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Song L, Hou Y, Xu D, Dai X, Luo J, Liu Y, Huang Z, Yang M, Chen J, Hu Y, Chen C, Tang Y, Rao Z, Ma J, Zheng M, Shi K, Cai C, Lu M, Tang R, Ma X, Xie C, Luo Y, Li X, Huang Z. Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress. Cell Metab 2025; 37:104-120.e9. [PMID: 39393353 DOI: 10.1016/j.cmet.2024.09.008] [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: 03/11/2024] [Revised: 07/31/2024] [Accepted: 09/12/2024] [Indexed: 10/13/2024]
Abstract
Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the de novo paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown. We identified hepatic Fgf4 as a direct FXR target that paracrinally signals to downregulate Cyp7a1 and Cyp8b1. The effect of FXR-FGF4 is mediated by an uncharted intracellular FGF receptor 4 (FGFR4)-LRH-1 signaling node. This liver-centric pathway acts as a first-line checkpoint for intrahepatic and transhepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway, which together constitutes an integral hepatoenteric control mechanism that fine-tunes BA homeostasis, counteracting cholestasis and hepatobiliary damage. Our findings shed light on potential therapeutic strategies for cholestatic diseases.
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Affiliation(s)
- Lintao Song
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Yushu Hou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Da Xu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xijia Dai
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jianya Luo
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Liu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhuobing Huang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Miaomiao Yang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jie Chen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yue Hu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuchu Chen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yuli Tang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhiheng Rao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jianjia Ma
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Minghua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Keqing Shi
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chao Cai
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Mingqin Lu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yongde Luo
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiaokun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Zhifeng Huang
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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Shmet M, Amasha M, Khattib A, Schweitzer R, Khatib S, Hamudi J, Halabi M, Khatib S. Untargeted metabolomics reveals biomarkers for the diagnosis of coronary artery plaques as observed by coronary cardiac computed tomography. Biofactors 2025; 51:e2156. [PMID: 39878362 DOI: 10.1002/biof.2156] [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: 06/24/2024] [Accepted: 12/18/2024] [Indexed: 01/31/2025]
Abstract
Atherosclerosis is a major cause of morbidity and mortality worldwide; in Israel, ischemic heart disease is the second leading cause of death for both genders aged 45 and above. Atherosclerosis involves stiffening of the arteries due to the accumulation of lipids and oxidized lipids on the blood vessel walls, triggering the development of artery plaque. Coronary artery disease (CAD) is the most common manifestation of atherosclerosis. The prevalence of CAD in the general population remains high, despite efforts to improve the identification of risk factors and preventive treatments. The discovery of new biomarkers is vital to improving the diagnosis of CAD and its risk factors. We aimed to identify novel biomarkers that could provide an early diagnosis of coronary artery atherosclerotic plaques, their type, and the percentage of stenosis. We used an untargeted metabolomics approach to identify potential biomarkers that could enable highly sensitive and specific CAD detection. The study consisted of 109 patients who underwent cardiac computed tomography angiography at the Cardiology Department of Ziv Medical Center. Fifty-four patients were diagnosed with coronary atherosclerotic plaques (CAD group), and 55 without plaques used control. Untargeted metabolomics using LC-MS/MS revealed 2560 metabolites in the patients' serum: 106 showed statistically significant upregulation in the serum of the CAD group compared with the healthy control group (p < 0.05). These metabolites belonged to the following chemical families: acyl-carnitines, cyclodipeptides, lysophosphatidylcholine, and primary bile acids. In contrast, 98 metabolites displayed statistically significant downregulation in the serum of the CAD group compared with the control group, belonging to the following chemical families: GABA amino acids and derivatives (inhibitory neurotransmitters), lipids, and secondary bile acids. Our comprehensive untargeted serum metabolomic analysis revealed biomarkers that can be used for the diagnosis of patients with CAD. Further cohort studies with a larger number of participants are needed to validate the detected biomarkers.
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Affiliation(s)
- Manar Shmet
- Natural Products and Analytical Chemistry Laboratory, MIGAL - Galilee Research Institute, Kiryat Shemona, Israel
- Department of Biotechnology, Tel-Hai College, Qiryat Shemona, Israel
| | | | - Ali Khattib
- Natural Products and Analytical Chemistry Laboratory, MIGAL - Galilee Research Institute, Kiryat Shemona, Israel
- The Rappaport Family Institute for Research in the Medical Science and Rambam Medical Center, Haifa, Israel
| | - Ron Schweitzer
- Natural Products and Analytical Chemistry Laboratory, MIGAL - Galilee Research Institute, Kiryat Shemona, Israel
| | | | | | | | - Soliman Khatib
- Natural Products and Analytical Chemistry Laboratory, MIGAL - Galilee Research Institute, Kiryat Shemona, Israel
- Department of Biotechnology, Tel-Hai College, Qiryat Shemona, Israel
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Zhuang T, Wang X, Wang Z, Gu L, Yue D, Wang Z, Li X, Yang L, Huang W, Ding L. Biological functions and pharmacological behaviors of bile acids in metabolic diseases. J Adv Res 2024:S2090-1232(24)00495-8. [PMID: 39522690 DOI: 10.1016/j.jare.2024.11.003] [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: 07/17/2024] [Revised: 11/02/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Bile acids, synthesized endogenously from cholesterol, play a central role in metabolic regulation within the enterohepatic circulatory system. Traditionally known as emulsifying agents that facilitate the intestinal absorption of vitamins and lipids, recent research reveals their function as multifaceted signal modulators involved in various physiological processes. These molecules are now recognized as key regulators of chronic metabolic diseases and immune dysfunction. Despite progress in understanding their roles, their structural diversity and the specific functions of individual bile acids remain underexplored. AIM OF REVIEW This study categorizes the bile acids based on their chemical structures and their roles as signaling molecules in physiological processes. It consolidates current knowledge and provides a comprehensive overview of the current research. The review also includes natural and semisynthetic variants that have demonstrated potential in regulating metabolic processes in animal models or clinical contexts. KEY SCIENTIFIC CONCEPTS OF REVIEW Bile acids circulate primarily within the enterohepatic circulation, where they help maintain a healthy digestive system. Disruptions in their balance are linked to metabolic disorders, hepatobiliary diseases and intestinal inflammation. Through receptor-mediated pathways, bile acids influence the progression of metabolic diseases by regulating glucose and lipid metabolism, immune function, and energy expenditure. This review aims to provide a comprehensive, systematic foundation to for understanding their physiological roles and supporting future therapeutic developments for metabolic and inflammatory diseases.
