandran
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Madara Brice
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Elena F. Sutherland
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Anna M. Hoy
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Eleni Papachristoforou
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Li Jia
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Frances Turner
- Edinburgh Genomics, University of Edinburgh, Edinburgh, UK
| | - Timothy J. Kendall
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
- Edinburgh Pathology, University of Edinburgh, Edinburgh, UK
| | - John A. Marwick
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Neil O. Carragher
- Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | | | | | | | | | | | | | - Mary Erickson
- Intercept Pharmaceuticals Inc., San Diego, California, USA
| | | | | | - Jonathan A. Fallowfield
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
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2
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Lee MH, Nuccio SP, Mohanty I, Hagey LR, Dorrestein PC, Chu H, Raffatellu M. How bile acids and the microbiota interact to shape host immunity. Nat Rev Immunol 2024; 24:798-809. [PMID: 39009868 DOI: 10.1038/s41577-024-01057-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 07/17/2024]
Abstract
Bile acids are increasingly appearing in the spotlight owing to their novel impacts on various host processes. Similarly, there is growing attention on members of the microbiota that are responsible for bile acid modifications. With recent advances in technology enabling the discovery and continued identification of microbially conjugated bile acids, the chemical complexity of the bile acid landscape in the body is increasing at a rapid pace. In this Review, we summarize our current understanding of how bile acids and the gut microbiota interact to modulate immune responses during homeostasis and disease, with a particular focus on the gut.
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Affiliation(s)
- Michael H Lee
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA
| | - Sean-Paul Nuccio
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA
| | - Ipsita Mohanty
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Lee R Hagey
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
- Collaborative Mass Spectrometry Innovation Center, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
| | - Hiutung Chu
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA
| | - Manuela Raffatellu
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA.
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3
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Ding C, Wang Z, Dou X, Yang Q, Ning Y, Kao S, Sang X, Hao M, Wang K, Peng M, Zhang S, Han X, Cao G. Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis. Aging Dis 2024; 15:1508-1536. [PMID: 37815898 PMCID: PMC11272191 DOI: 10.14336/ad.2023.0830] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/30/2023] [Indexed: 10/12/2023] Open
Abstract
The farnesoid X receptor (FXR), a ligand-activated transcription factor, plays a crucial role in regulating bile acid metabolism within the enterohepatic circulation. Beyond its involvement in metabolic disorders and immune imbalances affecting various tissues, FXR is implicated in microbiota modulation, gut-to-brain communication, and liver disease. The liver, as a pivotal metabolic and detoxification organ, is susceptible to damage from factors such as alcohol, viruses, drugs, and high-fat diets. Chronic or recurrent liver injury can culminate in liver fibrosis, which, if left untreated, may progress to cirrhosis and even liver cancer, posing significant health risks. However, therapeutic options for liver fibrosis remain limited in terms of FDA-approved drugs. Recent insights into the structure of FXR, coupled with animal and clinical investigations, have shed light on its potential pharmacological role in hepatic fibrosis. Progress has been achieved in both fundamental research and clinical applications. This review critically examines recent advancements in FXR research, highlighting challenges and potential mechanisms underlying its role in liver fibrosis treatment.
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Affiliation(s)
- Chuan Ding
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
- Jinhua Institute, Zhejiang Chinese Medical University, Jinhua, China.
| | - Zeping Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Xinyue Dou
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Qiao Yang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Yan Ning
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Shi Kao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Xianan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Min Hao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Kuilong Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Mengyun Peng
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Shuosheng Zhang
- College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, China.
| | - Xin Han
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
- Jinhua Institute, Zhejiang Chinese Medical University, Jinhua, China.
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
- Jinhua Institute, Zhejiang Chinese Medical University, Jinhua, China.
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4
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Di Giorgio C, Morretta E, Lupia A, Bellini R, Massa C, Urbani G, Bordoni M, Marchianò S, Lachi G, Rapacciuolo P, Finamore C, Sepe V, Chiara Monti M, Moraca F, Natalizi N, Graziosi L, Distrutti E, Biagioli M, Catalanotti B, Donini A, Zampella A, Fiorucci S. Bile acids serve as endogenous antagonists of the Leukemia inhibitory factor (LIF) receptor in oncogenesis. Biochem Pharmacol 2024; 223:116134. [PMID: 38494064 DOI: 10.1016/j.bcp.2024.116134] [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: 12/04/2023] [Revised: 03/11/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
The leukemia inhibitory factor (LIF) is member of interleukin (IL)-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFRβ subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.
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Affiliation(s)
| | - Elva Morretta
- University of Salerno, Department of Pharmacy, Salerno, Italy
| | - Antonio Lupia
- University of Cagliari, Department of Life and Environmental Sciences, Cagliari, Italy; Net4Science srl, University "Magna Græcia", Campus Salvatore Venuta, Viale Europa, Catanzaro 88100, Italy
| | - Rachele Bellini
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Carmen Massa
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Ginevra Urbani
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Martina Bordoni
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Silvia Marchianò
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Ginevra Lachi
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | | | - Claudia Finamore
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Valentina Sepe
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | | | - Federica Moraca
- Net4Science srl, University "Magna Græcia", Campus Salvatore Venuta, Viale Europa, Catanzaro 88100, Italy; University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | | | | | | | - Michele Biagioli
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Bruno Catalanotti
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Annibale Donini
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Angela Zampella
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Stefano Fiorucci
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy.
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Cheng Z, Chen Y, Schnabl B, Chu H, Yang L. Bile acid and nonalcoholic steatohepatitis: Molecular insights and therapeutic targets. J Adv Res 2024; 59:173-187. [PMID: 37356804 PMCID: PMC11081971 DOI: 10.1016/j.jare.2023.06.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/06/2023] [Accepted: 06/20/2023] [Indexed: 06/27/2023] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) has been the second most common cause of liver transplantation in the United States. To date, NASH pathogenesis has not been fully elucidated but is multifactorial, involving insulin resistance, obesity, metabolic disorders, diet, dysbiosis, and gene polymorphism. An effective and approved therapy for NASH has also not been established. Bile acid is long known to have physiological detergent function in emulsifying and absorbing lipids and lipid-soluble molecules within the intestinal lumen. With more and more in-depth understandings of bile acid, it has been deemed to be a pivotal signaling molecule, which is capable of regulating lipid and glucose metabolism, liver inflammation, and fibrosis. In recent years, a plethora of studies have delineated that disrupted bile acid homeostasis is intimately correlated with NASH disease severity. AIMS The review aims to clarify the role of bile acid in hepatic lipid and glucose metabolism, liver inflammation, as well as liver fibrosis, and discusses the safety and efficacy of some pharmacological agents targeting bile acid and its associated pathways for NASH. KEY SCIENTIFIC CONCEPTS OF REVIEW Bile acid has a salutary effect on hepatic metabolic disorders, which can ameliorate liver fat accumulation and insulin resistance mainly through activating Takeda G-protein coupled receptor 5 and farnesoid X receptor. Moreover, bile acid also exerts anti-inflammation and anti-fibrosis properties. Furthermore, bile acid has great potential in nonalcoholic liver disease stratification and treatment of NASH.
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Affiliation(s)
- Zilu Cheng
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China
| | - Yixiong Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China.
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China.
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [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: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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7
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Wang J, Yang N, Xu Y. Natural Products in the Modulation of Farnesoid X Receptor Against Nonalcoholic Fatty Liver Disease. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:291-314. [PMID: 38480498 DOI: 10.1142/s0192415x24500137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global health concern with a high prevalence and increasing economic burden, but official medicine remains unavailable. Farnesoid X receptor (FXR), a nuclear receptor member, is one of the most promising drug targets for NAFLD therapy that plays a crucial role in modulating bile acid, glucose, and lipid homeostasis, as well as inhibits hepatic inflammation and fibrosis. However, the rejection of the FXR agonist, obecholic acid, by the Food and Drug Administration for treating hepatic fibrosis raises a question about the functions of FXR in NAFLD progression and the therapeutic strategy to be used. Natural products, such as FXR modulators, have become the focus of attention for NAFLD therapy with fewer adverse reactions. The anti-NAFLD mechanisms seem to act as FXR agonists and antagonists or are involved in the FXR signaling pathway activation, indicating a promising target of FXR therapeutic prospects using natural products. This review discusses the effective mechanisms of FXR in NAFLD alleviation, and summarizes currently available natural products such as silymarin, glycyrrhizin, cycloastragenol, berberine, and gypenosides, for targeting FXR, which can facilitate development of naturally targeted drug by medicinal specialists for effective treatment of NAFLD.