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Affiliation(s)
- Tongxi Zhuang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China; Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Xunjiang Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Zixuan Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Lihua Gu
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Dawei Yue
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Xiaohua Li
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200163, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
| | - Wendong Huang
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
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Uriarte I, Santamaria E, López-Pascual A, Monte MJ, Argemí J, Latasa MU, Adán-Villaescusa E, Irigaray A, Herranz JM, Arechederra M, Basualdo J, Lucena F, Corrales FJ, Rotellar F, Pardo F, Merlen G, Rainteau D, Sangro B, Tordjmann T, Berasain C, Marín JJG, Fernández-Barrena MG, Herrero I, Avila MA. New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167166. [PMID: 38642480 DOI: 10.1016/j.bbadis.2024.167166] [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: 11/16/2023] [Revised: 04/04/2024] [Accepted: 04/08/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND AND AIMS Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. METHODS Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. RESULTS Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. CONCLUSIONS In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.
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Affiliation(s)
- Iker Uriarte
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Eva Santamaria
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Amaya López-Pascual
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - María J Monte
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Université Paris-Saclay, Inserm U1193, Orsay, France
| | - Josepmaria Argemí
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
| | - M Ujue Latasa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Elena Adán-Villaescusa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Ainara Irigaray
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Jose M Herranz
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - María Arechederra
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Jorge Basualdo
- Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain; Internal Medicine Department, ICOT Hospital Ciudad de Telde, Las Palmas, Spain
| | - Felipe Lucena
- Internal Medicine Department, Navarra University Clinic, Pamplona, Spain
| | - Fernando J Corrales
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CSIC), Madrid, Spain
| | - Fernando Rotellar
- General Surgery Department, Navarra University Clinic, Pamplona, Spain
| | - Fernando Pardo
- General Surgery Department, Navarra University Clinic, Pamplona, Spain
| | | | - Dominique Rainteau
- Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine, Paris, France
| | - Bruno Sangro
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
| | | | - Carmen Berasain
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Jose J G Marín
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Maite G Fernández-Barrena
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Ignacio Herrero
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain.
| | - Matias A Avila
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
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Horn G, Demel T, Rothmiller S, Amend N, Worek F. The influence of the model pesticides parathion and paraoxon on human cytochrome P450 and associated oxygenases in HepaRG cells. Clin Toxicol (Phila) 2024; 62:288-295. [PMID: 38874383 DOI: 10.1080/15563650.2024.2361879] [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: 02/23/2024] [Accepted: 05/24/2024] [Indexed: 06/15/2024]
Abstract
INTRODUCTION Intentional and unintentional organophosphorus pesticide exposure is a public health concern. Organothiophosphate compounds require metabolic bioactivation by the cytochrome P450 system to their corresponding oxon analogues to act as potent inhibitors of acetylcholinesterase. It is known that interactions between cytochrome P450 and pesticides include the inhibition of major xenobiotic metabolizing cytochrome P450 enzymes and changes on the genetic level. METHODS In this in vitro study, the influence of the pesticides parathion and paraoxon on human cytochrome P450 and associated oxygenases was investigated with a metabolically competent cell line (HepaRG cells). First, the viability of the cells after exposure to parathion and paraoxon was evaluated. The inhibitory effect of both pesticides on cytochrome P450 3A4, which is a pivotal enzyme in the metabolism of xenobiotics, was examined by determining the dose-response curve. Changes on the transcription level of 92 oxygenase associated genes, including those for important cytochrome P450 enzymes, were evaluated. RESULTS The exposure of HepaRG cells to parathion and paraoxon at concentrations up to 100 µM resulted in a viability of 100 per cent. After exposure for 24 hours, pronounced inhibition of cytochrome P450 3A4 enzyme activity was shown, indicating 50 per cent effective concentrations of 1.2 µM (parathion) and 2.1 µM (paraoxon). The results revealed that cytochrome P450 involved in parathion metabolism were significantly upregulated. DISCUSSION Relevant changes of the cytochrome P450 3A4 enzyme activity and significant alteration of genes associated with cytochrome P450 suggest an interference of pesticide exposure with numerous metabolic processes. The major limitations of the work involve the use of a single pesticide and the in vitro model as surrogate to human hepatocytes. CONCLUSION The data of this study might be of relevance after survival of acute, life-threatening intoxications with organophosphorus compounds, particularly for the co-administration of drugs, which are metabolized by the affected cytochrome P450.
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Affiliation(s)
- Gabriele Horn
- Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany
| | - Tobias Demel
- Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany
| | - Simone Rothmiller
- Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany
| | - Niko Amend
- Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany
| | - Franz Worek
- Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany
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Li Z, Zheng D, Zhang T, Ruan S, Li N, Yu Y, Peng Y, Wang D. The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease. Hepatol Commun 2024; 8:e0343. [PMID: 38099854 PMCID: PMC10727660 DOI: 10.1097/hc9.0000000000000343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/28/2023] [Indexed: 12/18/2023] Open
Abstract
As the most prevalent chronic liver disease globally, NAFLD encompasses a pathological process that ranges from simple steatosis to NASH, fibrosis, cirrhosis, and HCC, closely associated with numerous extrahepatic diseases. While the initial etiology was believed to be hepatocyte injury caused by lipid toxicity from accumulated triglycerides, recent studies suggest that an imbalance of cholesterol homeostasis is of greater significance. The role of nuclear receptors in regulating liver cholesterol homeostasis has been demonstrated to be crucial. This review summarizes the roles and regulatory mechanisms of nuclear receptors in the 3 main aspects of cholesterol production, excretion, and storage in the liver, as well as their cross talk in reverse cholesterol transport. It is hoped that this review will offer new insights and theoretical foundations for the study of the pathogenesis and progression of NAFLD and provide new research directions for extrahepatic diseases associated with NAFLD.
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Luciano N, Barone E, Timilsina S, Gershwin ME, Selmi C. Tumor Necrosis Factor Alpha Inhibitors and Cardiovascular Risk in Rheumatoid Arthritis. Clin Rev Allergy Immunol 2023; 65:403-419. [PMID: 38157095 DOI: 10.1007/s12016-023-08975-z] [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] [Accepted: 12/01/2023] [Indexed: 01/03/2024]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by an increased risk of cardiovascular events, due to the complex interplay between traditional and disease-related risk factors. Chronic inflammation and persistent disease activity are the key determinants of this risk, but despite great improvement in the disease management and prognosis, cardiovascular events are still the main cause of morbidity and mortality in RA cohorts1. In the last decades, the advent of new biological and targeted-synthetic DMARDs was accompanied by an improvement in disease activity control, but the role of each class of drugs on CVD risk is still a matter a debate. Since their approval for RA treatment, tumor necrosis factor alpha (TNFα) inhibitors have been widely investigated to better understand their effects on cardiovascular outcomes. The hypothesis that the reduction of chronic inflammation with any treatment may reduce the cardiovascular risk has been recently confuted by the direct comparison of TNFα-inhibitors and JAK inhibitors in patients with RA and coexisting risk factors for cardiovascular disease. The aim of this literature review is to add to the available evidence to analyze the relationship between TNFα-inhibitors and CVD risk in patients with RA and also provide some clinical scenarios to better explain the treatment dilemmas. In particular, while data on major cardiovascular events and thromboembolism seem consistent with an inflammation-mediated benefit with TNFα-inhibitors, there remain concerns about the use of this class of bDMARDs in patients with chronic heart failure.
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Affiliation(s)
- Nicoletta Luciano
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Elisa Barone
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Suraj Timilsina
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA
| | - Carlo Selmi
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy.
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
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Feng C, Yang Y, Lu A, Tan D, Lu Y, Qin L, He Y. Multi‑omics‑based analysis of the regulatory mechanism of gypenosides on bile acids in hypercholesterolemic mice. Exp Ther Med 2023; 26:438. [PMID: 37614436 PMCID: PMC10443059 DOI: 10.3892/etm.2023.12136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 06/22/2023] [Indexed: 08/25/2023] Open
Abstract
Gynostemma pentaphyllum is a traditional medicine used by ethnic minorities in southwest China and gypenosides are currently recognized as essential components of the pharmacological substances of Gynostemma pentaphyllum, which are effective in regulating metabolic syndrome, especially in improving hepatic metabolic disorders. The present study randomly divided C57BL/6J male mice into the normal diet control group (ND), high-fat diet modeling group (HFD) and gypenosides group (GP). Liquid chromatography-mass spectrometry (UPLC-MS) was applied to quantify bile acids in the liver, bile and serum of mice in ND, HFD and GP groups. Liver proteins were extracted for trypsin hydrolysis and analyzed quantitatively using UPLC-MS + MS/MS (timsTOF Pro 2). Total mouse liver RNA was extracted from ND, HFD and GP groups respectively, cDNA sequencing libraries constructed and sequenced using BGISEQ-500 sequencing platform. The expression of key genes Fxr, Shp, Cyp7a1, Cyp8b1, and Abab11 was detected by RT-qPCR. The results showed that gypenosides accelerated free bile acid synthesis by promoting the expression of bile acid synthase CYP7A1 and CYP8B1 genes and proteins and accelerating the secretion of conjugated bile acids from the liver to the bile ducts. GP inhibited the bile acid transporters solute carrier organic anion transporter family member (SLCO) 1A1 and SLCO1A4, reducing the reabsorption of free bile acids and accelerating the excretion of free bile acids from the blood to the kidneys. It also promoted the metabolic enzyme CYP3A11, which accelerated the metabolism and clearance of bile acids, thus maintaining the balance of the bile acid internal environment.
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Affiliation(s)
- Chengcheng Feng
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yanping Yang
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Anjing Lu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Daopeng Tan
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yanliu Lu
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Lin Qin
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yuqi He
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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9
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Zeng J, Fan J, Zhou H. Bile acid-mediated signaling in cholestatic liver diseases. Cell Biosci 2023; 13:77. [PMID: 37120573 PMCID: PMC10149012 DOI: 10.1186/s13578-023-01035-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 04/18/2023] [Indexed: 05/01/2023] Open
Abstract
Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease.
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Affiliation(s)
- Jing Zeng
- Department of Microbiology and Immunology, Medical College of Virginia and Richmond VA Medical Center, Central Virginia Veterans Healthcare System, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Huiping Zhou
- Department of Microbiology and Immunology, Medical College of Virginia and Richmond VA Medical Center, Central Virginia Veterans Healthcare System, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA.
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10
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Yamashita M, Honda A, Shimoyama S, Umemura M, Ohta K, Chida T, Noritake H, Kurono N, Ichimura-Shimizu M, Tsuneyama K, Miyazaki T, Tanaka A, Leung PS, Gershwin ME, Suda T, Kawata K. Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis. J Autoimmun 2023; 136:103027. [PMID: 36996700 DOI: 10.1016/j.jaut.2023.103027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 03/01/2023] [Accepted: 03/09/2023] [Indexed: 03/30/2023]
Abstract
Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC.
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Zhao J, Yang Q, Liu Z, Xu P, Tian L, Yan J, Li K, Lin B, Bian L, Xi Z, Liu X. The impact of subchronic ozone exposure on serum metabolome and the mechanisms of abnormal bile acid and arachidonic acid metabolisms in the liver. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 252:114573. [PMID: 36701875 DOI: 10.1016/j.ecoenv.2023.114573] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 12/28/2022] [Accepted: 01/22/2023] [Indexed: 06/17/2023]
Abstract
Ambient ozone (O3) pollution can induce respiratory and cardiovascular toxicity. However, its impact on the metabolome and the underlying mechanisms remain unclear. This study first investigated the serum metabolite changes in rats exposed to 0.5 ppm O3 for 3 months using untargeted metabolomic approach. Results showed chronic ozone exposure significantly altered the serum levels of 34 metabolites with potential increased risk of digestive, respiratory and cardiovascular disease. Moreover, bile acid synthesis and secretion, and arachidonic acid (AA) metabolism became the most prominent affected metabolic pathways after O3 exposure. Further studies on the mechanisms found that the elevated serum toxic bile acid was not due to the increased biosynthesis in the liver, but the reduced reuptake from the portal vein to hepatocytes owing to repressed Ntcp and Oatp1a1, and the decreased bile acid efflux in hepatocytes as a results of inhibited Bsep, Ostalpha and Ostbeta. Meanwhile, decreased expressions of detoxification enzyme of SULT2A1 and the important regulators of FXR, PXR and HNF4α also contributed to the abnormal bile acids. In addition, O3 promoted the conversion of AA into thromboxane A2 (TXA2) and 20-hydroxyarachidonic acid (20-HETE) in the liver by up-regulation of Fads2, Cyp4a and Tbxas1 which resulting in decreased AA and linoleic acid (LA), and increased thromboxane B2 (TXB2) and 20-HETE in the serum. Furthermore, apparent hepatic chronic inflammation, fibrosis and abnormal function were found in ozone-exposed rats. These results indicated chronic ozone exposure could alter serum metabolites by interfering their metabolism in the liver, and inducing liver injury to aggravate metabolic disorders.