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Affiliation(s)
- Jing Wang
- Department of Pharmacy, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, P. R. China
| | - Na Yang
- Department of Pharmacy, Nanjing Drum Tower Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, P. R. China
| | - Yu Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Cailun Road 1200, Shanghai 201203, P. R. China
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8
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Azizsoltani A, Hatami B, Zali MR, Mahdavi V, Baghaei K, Alizadeh E. Obeticholic acid-loaded exosomes attenuate liver fibrosis through dual targeting of the FXR signaling pathway and ECM remodeling. Biomed Pharmacother 2023; 168:115777. [PMID: 37913732 DOI: 10.1016/j.biopha.2023.115777] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/12/2023] [Accepted: 10/20/2023] [Indexed: 11/03/2023] Open
Abstract
End-stage of liver fibrosis as a precancerous state could lead to cirrhosis and hepatocellular carcinoma which liver transplantation is the only effective treatment. Previous studies have indicated that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) protect against hepatic injuries. However, free OCA administration results in side effects in clinical trials that could be alleviated by applying bio carriers such as MSC-derived exosomes (Exo) with the potential to mimic the biological regenerative effect of their parent cells, as proposed in this study. Loading OCA into the Exo was conducted via water bath sonication. Ex vivo bio distribution studies validated the Exo-loaded OCA more permanently accumulated in the liver. Using CCL4-induced liver fibrosis, we proposed whether Exo isolated from human Warton's Jelly mesenchymal stem cells loaded with a minimal dosage of OCA can facilitate liver recovery. Notably, Exo-loaded OCA exerted additive anti-fibrotic efficacy on histopathological features in CCL4-induced fibrotic mice. Compared to baseline, Exo-mediated delivery OCA results in marked improvements in the fibrotic-related indicators as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations. Accordingly, the synergistic impact of Exo-loaded OCA as a promising approach is associated with the inactivation of hepatic stellate cells (HSCs), extracellular matrix (ECM) remodeling, and Fxr-Cyp7a1 cascade on CCL4-induced liver fibrosis mice. In conclusion, our data confirmed the additive protective effects of Exo-loaded OCA in fibrotic mice, which suggests a valuable therapeutic strategy to combat liver fibrosis. Furthermore, the use of Exo for accurate drug delivery to the liver tissue can be inspiring.
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Affiliation(s)
- Arezou Azizsoltani
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahideh Mahdavi
- Iranian Research Institute of Plant Protection (IRIPP), Agricultural Research, Education and Extension Organization (AREEO), Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Effat Alizadeh
- Drug Applied Research Center and Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Di Ciaula A, Bonfrate L, Khalil M, Portincasa P. The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease. Intern Emerg Med 2023; 18:2181-2197. [PMID: 37515676 PMCID: PMC10635993 DOI: 10.1007/s11739-023-03343-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 06/08/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy.
| | - Mohamad Khalil
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Piero Portincasa
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
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10
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Zhu F, Zheng S, Zhao M, Shi F, Zheng L, Wang H. The regulatory role of bile acid microbiota in the progression of liver cirrhosis. Front Pharmacol 2023; 14:1214685. [PMID: 37416060 PMCID: PMC10320161 DOI: 10.3389/fphar.2023.1214685] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023] Open
Abstract
Bile acids (BAs) are synthesized in liver tissue from cholesterol and are an important endocrine regulator and signaling molecule in the liver and intestine. It maintains BAs homeostasis, and the integrity of intestinal barrier function, and regulates enterohepatic circulation in vivo by modulating farnesoid X receptors (FXR) and membrane receptors. Cirrhosis and its associated complications can lead to changes in the composition of intestinal micro-ecosystem, resulting in dysbiosis of the intestinal microbiota. These changes may be related to the altered composition of BAs. The BAs transported to the intestinal cavity through the enterohepatic circulation are hydrolyzed and oxidized by intestinal microorganisms, resulting in changes in their physicochemical properties, which can also lead to dysbiosis of intestinal microbiota and overgrowth of pathogenic bacteria, induction of inflammation, and damage to the intestinal barrier, thus aggravating the progression of cirrhosis. In this paper, we review the discussion of BAs synthesis pathway and signal transduction, the bidirectional regulation of bile acids and intestinal microbiota, and further explore the role of reduced total bile acid concentration and dysregulated intestinal microbiota ratio in the development of cirrhosis, in order to provide a new theoretical basis for the clinical treatment of cirrhosis and its complications.
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Affiliation(s)
- Feng Zhu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shudan Zheng
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Mei Zhao
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fan Shi
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lihong Zheng
- Department of Gastroenterology, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Haiqiang Wang
- Department of Gastroenterology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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11
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Aseem SO, Hylemon PB, Zhou H. Bile Acids and Biliary Fibrosis. Cells 2023; 12:cells12050792. [PMID: 36899928 PMCID: PMC10001305 DOI: 10.3390/cells12050792] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Biliary fibrosis is the driving pathological process in cholangiopathies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholangiopathies are also associated with cholestasis, which is the retention of biliary components, including bile acids, in the liver and blood. Cholestasis may worsen with biliary fibrosis. Furthermore, bile acid levels, composition and homeostasis are dysregulated in PBC and PSC. In fact, mounting data from animal models and human cholangiopathies suggest that bile acids play a crucial role in the pathogenesis and progression of biliary fibrosis. The identification of bile acid receptors has advanced our understanding of various signaling pathways involved in regulating cholangiocyte functions and the potential impact on biliary fibrosis. We will also briefly review recent findings linking these receptors with epigenetic regulatory mechanisms. Further detailed understanding of bile acid signaling in the pathogenesis of biliary fibrosis will uncover additional therapeutic avenues for cholangiopathies.
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Affiliation(s)
- Sayed Obaidullah Aseem
- Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence:
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Central Virginia Veterans Healthcare System, Richmond, VA 23249, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Central Virginia Veterans Healthcare System, Richmond, VA 23249, USA
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12
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Ha S, Yang Y, Won Kim J, Son M, Kim D, Kim MJ, Im DS, Young Chung H, Chung KW. Diminished Tubule Epithelial Farnesoid X Receptor Expression Exacerbates Inflammation and Fibrosis Response in Aged Rat Kidney. J Gerontol A Biol Sci Med Sci 2023; 78:60-68. [PMID: 35867996 DOI: 10.1093/gerona/glac148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Indexed: 01/31/2023] Open
Abstract
The age-associated functional decline of the kidney is accompanied by structural changes including glomerular sclerosis and interstitial fibrosis. Aging kidneys also exhibit increased vulnerability in stressful environmental conditions. In this study, we assessed the differences in responses between young and aged animals to folic acid (FA)-induced renal fibrosis. To monitor the effects of aging on FA-induced kidney fibrosis, we administered FA (250 mg/kg) to young (6-month old) and aged (20-month old) rats. The development of severe fibrosis was only detected in aged rat kidneys, which was accompanied by increased kidney injury and inflammation. Furthermore, we found that FA-treated aged rats had significantly lower farnesoid X receptor (FXR) expression in the tubular epithelial cells than the rats not treated with FA. Interestingly, the extent of inflammation was severe in the kidneys of aged rat, where the FXR expression was low. To explore the role of FXR in kidney inflammation, in vitro studies were performed using NRK52E kidney tubule epithelial cells. NF-κB activation by lipopolysaccharide treatment induces chemokine production in NRK52E cells. The activation of FXR by obeticholic acid significantly reduced the transcriptional activity of NF-κB and chemokine production. In contrast, FXR knockdown increased LPS-induced chemokine production in NRK52E cells. Finally, FXR-knockout mice that were administered FA showed increased inflammation and severe fibrosis. In summary, we demonstrated that diminished FXR expression in the epithelial cells of the renal tubules exacerbated the fibrotic response in aged rat kidneys by upregulating pro-inflammatory NF-κB activation.