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Affiliation(s)
- Jiao Zhao
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Qingcheng Yang
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Zhiyuan Liu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Pengfei Xu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Lei Tian
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Jun Yan
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Kang Li
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Bencheng Lin
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Liping Bian
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Zhuge Xi
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Xiaohua Liu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
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12
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Kinoo SM, Naidoo P, Singh B, Chuturgoon A, Nagiah S. Human Hepatocyte Nuclear Factors (HNF1 and LXRb) Regulate CYP7A1 in HIV-Infected Black South African Women with Gallstone Disease: A Preliminary Study. Life (Basel) 2023; 13:life13020273. [PMID: 36836631 PMCID: PMC9968087 DOI: 10.3390/life13020273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/13/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Female sex, high estrogen levels, aging, obesity, and dyslipidemia are some of the risk factors associated with gallstone formation. HIV-infected patients on combination antiretroviral therapy (cART) are more prone to hypercholesterolemia. Bile acid synthesis is initiated by cholesterol 7-alpha hydroxylase (CYP7A1) and regulated by hepatocyte nuclear factors (HNF1α, HNF4α, and LXRb). The aim of this study was to evaluate the expression of HNF1α, HNF4α, LXRb, and miRNAs (HNF4α specific: miR-194-5p and miR-122*_1) that regulate CYP7A1 transcription in HIV-infected Black South African women on cART and presenting with gallstones relative to HIV-negative patients with gallstone disease. Females (n = 96) presenting with gallstone disease were stratified based on HIV status. The gene expression of CYP7A1, HNF1α, HNF4α, LXRb, miR-194-5p, and miR-122*_1 was determined using RT-qPCR. Messenger RNA and miRNA levels were reported as fold change expressed as 2-ΔΔCt (RQ min; RQ max). Fold changes >2 and <0.5 were considered significant. HIV-infected females were older in age (p = 0.0267) and displayed higher low-density lipoprotein cholesterol (LDL-c) (p = 0.0419), CYP7A1 [2.078-fold (RQ min: 1.278; RQ max: 3.381)], LXRb [2.595-fold (RQ min: 2.001; RQ max: 3.000)], and HNF1α [3.428 (RQ min: 1.806; RQ max: 6.507] levels. HNF4α [0.642-fold (RQ min: 0.266; RQ max: 1.55)], miR-194-5p [0.527-fold (RQ min: 0.37; RQ max: 0.752)], and miR-122*_1 [0.595-fold (RQ min: 0.332; RQ max: 1.066)] levels were lower in HIV-infected females. In conclusion, HIV-infected women with gallstone disease displayed higher LDL-c levels and increased bile acid synthesis, which was evidenced by the elevated expression of CYP7A1, HNF1α, and LXRb. This could have been further influenced by cART and aging.
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Affiliation(s)
- Suman Mewa Kinoo
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Glenwood, Durban 4041, South Africa
- Discipline of General Surgery, School of Clinical Medicine, College of Health Science, University of KwaZulu Natal, Umbilo, Durban 4001, South Africa
| | - Pragalathan Naidoo
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Glenwood, Durban 4041, South Africa
| | - Bhugwan Singh
- Discipline of General Surgery, School of Clinical Medicine, College of Health Science, University of KwaZulu Natal, Umbilo, Durban 4001, South Africa
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Glenwood, Durban 4041, South Africa
- Correspondence: (A.C.); (S.N.)
| | - Savania Nagiah
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Glenwood, Durban 4041, South Africa
- Department of Human Biology, Medical School, Faculty of Health Sciences, Nelson Mandela University, Missionvale, Port Elizabeth 6065, South Africa
- Correspondence: (A.C.); (S.N.)
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13
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Zhao P, Sun X, Liao Z, Yu H, Li D, Shen Z, Glass CK, Witztum JL, Saltiel AR. The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis. JCI Insight 2022; 7:155552. [PMID: 35917178 PMCID: PMC9536260 DOI: 10.1172/jci.insight.155552] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 07/27/2022] [Indexed: 01/09/2023] Open
Abstract
Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase 1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human patients. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet-fed (WD-fed) Ldlr-/- mice and protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrated an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a therapy for hypercholesterolemia and atherosclerosis.
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Affiliation(s)
- Peng Zhao
- Department of Biochemistry and Structural Biology and,Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Department of Medicine, University of California, San Diego (UCSD), La Jolla, California, USA
| | - Xiaoli Sun
- Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Department of Medicine, University of California, San Diego (UCSD), La Jolla, California, USA.,Department of Pharmacology and,Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Zhongji Liao
- Department of Medicine, University of California, San Diego (UCSD), La Jolla, California, USA
| | - Hong Yu
- Department of Pharmacology and
| | - Dan Li
- Department of Biochemistry and Structural Biology and
| | - Zeyang Shen
- Department of Cellular and Molecular Medicine, School of Medicine;,Department of Bioengineering, Jacobs School of Engineering; and
| | - Christopher K. Glass
- Department of Medicine, University of California, San Diego (UCSD), La Jolla, California, USA.,Department of Cellular and Molecular Medicine, School of Medicine
| | - Joseph L. Witztum
- Department of Medicine, University of California, San Diego (UCSD), La Jolla, California, USA
| | - Alan R. Saltiel
- Department of Medicine, University of California, San Diego (UCSD), La Jolla, California, USA.,Department of Pharmacology, School of Medicine, UCSD, La Jolla, California, USA
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14
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Chiang JYL, Ferrell JM. Discovery of farnesoid X receptor and its role in bile acid metabolism. Mol Cell Endocrinol 2022; 548:111618. [PMID: 35283218 PMCID: PMC9038687 DOI: 10.1016/j.mce.2022.111618] [Citation(s) in RCA: 119] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 01/07/2022] [Accepted: 01/18/2022] [Indexed: 12/14/2022]
Abstract
In 1995, the nuclear hormone orphan receptor farnesoid X receptor (FXR, NR1H4) was identified as a farnesol receptor expressed mainly in liver, kidney, and adrenal gland of rats. In 1999, bile acids were identified as endogenous FXR ligands. Subsequently, FXR target genes involved in the regulation of hepatic bile acid synthesis, secretion, and intestinal re-absorption were identified. FXR signaling was proposed as a mechanism of feedback regulation of the rate-limiting enzyme for bile acid synthesis, cholesterol 7⍺-hydroxylase (CYP7A1). The primary bile acids synthesized in the liver are transformed to secondary bile acids by the gut microbiota. The gut-to-liver axis plays a critical role in the regulation of bile acid synthesis, composition and circulating bile acid pool size, which in turn regulates glucose, lipid, and energy metabolism. Dysregulation of bile acid metabolism and FXR signaling in the gut-to-liver axis contributes to metabolic diseases including obesity, diabetes, and non-alcoholic fatty liver disease. This review will cover the discovery of FXR as a bile acid sensor in the regulation of bile acid metabolism and as a metabolic regulator of lipid, glucose, and energy homeostasis. It will also provide an update of FXR functions in the gut-to-liver axis and the drug therapies targeting bile acids and FXR for the treatment of liver metabolic diseases.
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Affiliation(s)
- John Y L Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4029 SR 44, P.O. Box 95, Rootstown, OH, 44272, United States.
| | - Jessica M Ferrell
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4029 SR 44, P.O. Box 95, Rootstown, OH, 44272, United States
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15
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Weng ZB, Chen YR, Lv JT, Wang MX, Chen ZY, Zhou W, Shen XC, Zhan LB, Wang F. A Review of Bile Acid Metabolism and Signaling in Cognitive Dysfunction-Related Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4289383. [PMID: 35308170 PMCID: PMC8933076 DOI: 10.1155/2022/4289383] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/14/2021] [Accepted: 02/23/2022] [Indexed: 12/12/2022]
Abstract
Bile acids are commonly known as one of the vital metabolites derived from cholesterol. The role of bile acids in glycolipid metabolism and their mechanisms in liver and cholestatic diseases have been well studied. In addition, bile acids also serve as ligands of signal molecules such as FXR, TGR5, and S1PR2 to regulate some physiological processes in vivo. Recent studies have found that bile acids signaling may also play a critical role in the central nervous system. Evidence showed that some bile acids have exhibited neuroprotective effects in experimental animal models and clinical trials of many cognitive dysfunction-related diseases. Besides, alterations in bile acid metabolisms well as the expression of different bile acid receptors have been discovered as possible biomarkers for prognosis tools in multiple cognitive dysfunction-related diseases. This review summarizes biosynthesis and regulation of bile acids, receptor classification and characteristics, receptor agonists and signaling transduction, and recent findings in cognitive dysfunction-related diseases.
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Affiliation(s)
- Ze-Bin Weng
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuan-Rong Chen
- College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, China
| | - Jin-Tao Lv
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Min-Xin Wang
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zheng-Yuan Chen
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wen Zhou
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xin-Chun Shen
- College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, China
| | - Li-Bin Zhan
- The Innovation Engineering Technology Center of Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Fang Wang
- College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, China
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16
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Tagawa R, Kobayashi M, Sakurai M, Yoshida M, Kaneko H, Mizunoe Y, Nozaki Y, Okita N, Sudo Y, Higami Y. Long-Term Dietary Taurine Lowers Plasma Levels of Cholesterol and Bile Acids. Int J Mol Sci 2022; 23:ijms23031793. [PMID: 35163722 PMCID: PMC8836270 DOI: 10.3390/ijms23031793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 01/29/2022] [Accepted: 02/02/2022] [Indexed: 11/16/2022] Open
Abstract
Cholesterol is an essential lipid in vertebrates, but excess blood cholesterol promotes atherosclerosis. In the liver, cholesterol is metabolized to bile acids by cytochrome P450, family 7, subfamily a, polypeptide 1 (CYP7A1), the transcription of which is negatively regulated by the ERK pathway. Fibroblast growth factor 21 (FGF21), a hepatokine, induces ERK phosphorylation and suppresses Cyp7a1 transcription. Taurine, a sulfur-containing amino acid, reportedly promotes cholesterol metabolism and lowers blood and hepatic cholesterol levels. However, the influence of long-term feeding of taurine on cholesterol levels and metabolism remains unclear. Here, to evaluate the more chronic effects of taurine on cholesterol levels, we analyzed mice fed a taurine-rich diet for 14-16 weeks. Long-term feeding of taurine lowered plasma cholesterol and bile acids without significantly changing other metabolic parameters, but hardly affected these levels in the liver. Moreover, taurine upregulated Cyp7a1 levels, while downregulated phosphorylated ERK and Fgf21 levels in the liver. Likewise, taurine-treated Hepa1-6 cells, a mouse hepatocyte line, exhibited downregulated Fgf21 levels and upregulated promoter activity of Cyp7a1. These results indicate that taurine promotes cholesterol metabolism by suppressing the FGF21/ERK pathway followed by upregulating Cyp7a1 expression. Collectively, this study shows that long-term feeding of taurine lowers both plasma cholesterol and bile acids, reinforcing that taurine effectively prevents hypercholesterolemia.
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Affiliation(s)
- Ryoma Tagawa
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (R.T.); (M.S.); (M.Y.); (H.K.); (Y.N.); (Y.S.)
| | - Masaki Kobayashi
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (R.T.); (M.S.); (M.Y.); (H.K.); (Y.N.); (Y.S.)
- Correspondence: (M.K.); (Y.H.); Tel.: +81-4-7121-3676 (M.K.); +81-4-7121-3675 (Y.H.)
| | - Misako Sakurai
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (R.T.); (M.S.); (M.Y.); (H.K.); (Y.N.); (Y.S.)
| | - Maho Yoshida
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (R.T.); (M.S.); (M.Y.); (H.K.); (Y.N.); (Y.S.)
| | - Hiroki Kaneko
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (R.T.); (M.S.); (M.Y.); (H.K.); (Y.N.); (Y.S.)
| | - Yuhei Mizunoe
- Department of Internal Medicine Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan;
| | - Yuka Nozaki
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (R.T.); (M.S.); (M.Y.); (H.K.); (Y.N.); (Y.S.)
| | - Naoyuki Okita
- Division of Pathological Biochemistry, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan;
| | - Yuka Sudo
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (R.T.); (M.S.); (M.Y.); (H.K.); (Y.N.); (Y.S.)
| | - Yoshikazu Higami
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (R.T.); (M.S.); (M.Y.); (H.K.); (Y.N.); (Y.S.)
- Division of Integrated Research, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
- Correspondence: (M.K.); (Y.H.); Tel.: +81-4-7121-3676 (M.K.); +81-4-7121-3675 (Y.H.)
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She J, Gu T, Pang X, Liu Y, Tang L, Zhou X. Natural Products Targeting Liver X Receptors or Farnesoid X Receptor. Front Pharmacol 2022; 12:772435. [PMID: 35069197 PMCID: PMC8766425 DOI: 10.3389/fphar.2021.772435] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/22/2021] [Indexed: 12/18/2022] Open
Abstract
Nuclear receptors (NRs) are a superfamily of transcription factors induced by ligands and also function as integrators of hormonal and nutritional signals. Among NRs, the liver X receptors (LXRs) and farnesoid X receptor (FXR) have been of significance as targets for the treatment of metabolic syndrome-related diseases. In recent years, natural products targeting LXRs and FXR have received remarkable interests as a valuable source of novel ligands encompassing diverse chemical structures and bioactive properties. This review aims to survey natural products, originating from terrestrial plants and microorganisms, marine organisms, and marine-derived microorganisms, which could influence LXRs and FXR. In the recent two decades (2000-2020), 261 natural products were discovered from natural resources such as LXRs/FXR modulators, 109 agonists and 38 antagonists targeting LXRs, and 72 agonists and 55 antagonists targeting FXR. The docking evaluation of desired natural products targeted LXRs/FXR is finally discussed. This comprehensive overview will provide a reference for future study of novel LXRs and FXR agonists and antagonists to target human diseases, and attract an increasing number of professional scholars majoring in pharmacy and biology with more in-depth discussion.