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Affiliation(s)
- Sugyeong Ha
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Yejin Yang
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Jeong Won Kim
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Minjung Son
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Doyeon Kim
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Mi-Jeong Kim
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Dong-Soon Im
- Laboratory of Pharmacology, College of Pharmacy, and Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Hae Young Chung
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Ki Wung Chung
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
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13
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Yuan Z, Wang J, Zhang H, Chai Y, Xu Y, Miao Y, Yuan Z, Zhang L, Jiang Z, Yu Q. Glycocholic acid aggravates liver fibrosis by promoting the up-regulation of connective tissue growth factor in hepatocytes. Cell Signal 2023; 101:110508. [PMID: 36341984 DOI: 10.1016/j.cellsig.2022.110508] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/18/2022] [Accepted: 10/26/2022] [Indexed: 11/25/2022]
Abstract
AIMS The precise role of bile acid in the progression of liver fibrosis has yet to be elucidated. In this study, common bile duct ligation was used as an in vivo mouse model for the evaluation of bile acids that promote liver connective tissue growth factor expression. MAIN METHODS Primary rat and mice hepatocytes, as well as primary rat hepatic stellate and HepaRG cells were evaluated as in vitro models for promoting the expression of connective tissue growth factor by bile acids. KEY FINDINGS Compared with taurochenodeoxycholic acid, glycochenodeoxycholic acid, and taurocholic acid, glycocholic acid (GCA) most strongly promoted the secretion of connective tissue growth factor in mouse primary hepatocytes, rat primary hepatocytes and HepaRGs. GCA did not directly promote the activation of hepatic stellate cells. The administration of GCA in mice with ligated bile ducts promotes the progression of liver fibrosis, which may promote the yes-associated protein of hepatocytes into the nucleus, resulting in the hepatocytes secreting more connective tissue growth factor for hepatic stellate cell activation. In conclusion, our data showed that GCA can induce the expression of connective tissue growth factor in hepatocytes by promoting the nuclear translocation of yes-associated protein, thereby activating hepatic stellate cells. SIGNIFICANCE Our findings help to elucidate the contribution of GCA to the progression of hepatic fibrosis in cholestatic disease and aid the clinical monitoring of cholestatic liver fibrosis development.
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Affiliation(s)
- Zihang Yuan
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Jie Wang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Haoran Zhang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanyuan Chai
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yunxia Xu
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yingying Miao
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Ziqiao Yuan
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Luyong Zhang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhenzhou Jiang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
| | - Qinwei Yu
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
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14
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Di Ciaula A, Bonfrate L, Baj J, Khalil M, Garruti G, Stellaard F, Wang HH, Wang DQH, Portincasa P. Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling. Nutrients 2022; 14:4950. [PMID: 36500979 PMCID: PMC9738051 DOI: 10.3390/nu14234950] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/18/2022] [Accepted: 11/20/2022] [Indexed: 11/23/2022] Open
Abstract
Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/β-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-059 Lublin, Poland
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Frans Stellaard
- Institute of Clinical Chemistry and Clinical Pharmacology, Venusberg-Campus 1, University Hospital Bonn, 53127 Bonn, Germany
| | - Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
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15
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Liu CH, Bowlus CL. Treatment of Primary Biliary Cholangitis: First-Line and Second-Line Therapies. Clin Liver Dis 2022; 26:705-726. [PMID: 36270725 DOI: 10.1016/j.cld.2022.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease of the interlobular bile ducts leading to secondary damage of hepatocytes and may progress to cirrhosis and liver failure. The first-line treatment is ursodeoxycholic acid; up to 40% of patients do not have an adequate response and remain at risk of disease progression. Obeticholic acid has been conditionally approved for the treatment of PBC as add-on therapy and bezafibrate has shown similar efficacy in this group of patients. Several new therapies are in development and may further add to the treatment options available to patients with PBC.
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Affiliation(s)
- Chung-Heng Liu
- Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129 USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA.
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16
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Marchianò S, Biagioli M, Roselli R, Zampella A, Di Giorgio C, Bordoni M, Bellini R, Urbani G, Morretta E, Monti MC, Distrutti E, Fiorucci S. Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159218. [PMID: 35985473 DOI: 10.1016/j.bbalip.2022.159218] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/25/2022] [Accepted: 08/09/2022] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids play an essential role in regulating liver metabolism, and several bile acids-based therapy are currently investigated for their potential therapeutic efficacy in NAFLD/NASH. Bile acids exert their functions, at least in part, by modulating two main receptors the Farnesoid-x-receptor (FXR) and the G protein-coupled receptor, GPBAR1. In the present study we have compared the pharmacological effects of two bile acids, the ursodeoxycholic acid (UDCA) and its derivative norUDCA, in a model of NAFLD/NASH induced by feeding mice with a Western diet for 12 weeks. The results of these studies demonstrated that both UDCA and norUDCA protected against development of steatosis and fibrosis, but did not reduce the hepatocytes ballooning nor the development of a pro-atherogenic lipid profile. Both agents reduced liver lipogenesis and ameliorated insulin sensitivity and adipocytes signaling as shown by increased expression of adiponectin. Mechanistically, UDCA acts as weak GPBAR1 agonist, while norUDCA exerted no effect on both GPBAR1 and FXR. In vivo administration of UDCA resets bile acid synthesis and promotes a shift toward bile acids species that are GPBAR1 agonists, UDCA, TUDCA and hyodeoxycholic acid, and increases GLP1 expression in the ileum. In contrast norUDCA is poorly metabolized exerting a minimal impact on GPBAR1 signaling. Together, these data, highlight the potential role of UDCA and norUDCA in treating of NAFLD, though these beneficial effects are supported by different mechanisms.
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Affiliation(s)
- Silvia Marchianò
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Michele Biagioli
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Rosalinda Roselli
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Angela Zampella
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | | | - Martina Bordoni
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Rachele Bellini
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Ginevra Urbani
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Italy
| | | | | | - Stefano Fiorucci
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy.
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17
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Panzitt K, Zollner G, Marschall HU, Wagner M. Recent advances on FXR-targeting therapeutics. Mol Cell Endocrinol 2022; 552:111678. [PMID: 35605722 DOI: 10.1016/j.mce.2022.111678] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/25/2022]
Abstract
The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.
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Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Gernot Zollner
- Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
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18
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Fiorucci S, Zampella A, Ricci P, Distrutti E, Biagioli M. Immunomodulatory functions of FXR. Mol Cell Endocrinol 2022; 551:111650. [PMID: 35472625 DOI: 10.1016/j.mce.2022.111650] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/31/2022] [Accepted: 04/04/2022] [Indexed: 02/08/2023]
Abstract
The Farnesoid-x-receptor (FXR) is a bile acids sensor activated in humans by primary bile acids. FXR is mostly expressed in liver, intestine and adrenal glands but also by cells of innate immunity, including macrophages, liver resident macrophages, the Kupffer cells, natural killer cells and dendritic cells. In normal physiology and clinical disorders, cells of innate immunity mediate communications between liver, intestine and adipose tissues. In addition to FXR, the G protein coupled receptor (GPBAR1), that is mainly activated by secondary bile acids, whose expression largely overlaps FXR, modulates chemical communications from the intestinal microbiota and the host's immune system, integrating epithelial cells and immune cells in the entero-hepatic system, providing a mechanism for development of a tolerogenic state toward the intestinal microbiota. Disruption of FXR results in generalized inflammation and disrupted bile acids metabolism. While FXR agonism in preclinical models provides counter-regulatory signals that attenuate inflammation-driven immune dysfunction in a variety of liver and intestinal disease models, the clinical relevance of these mechanisms in the setting of FXR-related disorders remain poorly defined.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy. http://www.gastroenterologia.unipg.it
| | - Angela Zampella
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Patrizia Ricci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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19
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Wang T, Rong X, Zhao C. Circadian Rhythms Coordinated With Gut Microbiota Partially Account for Individual Differences in Hepatitis B-Related Cirrhosis. Front Cell Infect Microbiol 2022; 12:936815. [PMID: 35846774 PMCID: PMC9283756 DOI: 10.3389/fcimb.2022.936815] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Cirrhosis is the end stage of chronic liver diseases like chronic hepatitis B. In China, hepatitis B accounts for around 60% of cases of cirrhosis. So far, clinical and laboratory indexes for the early diagnosis of cirrhosis are far from satisfactory. Nevertheless, there haven't been specific drugs for cirrhosis. Thus, it is quite necessary to uncover more specific factors which play their roles in cirrhosis and figure out the possible therapeutic targets. Among emerging factors taking part in the initiation and progression of cirrhosis, gut microbiota might be a pivot of systemic factors like metabolism and immune and different organs like gut and liver. Discovery of detailed molecular mechanism in gut microbiota and gut liver axis leads to a more promising prospect of developing new drugs intervening in these pathways. Time-based medication regimen has been proofed to be helpful in hormonotherapy, especially in the use of glucocorticoid. Thus, circadian rhythms, though haven't been strongly linked to hepatitis B and its complications, are still pivotal to various pathophysiological progresses. Gut microbiota as a potential effective factor of circadian rhythms has also received increasing attentions. Here, our work, restricting cirrhosis to the post-hepatitis B one, is aimed to summarize how circadian rhythms and hepatitis B-related cirrhosis can intersect via gut microbiota, and to throw new insights on the development of new and time-based therapies for hepatitis B-related cirrhosis and other cirrhosis.
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Affiliation(s)
- Tongyao Wang
- Ministry of Education (MOE)/National Health Commission (NHC)/Chinese Academy of Medical Science (CAMS) Key Lab of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xingyu Rong
- Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Chao Zhao
- Ministry of Education (MOE)/National Health Commission (NHC)/Chinese Academy of Medical Science (CAMS) Key Lab of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai, China
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20
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Jiao TY, Ma YD, Guo XZ, Ye YF, Xie C. Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease. Acta Pharmacol Sin 2022; 43:1103-1119. [PMID: 35217817 PMCID: PMC9061718 DOI: 10.1038/s41401-022-00880-z] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 01/25/2022] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), a series of liver metabolic disorders manifested by lipid accumulation within hepatocytes, has become the primary cause of chronic liver diseases worldwide. About 20%-30% of NAFLD patients advance to nonalcoholic steatohepatitis (NASH), along with cell death, inflammation response and fibrogenesis. The pathogenesis of NASH is complex and its development is strongly related to multiple metabolic disorders (e.g. obesity, type 2 diabetes and cardiovascular diseases). The clinical outcomes include liver failure and hepatocellular cancer. There is no FDA-approved NASH drug so far, and thus effective therapeutics are urgently needed. Bile acids are synthesized in hepatocytes, transported into the intestine, metabolized by gut bacteria and recirculated back to the liver by the enterohepatic system. They exert pleiotropic roles in the absorption of fats and regulation of metabolism. Studies on the relevance of bile acid disturbance with NASH render it as an etiological factor in NASH pathogenesis. Recent findings on the functional identification of bile acid receptors have led to a further understanding of the pathophysiology of NASH such as metabolic dysregulation and inflammation, and bile acid receptors are recognized as attractive targets for NASH treatment. In this review, we summarize the current knowledge on the role of bile acids and the receptors in the development of NAFLD and NASH, especially the functions of farnesoid X receptor (FXR) in different tissues including liver and intestine. The progress in the development of bile acid and its receptors-based drugs for the treatment of NASH including bile acid analogs and non-bile acid modulators on bile acid metabolism is also discussed.
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Affiliation(s)
- Ting-Ying Jiao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yuan-di Ma
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiao-Zhen Guo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yun-Fei Ye
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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21
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Synthesis of Novel C/D Ring Modified Bile Acids. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27072364. [PMID: 35408759 PMCID: PMC9000252 DOI: 10.3390/molecules27072364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/01/2022] [Accepted: 04/04/2022] [Indexed: 11/17/2022]
Abstract
Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure–activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro–furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation.
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22
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Namisaki T, Kaji K, Shimozato N, Kaya D, Ozutsumi T, Tsuji Y, Fujinaga Y, Kitagawa K, Furukawa M, Sato S, Sawada Y, Nishimura N, Takaya H, Okura Y, Seki K, Kawaratani H, Moriya K, Noguchi R, Asada K, Akahane T, Mitoro A, Yoshiji H. Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on ongoing hepatic fibrosis. Indian J Gastroenterol 2022; 41:169-180. [PMID: 35279807 DOI: 10.1007/s12664-021-01220-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/19/2021] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Nonalcoholic steatohepatitis (NASH) is difficult to diagnose in patients with no symptoms. We aimed to investigate the combined effect of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), and angiotensin II type 1 receptor blocker (ARB: losartan) on an ongoing hepatic fibrosis in a NASH rat model. METHODS Fischer 344 rats were fed with choline-deficient L-amino-acid-defined (CDAA) diet for 16 weeks. After 8-week administration of CDAA diet, OCA, losartan, or a combination of these drugs was administered at a dose of 30 mg/kg/day for 8 weeks by oral gavage. The in vivo and in vitro effects of OCA + losartan and liver fibrosis progression, lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) regulatory cascade, and gut barrier function were evaluated. RESULTS OCA + losartan alleviated hepatic fibrosis progression by suppressing α-SMA expression. It inhibited the proliferation of activated hepatic stellate cell (Ac-HSC) and mRNA expression of hepatic transforming growth factor-β1 (TGF-β1), TLR4, and tissue inhibitor of metalloproteinase-1 (TIMP-1) and decreased the hydroxyproline levels. OCA increased the hepatic matrix metalloproteinase-2 (MMP-2) mRNA expression. OCA decreased the mRNA expression of hepatic LPS-binding protein and intestinal permeability by ameliorating the disruption of CDAA diet-induced zonula occludens-1. Losartan directly inhibited the proliferation of Ac-HSC. The in vitro suppressive effects of OCA + losartan on the mRNA expressions of TGF-β1 and α1(I)-procollagen, TLR4, and TIMP-1 in Ac-HSCs were almost in parallel. CONCLUSIONS OCA + losartan suppressed the ongoing hepatic fibrosis by attenuating gut barrier dysfunction and suppressing Ac-HSC proliferation. Combined therapy may be a promising novel approach for NASH with fibrosis.
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Affiliation(s)
- Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Naotaka Shimozato
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Daisuke Kaya
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Takahiro Ozutsumi
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Yuki Tsuji
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Yukihisa Fujinaga
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Koh Kitagawa
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Masanori Furukawa
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Shinya Sato
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Yasuhiko Sawada
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Norihisa Nishimura
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Hiroaki Takaya
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Yasushi Okura
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Kenichiro Seki
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Hideto Kawaratani
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Kei Moriya
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Ryuichi Noguchi
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Kiyoshi Asada
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Akira Mitoro
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
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Simbrunner B, Trauner M, Reiberger T. Review article: therapeutic aspects of bile acid signalling in the gut-liver axis. Aliment Pharmacol Ther 2021; 54:1243-1262. [PMID: 34555862 PMCID: PMC9290708 DOI: 10.1111/apt.16602] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues. AIM This review summarises important aspects of bile acid-mediated crosstalk between the gut and the liver ("gut-liver axis") as well as recent findings from experimental and clinical studies. METHODS We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease. RESULTS Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid-mediated gut-liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target. CONCLUSIONS Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.
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Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
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Biagioli M, Fiorucci S. Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease. LIVER RESEARCH 2021; 5:119-141. [PMID: 39957845 PMCID: PMC11791866 DOI: 10.1016/j.livres.2021.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/29/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023]
Abstract
Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors. The two best characterized receptors of this family are the nuclear receptor, farnesoid X receptor (FXR) and the G protein-coupled receptor, G protein-coupled bile acid receptor 1 (GPBAR1). FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism, energy balance, autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders. Clinical trials in non-alcoholic fatty liver disease (NAFLD), however, have shown that selective FXR agonists cause side effects while their efficacy is partial. Because FXR and GPBAR1 exert additive effects, dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials. Here, we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Monroy-Ramirez HC, Galicia-Moreno M, Sandoval-Rodriguez A, Meza-Rios A, Santos A, Armendariz-Borunda J. PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases. Int J Mol Sci 2021; 22:ijms22158298. [PMID: 34361064 PMCID: PMC8347792 DOI: 10.3390/ijms22158298] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.
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Affiliation(s)
- Hugo Christian Monroy-Ramirez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Marina Galicia-Moreno
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Ana Sandoval-Rodriguez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Alejandra Meza-Rios
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Juan Armendariz-Borunda
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
- Correspondence:
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Abstract
Introduction: Hepatic stellate cells (HSCs) are essential for physiological homeostasis of the liver extracellular matrix (ECM). Excessive transdifferentiation of HSC from a quiescent to an activated phenotype contributes to disrupt this balance and can lead to liver fibrosis. Accumulating evidence has suggested that nuclear receptors (NRs) are involved in the regulation of HSC activation, proliferation, and function. Therefore, these NRs may be therapeutic targets to balance ECM homeostasis and inhibit HSC activation in liver fibrosis.Areas covered: In this review, the authors summarized the recent progress in the understanding of the regulatory role of NRs in HSCs and their potential as drug targets in liver fibrosis.Expert opinion: NRs are still potential therapy targets for inhibiting HSCs activation and liver fibrosis. However, the development of NRs agonists or antagonists to inhibit HSCs requires fully consideration of systemic effects.