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Affiliation(s)
- Jianglian She
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.,College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Tanwei Gu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaoyan Pang
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China
| | - Yonghong Liu
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.,College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, China.,Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
| | - Lan Tang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Xuefeng Zhou
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
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18
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Hannemann C, Schecker JH, Brettschneider A, Grune J, Rösener N, Weller A, Stangl V, Fisher EA, Stangl K, Ludwig A, Hewing B. Deficiency of inactive rhomboid protein 2 (iRhom2) attenuates diet-induced hyperlipidaemia and early atherogenesis. Cardiovasc Res 2022; 118:156-168. [PMID: 33576385 PMCID: PMC8932158 DOI: 10.1093/cvr/cvab041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 02/09/2021] [Indexed: 01/10/2023] Open
Abstract
AIMS Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and anti-inflammatory treatment strategies are currently pursued to lower cardiovascular disease burden. Modulation of recently discovered inactive rhomboid protein 2 (iRhom2) attenuates shedding of tumour necrosis factor-alpha (TNF-α) selectively from immune cells. The present study aims at investigating the impact of iRhom2 deficiency on the development of atherosclerosis. METHODS AND RESULTS Low-density lipoprotein receptor (LDLR)-deficient mice with additional deficiency of iRhom2 (LDLR-/-iRhom2-/-) and control (LDLR-/-) mice were fed a Western-type diet (WD) for 8 or 20 weeks to induce early or advanced atherosclerosis. Deficiency of iRhom2 resulted in a significant decrease in the size of early atherosclerotic plaques as determined in aortic root cross-sections. LDLR-/-iRhom2-/- mice exhibited significantly lower serum levels of TNF-α and lower circulating and hepatic levels of cholesterol and triglycerides compared to LDLR-/- mice at 8 weeks of WD. Analyses of hepatic bile acid concentration and gene expression at 8 weeks of WD revealed that iRhom2 deficiency prevented WD-induced repression of hepatic bile acid synthesis in LDLR-/- mice. In contrast, at 20 weeks of WD, plaque size, plaque composition, and serum levels of TNF-α or cholesterol were not different between genotypes. CONCLUSION Modulation of inflammation by iRhom2 deficiency attenuated diet-induced hyperlipidaemia and early atherogenesis in LDLR-/- mice. iRhom2 deficiency did not affect diet-induced plaque burden and composition in advanced atherosclerosis in LDLR-/- mice.
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Affiliation(s)
- Carmen Hannemann
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany
- Division of Cardiology, Department of Medicine, New York University School of Medicine, Hannemann435 East 30th St., 10016 New York, NY, USA
| | - Johannes H Schecker
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Alica Brettschneider
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Jana Grune
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Physiology, Charitéplatz 1, 10117 Berlin, Germany
| | - Nicole Rösener
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - Andrea Weller
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - Verena Stangl
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Edward A Fisher
- Division of Cardiology, Department of Medicine, New York University School of Medicine, Hannemann435 East 30th St., 10016 New York, NY, USA
| | - Karl Stangl
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Antje Ludwig
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Klinik für Radiologie, Charitéplatz 1, 10117 Berlin, Germany
| | - Bernd Hewing
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany
- Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany
- Zentrum für Kardiologie, Kardiologische Gemeinschaftspraxis, Loerstr. 19, 48143, Muenster, Germany
- Department of Cardiology III-Adult Congenital and Valvular Heart Disease, University Hospital Muenster, Albert-Schweitzer-Str. 33, 48149 Muenster, Germany
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19
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Song Q, Guo J, Zhang Y, Chen W. The beneficial effects of taurine in alleviating fatty liver disease. J Funct Foods 2021. [DOI: 10.1016/j.jff.2020.104351] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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20
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Li C, Yang J, Wang Y, Qi Y, Yang W, Li Y. Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases. Front Pharmacol 2020; 11:1247. [PMID: 32982723 PMCID: PMC7479173 DOI: 10.3389/fphar.2020.01247] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus and dyslipidemia. Cardiometabolic diseases are closely associated with cell glucose and lipid metabolism, inflammatory response and mitochondrial function. Farnesoid X Receptor (FXR), a metabolic nuclear receptor, are found to be activated by primary BAs such as chenodeoxycholic acid (CDCA), cholic acid (CA) and synthetic agonists such as obeticholic acid (OCA). FXR plays crucial roles in regulating cholesterol homeostasis, lipid metabolism, glucose metabolism, and intestinal microorganism. Recently, emerging evidence suggests that FXR agonists are functional for metabolic syndrome and cardiovascular diseases and are considered as a potential therapeutic agent. This review will discuss the pathological mechanism of cardiometabolic disease and reviews the potential mechanisms of FXR agonists in the treatment of cardiometabolic disease.
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Affiliation(s)
- Chao Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Yang
- Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yu Wang
- Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yingzi Qi
- School of Health, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenqing Yang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yunlun Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China.,Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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21
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Li C, Zhang S, Chen X, Ji J, Yang W, Gui T, Gai Z, Li Y. Farnesoid X receptor activation inhibits TGFBR1/TAK1-mediated vascular inflammation and calcification via miR-135a-5p. Commun Biol 2020; 3:327. [PMID: 32581266 PMCID: PMC7314757 DOI: 10.1038/s42003-020-1058-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 06/08/2020] [Indexed: 01/06/2023] Open
Abstract
Chronic inflammation plays a crucial role in vascular calcification. However, only a few studies have revealed the mechanisms underlying the development of inflammation under high-phosphate conditions in chronic kidney disease (CKD) patients. Here, we show that inflammation resulting from the activation of the TGFBR1/TAK1 pathway is involved in calcification in CKD rats or osteogenic medium-cultured human aortic smooth muscle cells (HASMCs). Moreover, miR-135a-5p is demonstrated to be a key regulator of the TGFBR1/TAK1 pathway, which has been reported to be decreased in CKD rats. We further reveal that farnesoid X receptor (FXR) activation increases miR-135a-5p expression, thereby inhibiting the activation of the TGFBR1/TAK1 pathway, ultimately resulting in the attenuation of vascular inflammation and calcification in CKD rats. Our findings provide advanced insights into the mechanisms underlying the development of inflammation in vascular calcification, and evidence that FXR activation could serve as a therapeutic strategy for retarding vascular calcification in CKD patients.
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MESH Headings
- Animals
- Aorta/cytology
- Calcinosis/genetics
- Calcinosis/metabolism
- Cells, Cultured
- Female
- Humans
- MAP Kinase Kinase Kinases/genetics
- MAP Kinase Kinase Kinases/metabolism
- Male
- MicroRNAs/genetics
- Muscle, Smooth, Vascular/cytology
- Osteogenesis
- Rats, Wistar
- Receptor, Transforming Growth Factor-beta Type I/genetics
- Receptor, Transforming Growth Factor-beta Type I/metabolism
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Renal Insufficiency, Chronic/etiology
- Renal Insufficiency, Chronic/pathology
- Vasculitis/genetics
- Vasculitis/metabolism
- Vasculitis/pathology
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Affiliation(s)
- Chao Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, 8032, Switzerland
| | - Shijun Zhang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Xiaoqing Chen
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Jingkang Ji
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Wenqing Yang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Ting Gui
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Zhibo Gai
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, 8032, Switzerland.
| | - Yunlun Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250000, China.