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Affiliation(s)
- Shiyun Pu
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Hongjing Zhou
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Yan Liu
- Department of Interventional Therapy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Jiao Liu
- Department of Interventional Therapy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
- Department of Hepatobiliary Surgery, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Yuanxin Guo
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Houfeng Zhou
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
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Fiorucci S, Biagioli M, Baldoni M, Ricci P, Sepe V, Zampella A, Distrutti E. The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease. Expert Opin Drug Discov 2021; 16:1193-1208. [PMID: 33849361 DOI: 10.1080/17460441.2021.1916465] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The farnesoid-x-receptor (FXR) is a ubiquitously expressed nuclear receptor selectively activated by primary bile acids. AREA COVERED FXR is a validated pharmacological target. Herein, the authors review preclinical and clinical data supporting the development of FXR agonists in the treatment of nonalcoholic fatty liver disease. EXPERT OPINION Development of systemic FXR agonists to treat the metabolic liver disease has been proven challenging because the side effects associated with these agents including increased levels of cholesterol and LDL-c and reduced HDL-c raising concerns over their long-term cardiovascular safety. Additionally, pruritus has emerged as a common, although poorly explained, dose-related side effect with all FXR ligands, but is especially common with OCA. FXR agonists that are currently undergoing phase 2/3 trials are cilofexor, tropifexor, nidufexor and MET409. Some of these agents are currently being developed as combination therapies with other agents including cenicriviroc, a CCR2/CCR5 inhibitor, or firsocostat an acetyl CoA carboxylase inhibitor. Additional investigations are needed to evaluate the beneficial effects of combination of these agents with statins. It is expected that in the coming years, FXR agonists will be developed as a combination therapy to minimize side effects and increase likelihood of success by targeting different metabolic pathways.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento Di Medicina E Chirurgia, Università Di Perugia, Perugia, Italy
| | - Michele Biagioli
- Dipartimento Di Medicina E Chirurgia, Università Di Perugia, Perugia, Italy
| | - Monia Baldoni
- Dipartimento Di Medicina E Chirurgia, Università Di Perugia, Perugia, Italy
| | - Patrizia Ricci
- Dipartimento Di Medicina E Chirurgia, Università Di Perugia, Perugia, Italy
| | - Valentina Sepe
- Department of Pharmacy University of Napoli, Federico II, Napoli, Italy
| | - Angela Zampella
- Department of Pharmacy University of Napoli, Federico II, Napoli, Italy
| | - Eleonora Distrutti
- SC Di Gastroenterologia Ed Epatologia, Azienda Ospedaliera Di Perugia, Perugia, Italy
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28
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The pathophysiological function of non-gastrointestinal farnesoid X receptor. Pharmacol Ther 2021; 226:107867. [PMID: 33895191 DOI: 10.1016/j.pharmthera.2021.107867] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
Farnesoid X receptor (FXR) influences bile acid homeostasis and the progression of various diseases. While the roles of hepatic and intestinal FXR in enterohepatic transport of bile acids and metabolic diseases were reviewed previously, the pathophysiological functions of FXR in non-gastrointestinal cells and tissues have received little attention. Thus, the roles of FXR in the liver, immune system, nervous system, cardiovascular system, kidney, and pancreas beyond the gastrointestinal system are reviewed herein. Gain of FXR function studies in non-gastrointestinal tissues reveal that FXR signaling improves various experimentally-induced metabolic and immune diseases, including non-alcoholic fatty liver disease, type 2 diabetes, primary biliary cholangitis, sepsis, autoimmune diseases, multiple sclerosis, and diabetic nephropathy, while loss of FXR promotes regulatory T cells production, protects the brain against ischemic injury, atherosclerosis, and inhibits pancreatic tumor progression. The downstream pathways regulated by FXR are diverse and tissue/cell-specific, and FXR has both ligand-dependent and ligand-independent activities, all of which may explain why activation and inhibition of FXR signaling could produce paradoxical or even opposite effects in some experimental disease models. FXR signaling is frequently compromised by diseases, especially during the progressive stage, and rescuing FXR expression may provide a promising strategy for boosting the therapeutic effect of FXR agonists. Tissue/cell-specific modulation of non-gastrointestinal FXR could influence the treatment of various diseases. This review provides a guide for drug discovery and clinical use of FXR modulators.
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Thibaut R, Gage MC, Pineda-Torra I, Chabrier G, Venteclef N, Alzaid F. Liver macrophages and inflammation in physiology and physiopathology of non-alcoholic fatty liver disease. FEBS J 2021; 289:3024-3057. [PMID: 33860630 PMCID: PMC9290065 DOI: 10.1111/febs.15877] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/05/2021] [Accepted: 04/12/2021] [Indexed: 12/13/2022]
Abstract
Non‐alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, being a common comorbidity of type 2 diabetes and with important links to inflammation and insulin resistance. NAFLD represents a spectrum of liver conditions ranging from steatosis in the form of ectopic lipid storage, to inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Macrophages that populate the liver play important roles in maintaining liver homeostasis under normal physiology and in promoting inflammation and mediating fibrosis in the progression of NAFLD toward to NASH. Liver macrophages are a heterogenous group of innate immune cells, originating from the yolk sac or from circulating monocytes, that are required to maintain immune tolerance while being exposed portal and pancreatic blood flow rich in nutrients and hormones. Yet, liver macrophages retain a limited capacity to raise the alarm in response to danger signals. We now know that macrophages in the liver play both inflammatory and noninflammatory roles throughout the progression of NAFLD. Macrophage responses are mediated first at the level of cell surface receptors that integrate environmental stimuli, signals are transduced through multiple levels of regulation in the cell, and specific transcriptional programmes dictate effector functions. These effector functions play paramount roles in determining the course of disease in NAFLD and even more so in the progression towards NASH. The current review covers recent reports in the physiological and pathophysiological roles of liver macrophages in NAFLD. We emphasise the responses of liver macrophages to insulin resistance and the transcriptional machinery that dictates liver macrophage function.
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Affiliation(s)
- Ronan Thibaut
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
| | - Matthew C Gage
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Inès Pineda-Torra
- Department of Medicine, Centre for Cardiometabolic and Vascular Science, University College London, UK
| | - Gwladys Chabrier
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Nicolas Venteclef
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
| | - Fawaz Alzaid
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
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Ma Y, Harris J, Li P, Cao H. Long noncoding RNAs-a new dimension in the molecular architecture of the bile acid/FXR pathway. Mol Cell Endocrinol 2021; 525:111191. [PMID: 33539963 PMCID: PMC8437140 DOI: 10.1016/j.mce.2021.111191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 11/15/2022]
Abstract
Bile acids, regarded as the body's detergent for digesting lipids, also function as critical signaling molecules that regulate cholesterol and triglyceride levels in the body. Bile acids are the natural ligands of the nuclear receptor, FXR, which controls an intricate network of cellular pathways to maintain metabolic homeostasis. In recent years, growing evidence supports that many cellular actions of the bile acid/FXR pathway are mediated by long non-coding RNAs (lncRNAs), and lncRNAs are in turn powerful regulators of bile acid levels and FXR activities. In this review, we highlight the substantial progress made in the understanding of the functional and mechanistic role of lncRNAs in bile acid metabolism and how lncRNAs connect bile acid activity to additional metabolic processes. We also discuss the potential of lncRNA studies in elucidating novel molecular mechanisms of the bile acid/FXR pathway and the promise of lncRNAs as potential diagnostic markers and therapeutic targets for diseases associated with altered bile acid metabolism.
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Affiliation(s)
- Yonghe Ma
- Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jamie Harris
- Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ping Li
- Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Haiming Cao
- Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
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Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis-Roles as Putative Treatment Targets? Biomedicines 2021; 9:biomedicines9040365. [PMID: 33807461 PMCID: PMC8066583 DOI: 10.3390/biomedicines9040365] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis is the primary predictor of mortality in patients with non-alcoholic steatohepatitis (NASH). In this process, the activated hepatic stellate cells (HSCs) constitute the principal cells responsible for the deposition of a fibrous extracellular matrix, thereby driving the hepatic scarring. HSC activation, migration, and proliferation are controlled by a complex signaling network involving growth factors, lipotoxicity, inflammation, and cellular stress. Conversely, the clearance of activated HSCs is a prerequisite for the resolution of the extracellular fibrosis. Hence, pathways regulating the fate of the HSCs may represent attractive therapeutic targets for the treatment and prevention of NASH-associated hepatic fibrosis. However, the development of anti-fibrotic drugs for NASH patients has not yet resulted in clinically approved therapeutics, underscoring the complex biology and challenges involved when targeting the intricate cellular signaling mechanisms. This narrative review investigated the mechanisms of activation and inactivation of HSCs with a focus on NASH-associated hepatic fibrosis. Presenting an updated overview, this review highlights key cellular pathways with potential value for the development of future treatment modalities.
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FXR in liver physiology: Multiple faces to regulate liver metabolism. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166133. [PMID: 33771667 DOI: 10.1016/j.bbadis.2021.166133] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/11/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022]
Abstract
The liver is the central metabolic hub which coordinates nutritional inputs and metabolic outputs. Food intake releases bile acids which can be sensed by the bile acid receptor FXR in the liver and the intestine. Hepatic and intestinal FXR coordinately regulate postprandial nutrient disposal in a network of interacting metabolic nuclear receptors. In this review we summarize and update the "classical roles" of FXR as a central integrator of the feeding state response, which orchestrates the metabolic processing of carbohydrates, lipids, proteins and bile acids. We also discuss more recent and less well studied FXR effects on amino acid, protein metabolism, autophagic turnover and inflammation. In addition, we summarize the recent understanding of how FXR signaling is affected by posttranslational modifications and by different FXR isoforms. These modifications and variations in FXR signaling might be considered when FXR is targeted pharmaceutically in clinical applications.