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22
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Glaser F, John C, Engel B, Höh B, Weidemann S, Dieckhoff J, Stein S, Becker N, Casar C, Schuran FA, Wieschendorf B, Preti M, Jessen F, Franke A, Carambia A, Lohse AW, Ittrich H, Herkel J, Heeren J, Schramm C, Schwinge D. Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis. J Hepatol 2019; 71:783-792. [PMID: 31207266 DOI: 10.1016/j.jhep.2019.05.030] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 05/20/2019] [Accepted: 05/21/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS T cells are central mediators of liver inflammation and represent potential treatment targets in cholestatic liver disease. Whereas emerging evidence shows that bile acids (BAs) affect T cell function, the role of T cells for the regulation of BA metabolism is unknown. In order to understand this interplay, we investigated the influence of T cells on BA metabolism in a novel mouse model of cholangitis. METHODS Mdr2-/- mice were crossed with transgenic K14-OVAp mice, which express an MHC class I restricted ovalbumin peptide on biliary epithelial cells (Mdr2-/-xK14-OVAp). T cell-mediated cholangitis was induced by the adoptive transfer of antigen-specific CD8+ T cells. BA levels were quantified using a targeted liquid chromatography-mass spectrometry-based approach. RESULTS T cell-induced cholangitis resulted in reduced levels of unconjugated BAs in the liver and significantly increased serum and hepatic levels of conjugated BAs. Genes responsible for BA synthesis and uptake were downregulated and expression of the bile salt export pump was increased. The transferred antigen-specific CD8+ T cells alone were able to induce these changes, as demonstrated using Mdr2-/-xK14-OVAp recipient mice on the Rag1-/- background. Mechanistically, we showed by depletion experiments that alterations in BA metabolism were partly mediated by the proinflammatory cytokines TNF and IFN-γ in an FXR-dependent manner, a process that in vitro required cell contact between T cells and hepatocytes. CONCLUSION Whereas it is known that BA metabolism is dysregulated in sepsis and related conditions, we have shown that T cells are able to control the synthesis and metabolism of BAs, a process which depends on TNF and IFN-γ. Understanding the effect of lymphocytes on BA metabolism will help in the design of combined treatment strategies for cholestatic liver diseases. LAY SUMMARY Dysregulation of bile acid metabolism and T cells can contribute to the development of cholangiopathies. Before targeting T cells for the treatment of cholangiopathies, it should be determined whether they exert protective effects on bile acid metabolism. Herein, we demonstrate that T cell-induced cholangitis resulted in decreased levels of harmful unconjugated bile acids. T cells were able to directly control synthesis and metabolism of bile acids, a process which was dependent on the proinflammatory cytokines TNF and IFN-γ. Understanding the effect of lymphocytes on bile acid metabolism will help in the design of combined treatment strategies for cholestatic liver diseases.
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Affiliation(s)
- Fabian Glaser
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Clara John
- Department of Biochemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bastian Engel
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Benedikt Höh
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Dieckhoff
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stephanie Stein
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nathalie Becker
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Casar
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fenja Amrei Schuran
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Björn Wieschendorf
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Max Preti
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Friederike Jessen
- Department of Biochemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Antonella Carambia
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Harald Ittrich
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Herkel
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Joerg Heeren
- Department of Biochemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Centre for Rare Diseases, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
| | - Dorothee Schwinge
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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23
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Xie C, Takahashi S, Brocker CN, He S, Chen L, Xie G, Jang K, Gao X, Krausz KW, Qu A, Levi M, Gonzalez FJ. Hepatocyte peroxisome proliferator-activated receptor α regulates bile acid synthesis and transport. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:1396-1411. [PMID: 31195146 DOI: 10.1016/j.bbalip.2019.05.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 02/05/2019] [Accepted: 05/28/2019] [Indexed: 12/12/2022]
Abstract
Peroxisome proliferator-activated receptor alpha (PPARα) controls lipid homeostasis through regulation of lipid transport and catabolism. PPARα activators are clinically used for hyperlipidemia treatment. The role of PPARα in bile acid (BA) homeostasis is beginning to emerge. Herein, Ppara-null and hepatocyte-specific Ppara-null (Ppara∆Hep) as well as the respective wild-type mice were treated with the potent PPARα agonist Wy-14,643 (Wy) and global metabolomics performed to clarify the role of hepatocyte PPARα in the regulation of BA homeostasis. Levels of all serum BAs were markedly elevated in Wy-treated wild-type mice but not in Ppara-null and Ppara∆Hep mice. Gene expression analysis showed that PPARα activation (1) down-regulated the expression of sodium-taurocholate acid transporting polypeptide and organic ion transporting polypeptide 1 and 4, responsible for the uptake of BAs into the liver; (2) decreased the expression of bile salt export pump transporting BA from hepatocytes into the bile canaliculus; (3) upregulated the expression of multidrug resistance-associated protein 3 and 4 transporting BA from hepatocytes into the portal vein. Moreover, there was a notable increase in the compositions of serum, hepatic and biliary cholic acid and taurocholic acid following Wy treatment, which correlated with the upregulated expression of the Cyp8b1 gene encoding sterol 12α-hydroxylase. The effects of Wy were identical between the Ppara∆Hep and Ppara-null mice. Hepatocyte PPARα controlled BA synthesis and transport not only via direct transcriptional regulation but also via crosstalk with hepatic farnesoid X receptor signaling. These findings underscore a key role for hepatocyte PPARα in the control of BA homeostasis.
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Affiliation(s)
- Cen Xie
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 2089, United States of America; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
| | - Shogo Takahashi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 2089, United States of America; Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, United States of America.
| | - Chad N Brocker
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 2089, United States of America.
| | - Shijun He
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
| | - Li Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
| | - Guomin Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China.
| | - Katrina Jang
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 2089, United States of America.
| | - Xiaoxia Gao
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 2089, United States of America.
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 2089, United States of America.
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China.
| | - Moshe Levi
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, United States of America.
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 2089, United States of America.
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24
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Won KJ, Park JS, Jeong H. Repression of hepatocyte nuclear factor 4 alpha by AP-1 underlies dyslipidemia associated with retinoic acid. J Lipid Res 2019; 60:794-804. [PMID: 30709899 PMCID: PMC6446710 DOI: 10.1194/jlr.m088880] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 01/28/2019] [Indexed: 11/20/2022] Open
Abstract
All-trans retinoic acid (atRA) is used to treat certain cancers and dermatologic diseases. A common adverse effect of atRA is hypercholesterolemia; cytochrome P450 (CYP) 7A repression is suggested as a driver. However, the underlying molecular mechanisms remain unclear. We investigated CYP7A1 expression in the presence of atRA in human hepatocytes and hepatic cell lines. In HepaRG cells, atRA increased cholesterol levels dose-dependently alongside dramatic decreases in CYP7A1 expression. Lentiviral-mediated CYP7A1 overexpression reversed atRA-induced cholesterol accumulation, suggesting that CYP7A1 repression mediated cholesterol accumulation. In CYP7A1 promoter reporter assays and gene-knockdown studies, altered binding of hepatocyte nuclear factor 4 α (HNF4α) to the proximal promoter was essential for atRA-mediated CYP7A1 repression. Pharmacologic inhibition of c-Jun N-terminal kinase (JNK) and ERK pathways attenuated atRA-mediated CYP7A1 repression and cholesterol accumulation. Overexpression of AP-1 (c-Jun/c-Fos), a downstream target of JNK and ERK, repressed CYP7A1 expression. In DNA pull-down and chromatin immunoprecipitation assays, AP-1 exhibited sequence-specific binding to the proximal CYP7A1 promoter region overlapping the HNF4α binding site, and atRA increased AP-1 but decreased HNF4α recruitment to the promoter. Collectively, these results indicate that atRA activates JNK and ERK pathways and the downstream target AP-1 represses HNF4α transactivation of the CYP7A1 promoter, potentially responsible for hypercholesterolemia.