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Lillich FF, Imig JD, Proschak E. Multi-Target Approaches in Metabolic Syndrome. Front Pharmacol 2021; 11:554961. [PMID: 33776749 PMCID: PMC7994619 DOI: 10.3389/fphar.2020.554961] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022] Open
Abstract
Metabolic syndrome (MetS) is a highly prevalent disease cluster worldwide. It requires polypharmacological treatment of the single conditions including type II diabetes, hypertension, and dyslipidemia, as well as the associated comorbidities. The complex treatment regimens with various drugs lead to drug-drug interactions and inadequate patient adherence, resulting in poor management of the disease. Multi-target approaches aim at reducing the polypharmacology and improving the efficacy. This review summarizes the medicinal chemistry efforts to develop multi-target ligands for MetS. Different combinations of pharmacological targets in context of in vivo efficacy and future perspective for multi-target drugs in MetS are discussed.
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Affiliation(s)
- Felix F. Lillich
- Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Frankfurt, Germany
| | - John D. Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Ewgenij Proschak
- Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Frankfurt, Germany
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Fiorucci S, Distrutti E, Carino A, Zampella A, Biagioli M. Bile acids and their receptors in metabolic disorders. Prog Lipid Res 2021; 82:101094. [PMID: 33636214 DOI: 10.1016/j.plipres.2021.101094] [Citation(s) in RCA: 153] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/03/2021] [Accepted: 02/12/2021] [Indexed: 02/08/2023]
Abstract
Bile acids are a large family of atypical steroids which exert their functions by binding to a family of ubiquitous cell membrane and nuclear receptors. There are two main bile acid activated receptors, FXR and GPBAR1, that are exclusively activated by bile acids, while other receptors CAR, LXRs, PXR, RORγT, S1PR2and VDR are activated by bile acids in addition to other more selective endogenous ligands. In the intestine, activation of FXR and GPBAR1 promotes the release of FGF15/19 and GLP1 which integrate their signaling with direct effects exerted by theother receptors in target tissues. This network is tuned in a time ordered manner by circadian rhythm and is critical for the regulation of metabolic process including autophagy, fast-to-feed transition, lipid and glucose metabolism, energy balance and immune responses. In the last decade FXR ligands have entered clinical trials but development of systemic FXR agonists has been proven challenging because their side effects including increased levels of cholesterol and Low Density Lipoproteins cholesterol (LDL-c) and reduced High-Density Lipoprotein cholesterol (HDL-c). In addition, pruritus has emerged as a common, dose related, side effect of FXR ligands. Intestinal-restricted FXR and GPBAR1 agonists and dual FXR/GPBAR1 agonists have been developed. Here we review the last decade in bile acids physiology and pharmacology.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Adriana Carino
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli, Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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35
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Cariello M, Piccinin E, Moschetta A. Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH. Cell Mol Gastroenterol Hepatol 2021; 11:1519-1539. [PMID: 33545430 PMCID: PMC8042405 DOI: 10.1016/j.jcmgh.2021.01.012] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Elena Piccinin
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro," Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy; National Institute for Biostructures and Biosystems (INBB), Rome, Italy; Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy.
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36
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Peroxisome proliferator-activated receptors in the pathogenesis and therapies of liver fibrosis. Pharmacol Ther 2020; 222:107791. [PMID: 33321113 DOI: 10.1016/j.pharmthera.2020.107791] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a dynamic wound-healing process associated with the deposition of extracellular matrix produced by myofibroblasts. HSCs activation, inflammation, oxidative stress, steatosis and aging play critical roles in the progression of liver fibrosis, which is correlated with the regulation of the peroxisome proliferator-activated receptor (PPAR) pathway. As nuclear receptors, PPARs reduce inflammatory response, regulate lipid metabolism, and inhibit fibrogenesis in the liver associated with aging. Thus, PPAR ligands have been investigated as possible therapeutic agents. Mounting evidence indicated that some PPAR agonists could reverse steatohepatitis and liver fibrosis. Consequently, targeting PPARs might be a promising and novel therapeutic option against liver fibrosis. This review summarizes recent studies on the role of PPARs on the pathogenesis and treatment of liver fibrosis.
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Wren SN, Donovan MG, Selmin OI, Doetschman TC, Romagnolo DF. A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet. Int J Mol Sci 2020; 21:ijms21217829. [PMID: 33105708 PMCID: PMC7659968 DOI: 10.3390/ijms21217829] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
A diet high in n-6 polyunsaturated fatty acids (PUFAs) may contribute to inflammation and tissue damage associated with obesity and pathologies of the colon and liver. One contributing factor may be dysregulation by n-6 fatty acids of enterohepatic bile acid (BA) metabolism. The farnesoid X receptor (FXR) is a nuclear receptor that regulates BA homeostasis in the liver and intestine. This study aims to compare the effects on FXR regulation and BA metabolism of a palm oil-based diet providing 28% energy (28%E) from fat and low n-6 linoleic acid (LA, 2.5%E) (CNTL) with those of a soybean oil-based diet providing 50%E from fat and high (28%E) in LA (n-6HFD). Wild-type (WT) littermates and a transgenic mouse line overexpressing the Fxrα1 isoform under the control of the intestine-specific Villin promoter (Fxrα1TG) were fed the CNTL or n-6HFD starting at weaning through 16 weeks of age. Compared to the CNTL diet, the n-6HFD supports higher weight gain in both WT and FxrαTG littermates; increases the expression of Fxrα1/2, and peroxisome proliferator-activated receptor-γ1 (Pparγ1) in the small intestine, Fxrα1/2 in the colon, and cytochrome P4507A1 (Cyp7a1) and small heterodimer protein (Shp) in the liver; and augments the levels of total BA in the liver, and primary chenodeoxycholic (CDCA), cholic (CA), and β-muricholic (βMCA) acid in the cecum. Intestinal overexpression of the Fxra1TG augments expression of Shp and ileal bile acid-binding protein (Ibabp) in the small intestine and Ibabp in the proximal colon. Conversely, it antagonizes n-6HFD-dependent accumulation of intestinal and hepatic CDCA and CA; hepatic levels of Cyp7a1; and expression of Pparγ in the small intestine. We conclude that intestinal Fxrα1 overexpression represses hepatic de novo BA synthesis and protects against n-6HFD-induced accumulation of human-specific primary bile acids in the cecum.
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Affiliation(s)
- Spencer N. Wren
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA; (S.N.W.); (O.I.S.)
| | - Micah G. Donovan
- Interdisciplinary Cancer Biology Graduate Program, The University of Arizona, Tucson, AZ 85724, USA;
| | - Ornella I. Selmin
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA; (S.N.W.); (O.I.S.)
- The University of Arizona Cancer Center, Tucson, AZ 85724, USA
| | - Tom C. Doetschman
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, AZ 85724, USA;
| | - Donato F. Romagnolo
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA; (S.N.W.); (O.I.S.)
- The University of Arizona Cancer Center, Tucson, AZ 85724, USA
- Correspondence: ; Tel.: +1-520-626-9108
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Tornai D, Szabo G. Emerging medical therapies for severe alcoholic hepatitis. Clin Mol Hepatol 2020; 26:686-696. [PMID: 32981291 PMCID: PMC7641578 DOI: 10.3350/cmh.2020.0145] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 08/28/2020] [Indexed: 12/12/2022] Open
Abstract
Severe alcoholic hepatitis (AH) is an acute and often devastating form of alcohol-associated liver disease. Clinically, AH is characterized by elevated bilirubin, model for end stage liver disease scores >20, and nonspecific symptoms that are caused by underlying inflammation, hepatocyte injury, and impaired intestinal barrier function. Compromised immune defense in AH contributes to infections, sepsis and organ failure. To date, corticosteroids are the only recommended treatment for severe AH, however it does not provide survival benefits beyond 1 month. Recent preclinical and early clinical studies in AH aided understanding of the disease and presented opportunities for new therapeutic options targeting inflammation, oxidative stress, liver regeneration and modification of intestinal microbiota. In this comprehensive review, we discuss promising preclinical results and ongoing clinical trials evaluating novel therapeutic agents for the treatment of severe AH.
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Affiliation(s)
- David Tornai
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Zhang JX, Xu QY, Yang Y, Li N, Zhang Y, Deng LH, Zhu QX, Shen T. Kupffer cell inactivation ameliorates immune liver injury via TNF-α/TNFR1 signal pathway in trichloroethylene sensitized mice. Immunopharmacol Immunotoxicol 2020; 42:545-555. [PMID: 32811237 DOI: 10.1080/08923973.2020.1811306] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
METHODS 36 female BALB/c mice were selected and randomly divided the mice into four groups. We established a BALB/c mouse model of TCE sensitization and pretreatment with GdCl3 (40 mg/kg) by intraperitoneal injection during the during the 17th and 19th days. RESULTS We found F4/80, the marker of Kupffer cell, was increased in TCE positive group. GdCl3 treatment successfully blocked the activation of Kupffer cell. TNF-α was increased significantly in liver of TCE sensitized mice and decreased significantly when low-dose GdCl3 was used. We found TNF receptor 1 (TNFR1) was increased significantly and GdCl3 treatment resumed the expression of TNFR1 to normal level, as well as the F4/80, TNF-α and TNFR1 mRNA. We also found both caspase-8 and caspase-3 increased in TCE positive group and decreased in TCE + GdCl3 positive group. The number of apoptotic cells in TCE sensitized mice increased by TUNEL staining, and GdCl3 treatment alleviated this increase. Some cells showed edema and inflammatory cell aggregation in liver of TCE positive group, while in the TCE + GdCl3 positive group, the cytoplasm became loose and vacuole-like degeneration occurred. CONCLUSION Our study unveils cross-talk between Kupffer cell activation and TNFR1 which mediate apoptosis in liver of TCE sensitized mice.
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Affiliation(s)
- Jia-Xiang Zhang
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China.,Ministry of Education, Key Laboratory of Dermatology, Anhui Medical University, Hefei, Anhui, China
| | - Qiong-Ying Xu
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China
| | - Yi Yang
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China
| | - Na Li
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China
| | - Yan Zhang
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China
| | - Li-Hua Deng
- Shenzhen Prevention and Treatment Center for Occupational Disease, Shenzhen, Guangdong, PR China
| | - Qi-Xing Zhu
- Ministry of Education, Key Laboratory of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China
| | - Tong Shen
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China.,Ministry of Education, Key Laboratory of Dermatology, Anhui Medical University, Hefei, Anhui, China
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40
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Stofan M, Guo GL. Bile Acids and FXR: Novel Targets for Liver Diseases. Front Med (Lausanne) 2020; 7:544. [PMID: 33015098 PMCID: PMC7516013 DOI: 10.3389/fmed.2020.00544] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022] Open
Abstract
Bile acids (BAs) are evolutionally conserved molecules synthesized in the liver from cholesterol and have been shown to be essential for lipid homeostasis. BAs regulate a variety of metabolic functions via modulating nuclear and membrane receptors. Farnesoid X receptor (FXR) is the most important nuclear receptor for maintaining BA homeostasis. FXR plays a tissue-specific role in suppressing BA synthesis and promoting BA enterohepatic circulation. Disruption of FXR in mice have been implicated in liver diseases commonly occurring in humans, including cholestasis, non-alcoholic fatty liver diseases, and hepatocellular carcinoma. Strategically targeting FXR activity has been rapidly used to develop novel therapies for the prevention and/or treatment of cholestasis and non-alcoholic steatohepatitis. This review provides an updated literature review on BA homeostasis and FXR modulator development.
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Affiliation(s)
- Mary Stofan
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.,Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ, United States.,VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ, United States
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41
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Li YY, Cao CY, Zhou YL, Nie YQ, Cao J, Zhou YJ. The roles and interaction of FXR and PPARs in the pathogenesis of nonalcoholic fatty liver disease. Arab J Gastroenterol 2020; 21:162-168. [DOI: 10.1016/j.ajg.2020.04.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 04/05/2020] [Accepted: 04/24/2020] [Indexed: 12/23/2022]
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Alatas FS, Matsuura T, Pudjiadi AH, Wijaya S, Taguchi T. Peroxisome Proliferator-Activated Receptor Gamma Agonist Attenuates Liver Fibrosis by Several Fibrogenic Pathways in an Animal Model of Cholestatic Fibrosis. Pediatr Gastroenterol Hepatol Nutr 2020; 23:346-355. [PMID: 32704495 PMCID: PMC7354870 DOI: 10.5223/pghn.2020.23.4.346] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 03/29/2020] [Accepted: 04/12/2020] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Peroxisome proliferator-activated receptor gamma (PPAR-γ) has a key role in hepatic fibrogenesis by virtue of its effect on the hepatic stellate cells (HSCs). Although many studies have shown that PPAR-γ agonists inhibit liver fibrosis, the mechanism remains largely unclear, especially regarding the cross-talk between PPAR-γ and other potent fibrogenic factors. METHODS This experimental study involved 25 male Wistar rats. Twenty rats were subjected to bile duct ligation (BDL) to induce liver fibrosis, further divided into an untreated group (BDL; n=10) and a group treated with the PPAR-γ agonist thiazolidinedione (TZD), at 14 days post-operation (BDL+TZD; n=10). The remaining 5 rats had a sham operation (sham; n=5). The effect of PPAR-γ agonist on liver fibrosis was evaluated by histopathology, protein immunohistochemistry, and mRNA expression quantitative polymerase chain reaction. RESULTS Histology and immunostaining showed markedly reduced collagen deposition, bile duct proliferation, and HSCs in the BDL+TZD group compared to those in the BDL group (p<0.001). Similarly, significantly lower mRNA expression of collagen α-1(I), matrix metalloproteinase-2, platelet-derived growth factor (PDGF)-B chain, and connective tissue growth factor (CTGF) were evident in the BDL+TZD group compared to those in the BDL group (p=0.0002, p<0.035, p<0.0001, and p=0.0123 respectively). Moreover, expression of the transforming growth factor beta1 (TGF-β1) was also downregulated in the BDL+TZD group (p=0.0087). CONCLUSION The PPAR-γ agonist inhibits HSC activation in vivo and attenuates liver fibrosis through several fibrogenic pathways. Potent fibrogenic factors such as PDGF, CTGF, and TGF-β1 were downregulated by the PPAR-γ agonist. Targeting PPAR-γ activity may be a potential strategy to control liver fibrosis.
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Affiliation(s)
- Fatima Safira Alatas
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Antonius Hocky Pudjiadi
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Stephanie Wijaya
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Schumacher JD, Kong B, Wu J, Rizzolo D, Armstrong LE, Chow MD, Goedken M, Lee YH, Guo GL. Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development. Hepatology 2020; 71:670-685. [PMID: 31206730 PMCID: PMC6918008 DOI: 10.1002/hep.30810] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 05/28/2019] [Indexed: 12/18/2022]
Abstract
Farnesoid X receptor (FXR) induces fibroblast growth factor 15 (FGF15; human ortholog FGF19) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15-/- mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/19 functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15-/- mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl4 -induced LF model in wild type (WT), Fgf15-/- , and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine- or cholic acid-containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15-/- mice; and (3) treatment of a human HSC line, LX-2, with FXR activators and/or recombinant FGF19 protein. The results showed that Fgf15-/- mice had lower basal collagen expression, which was increased by BA sequestration. CCl4 induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15-/- mice. HSCs from Fgf15-/- mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX-2 cells, FXR activation increased peroxisome proliferator-activated receptor gamma activity and reduced proliferation. FGF19 activated both signal transducer and activator of transcription 3 and c-Jun N-terminal kinase pathways and reduced nuclear factor kappa-light-chain-enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/19 does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.
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Affiliation(s)
- JD Schumacher
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - B Kong
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - J Wu
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - D Rizzolo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - LE Armstrong
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - MD Chow
- Department of Surgery, Robert Wood Johnson University Hospital, New Brunswick, NJ
| | - M Goedken
- Research pathology services, Rutgers University, Piscataway, NJ
| | - YH Lee
- Department of Surgery, Robert Wood Johnson University Hospital, New Brunswick, NJ
| | - GL Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ.,Environmental and Occupational Health Institute, Rutgers University, Piscataway, NJ.,VA New Jersey Health Care System, East Orange, NJ,Corresponding author: Grace L. Guo, MBBS, PhD, 170 Frelinghuysen Road, Piscataway, NJ, 08854; ; phone - 848-445-8186
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Zhou J, Cui S, He Q, Guo Y, Pan X, Zhang P, Huang N, Ge C, Wang G, Gonzalez FJ, Wang H, Hao H. SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nat Commun 2020; 11:240. [PMID: 31932588 PMCID: PMC6957516 DOI: 10.1038/s41467-019-14138-6] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023] Open
Abstract
Farnesoid X receptor (FXR) is a promising target for nonalcoholic steatohepatitis (NASH) and fibrosis. Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum. Here we report that prophylactic but not therapeutic administration of obeticholic acid (OCA) prevents hepatic stellate cell (HSC) activation and fibrogenesis. Activated HSCs show limited response to OCA and other FXR agonists due to enhanced FXR SUMOylation. SUMOylation inhibitors rescue FXR signaling and thereby increasing the efficacy of OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1, a direct target gene of FXR, to stabilize lipid droplets and thereby prevent HSC activation. Therapeutic coadministration of OCA and SUMOylation inhibitors drastically impedes liver fibrosis induced by CCl4, bile duct ligation, and more importantly NASH. In conclusion, we propose a promising therapeutic approach by combining SUMOylation inhibitors and FXR agonists for liver fibrosis.
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Affiliation(s)
- Jiyu Zhou
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Shuang Cui
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Qingxian He
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Yitong Guo
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Xiaojie Pan
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Pengfei Zhang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Ningning Huang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Chaoliang Ge
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, China
| | - Guangji Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China.
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Hong Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China.
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome (MetS) and comprises one of the largest health threats of the twenty-first century. In this chapter, we review the current state of knowledge of NAFLD and underline the striking similarities with atherosclerosis. We first describe current epidemiological data showing the staggering increase of NAFLD numbers and its related clinical and economic costs. We then provide an overview of pathophysiological hepatic processes in NAFLD and highlight the systemic aspects of NAFLD that point toward metabolic crosstalk between organs as an important cause of metabolic disease. Finally, we end by highlighting the currently investigated therapeutic approaches for NAFLD, which also show strong similarities with a range of treatment options for atherosclerosis.
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Hernández-Aquino E, Quezada-Ramírez MA, Silva-Olivares A, Casas-Grajales S, Ramos-Tovar E, Flores-Beltrán RE, Segovia J, Shibayama M, Muriel P. Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways. Eur J Pharmacol 2019; 865:172730. [PMID: 31618621 DOI: 10.1016/j.ejphar.2019.172730] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 10/08/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023]
Abstract
There is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl4)-induced fibrosis in rats and, if so, to search for the mechanisms involved. CCl4 was given to male Wistar rats (400 mg/kg, three times per week, i. p.) for 12 weeks; naringenin (100 mg/kg twice per day, p. o.) was administered from weeks 9-12 of the CCl4 treatment. Liver damage and oxidative stress markers were measured. Masson's trichrome, hematoxylin-eosin staining and immunohistochemistry were performed. Zymography assays for MMP-9 and MMP-2 were carried out. TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1β, IL-10, Smad7, pSmad3 and pJNK protein levels were determined by western blotting. In addition, α-SMA and Smad3 protein and mRNA levels were studied. Naringenin reversed liver damage, biochemical and oxidative stress marker elevation, and fibrosis and restored normal MMP-9 and MMP-2 activity. The flavonoid also preserved NF-κB, IL-1β, IL-10, TGF-β, CTGF, Col-I, MMP-13 and Smad7 protein levels. Moreover, naringenin decreased JNK activation and Smad3 phosphorylation in the linker region. Finally, α-SMA and Smad3 protein and mRNA levels were reduced by naringenin administration. The results of this study demonstrate that naringenin blocks oxidative stress, inflammation and the TGF-β-Smad3 and JNK-Smad3 pathways, thereby carrying out its antifibrotic effects and making it a good candidate to treat human fibrosis, as previously demonstrated in toxicological and clinical studies.
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Affiliation(s)
| | - Marco A Quezada-Ramírez
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Angélica Silva-Olivares
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Sael Casas-Grajales
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Erika Ramos-Tovar
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Rosa E Flores-Beltrán
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - José Segovia
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Mineko Shibayama
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Pablo Muriel
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico.
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47
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Shimozato N, Namisaki T, Kaji K, Kitade M, Okura Y, Sato S, Moriya K, Seki K, Kawaratani H, Takaya H, Sawada Y, Saikawa S, Nakanishi K, Furukawa M, Fujinaga Y, Kubo T, Asada K, Kitagawa K, Tsuji Y, Kaya D, Ozutsumi T, Akahane T, Mitoro A, Yoshiji H. Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase-4 inhibitor on hepatic fibrosis. Hepatol Res 2019; 49:1147-1161. [PMID: 31177586 DOI: 10.1111/hepr.13385] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 05/18/2019] [Accepted: 05/22/2019] [Indexed: 12/11/2022]
Abstract
AIM Non-alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase-4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH. METHODS Fifty Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac-HSCs) were assessed in vitro. RESULTS Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac-HSC proliferation and hepatic transforming growth factor (TGF)-β1, α1(I)-procollagen, and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase-2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet-induced zonula occludens-1 disruption, whereas sitagliptin directly inhibited Ac-HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF-β1 and α1(I)-procollagen mRNA expression and p38 phosphorylation in Ac-HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac-HSC. CONCLUSIONS Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac-HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH.
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Affiliation(s)
- Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yasushi Okura
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kenichiro Seki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Masanori Furukawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yukihisa Fujinaga
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Takuya Kubo
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kiyoshi Asada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Koh Kitagawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yuki Tsuji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Daisuke Kaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Takahiro Ozutsumi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
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48
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Schumacher JD, Guo GL. Pharmacologic Modulation of Bile Acid-FXR-FGF15/FGF19 Pathway for the Treatment of Nonalcoholic Steatohepatitis. Handb Exp Pharmacol 2019; 256:325-357. [PMID: 31201553 DOI: 10.1007/164_2019_228] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is within the spectrum of nonalcoholic fatty liver disease (NAFLD) and can progress to fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). The prevalence of NASH is rising and has become a large burden to the medical system worldwide. Unfortunately, despite its high prevalence and severe health consequences, there is currently no therapeutic agent approved to treat NASH. Therefore, the development of efficacious therapies is of utmost urgency and importance. Many molecular targets are currently under investigation for their ability to halt NASH progression. One of the most promising and well-studied targets is the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR). In this chapter, the characteristics, etiology, and prevalence of NASH will be discussed. A brief introduction to FXR regulation of BA homeostasis will be described. However, for more details regarding FXR in BA homeostasis, please refer to previous chapters. In this chapter, the mechanisms by which tissue and cell type-specific FXR regulates NASH development will be discussed in detail. Several FXR agonists have reached later phase clinical trials for treatment of NASH. The progress of these compounds and summary of released data will be provided. Lastly, this chapter will address safety liabilities specific to the development of FXR agonists.
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Affiliation(s)
- Justin D Schumacher
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA.
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49
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Makled MN, Sharawy MH, El-Awady MS. The dual PPAR-α/γ agonist saroglitazar ameliorates thioacetamide-induced liver fibrosis in rats through regulating leptin. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:1569-1576. [DOI: 10.1007/s00210-019-01703-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/23/2019] [Indexed: 12/11/2022]
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50
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Gong J, Yang F, Yang Q, Tang X, Shu F, Xu L, Wang Z, Yang L. Sweroside ameliorated carbon tetrachloride (CCl 4)-induced liver fibrosis through FXR-miR-29a signaling pathway. J Nat Med 2019; 74:17-25. [PMID: 31280460 DOI: 10.1007/s11418-019-01334-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 06/17/2019] [Indexed: 11/29/2022]
Abstract
To date, there are very few effective drugs for liver fibrosis treatment; therefore, it is urgent to develop novel therapeutic targets and approaches. In the present research, we sought to study the protective effect of sweroside contained in Lonicera japonica or blue honeysuckle berries in a mouse model of liver fibrosis and investigate the underlying mechanism. The mouse model of liver fibrosis in was induced by intraperitoneal injections of 10% CCl4 for 6 weeks (three times/week). At the beginning of the fourth week, sweroside was intragastrically administered once a day and at the end of the treatment, biochemical and histological studies were investigated. The expression of FXR, miR-29a and the downstream targets were analyzed as well. Moreover, the effect of sweroside on cell proliferation was observed in human hepatic stellate cells (HSCs) (LX-2), along with using the siRNA for FXR and miR-29a inhibitor to investigate the underpinning of the anti-fibrotic effect of sweroside. Sweroside successfully protected the liver fibrosis in CCl4-induced mouse model, accompanied by miR-29a induction. Furthermore, sweroside also induced miR-29a in HSCs, resulting in the inhibition of COL1 and TIMP1. Our data also showed that either silencing miR-29a or knockdown of FXR in LX-2 cell abolished the inhibition of COL1 and TIMP1 as well as the inhibition of cell proliferation by sweroside treatment. In conclusion, sweroside exerted its anti-fibrotic effect in vivo and in vitro by up-regulation of miR-29a and repression of COL1 and TIMP1, which was at least in part through FXR.
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Affiliation(s)
- Junting Gong
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Fan Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qiaoling Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaowen Tang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Fangfang Shu
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lieming Xu
- Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhengtao Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Li Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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