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Affiliation(s)
- Kyoung-Jae Won
- Departments of Pharmacy Practice College of Pharmacy, University of Illinois at Chicago, Chicago, IL
| | - Joo-Seop Park
- Divisions of Pediatric Urology Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH; Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Hyunyoung Jeong
- Departments of Pharmacy Practice College of Pharmacy, University of Illinois at Chicago, Chicago, IL; Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL.
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25
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Cariello M, Piglionica M, Gadaleta RM, Moschetta A. The Enterokine Fibroblast Growth Factor 15/19 in Bile Acid Metabolism. Handb Exp Pharmacol 2019; 256:73-93. [PMID: 31123830 DOI: 10.1007/164_2019_235] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The endocrine fibroblast growth factors (FGFs), FGF19, FGF21, and FGF23, play a key role in whole-body homeostasis. In particular, FGF19 is a postprandial hormone regulating glucose homeostasis, glycogen and protein synthesis, and primary bile acid (BA) metabolism. In the ileum, BA-dependent farnesoid X receptor (FXR) activation induces the production of FGF19, which reaches the liver through the portal system where it represses the expression of CYP7A1, the rate-limiting enzyme of hepatic de novo BAs synthesis. Dysregulation of BA levels associated with alteration in FGF19 level has been depicted in different pathological conditions of the gut-liver axis. Furthermore, FGF19 exploits strong anti-cholestatic and anti-fibrotic activities in the liver. However, native FGF19 seems to retain peculiar hepatic pro-tumorigenic actions. Recently engineered FGF19 analogues have been recently synthetized, with fully retained BA regulatory activity but without intrinsic pro-tumoral action, thus opening bona fide novel pharmacological strategy for the treatment of gut-liver axis diseases.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, Bari, Italy
| | - Marilidia Piglionica
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, Bari, Italy
| | | | - Antonio Moschetta
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, Bari, Italy.
- National Cancer Center, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.
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Ding L, Chang M, Guo Y, Zhang L, Xue C, Yanagita T, Zhang T, Wang Y. Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids Health Dis 2018; 17:286. [PMID: 30567573 PMCID: PMC6300890 DOI: 10.1186/s12944-018-0939-6] [Citation(s) in RCA: 152] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 12/03/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Recently, trimethylamine-N-oxide (TMAO) plasma levels have been proved to be associated with atherosclerosis development. Among the targets aimed to ameliorating atherosclerotic lesions, inducing bile acid synthesis to eliminate excess cholesterol in body is an effective way. Individual bile acid as endogenous ligands for the nuclear receptor has differential effects on regulating bile acid metabolism. It is unclear whether bile acid profiles are mechanistically linked to TMAO-induced development of atherosclerosis. METHODS Male apoE-/- mice were fed with control diet containing 0.3% TMAO for 8 weeks. Aortic lesion development and serum lipid profiles were determined. Bile acid profiles in bile, liver and serum were measured by liquid chromatographic separation and mass spectrometric detection (LC-MS). Real-time PCRs were performed to analyze mRNA expression of genes related to hepatic bile acid metabolism. RESULTS The total plaque areas in the aortas strongly increased 2-fold (P < 0.001) in TMAO administration mice. The levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) in TMAO group were also significantly increased by 25.5% (P = 0.044), 31.2% (P = 0.006), 28.3% (P = 0.032), respectively. TMAO notably changed bile acid profiles, especially in serum, the most prominent inductions were tauromuricholic acid (TMCA), deoxycholic acid (DCA) and cholic acid (CA). Mechanically, TMAO inhibited hepatic bile acid synthesis by specifically repressing the classical bile acid synthesis pathway, which might be mediated by activation of small heterodimer partner (SHP) and farnesoid X receptor (FXR). CONCLUSIONS These findings suggested that TMAO accelerated aortic lesion formation in apoE-/- mice by altering bile acid profiles, further activating nuclear receptor FXR and SHP to inhibit bile acid synthesis by reducing Cyp7a1 expression.
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Affiliation(s)
- Lin Ding
- College of Food Science and Engineering, Ocean University of China, No.5 Yushan Road, Qingdao, Shandong Province, 266003, People's Republic of China
| | - Mengru Chang
- College of Food Science and Engineering, Ocean University of China, No.5 Yushan Road, Qingdao, Shandong Province, 266003, People's Republic of China
| | - Ying Guo
- College of Food Science and Engineering, Ocean University of China, No.5 Yushan Road, Qingdao, Shandong Province, 266003, People's Republic of China
| | - Lingyu Zhang
- College of Food Science and Engineering, Ocean University of China, No.5 Yushan Road, Qingdao, Shandong Province, 266003, People's Republic of China
| | - Changhu Xue
- College of Food Science and Engineering, Ocean University of China, No.5 Yushan Road, Qingdao, Shandong Province, 266003, People's Republic of China.,Qingdao National Laboratory for Marine Science and Technology, Laboratory of Marine Drugs & Biological products, Qingdao, 266237, People's Republic of China
| | - Teruyoshi Yanagita
- Department of Applied Biochemistry and Food Science, Laboratory of Nutrition Biochemistry, Saga University, Saga, 840-8502, Japan
| | - Tiantian Zhang
- College of Food Science and Engineering, Ocean University of China, No.5 Yushan Road, Qingdao, Shandong Province, 266003, People's Republic of China.
| | - Yuming Wang
- College of Food Science and Engineering, Ocean University of China, No.5 Yushan Road, Qingdao, Shandong Province, 266003, People's Republic of China. .,Qingdao National Laboratory for Marine Science and Technology, Laboratory of Marine Drugs & Biological products, Qingdao, 266237, People's Republic of China.
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Xiao Y, Zhou K, Lu Y, Yan W, Cai W, Wang Y. Administration of antibiotics contributes to cholestasis in pediatric patients with intestinal failure via the alteration of FXR signaling. Exp Mol Med 2018; 50:1-14. [PMID: 30504803 PMCID: PMC6269533 DOI: 10.1038/s12276-018-0181-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 09/03/2018] [Accepted: 09/04/2018] [Indexed: 12/14/2022] Open
Abstract
The link between antibiotic treatment and IF-associated liver disease (IFALD) is unclear. Here, we study the effect of antibiotic treatment on bile acid (BA) metabolism and investigate the involved mechanisms. The results showed that pediatric IF patients with cholestasis had a significantly lower abundance of BA-biotransforming bacteria than patients without cholestasis. In addition, the BA composition was altered in the serum, feces, and liver of pediatric IF patients with cholestasis, as reflected by the increased proportion of primary BAs. In the ileum, farnesoid X receptor (FXR) expression was reduced in patients with cholestasis. Correspondingly, the serum FGF19 levels decreased significantly in patients with cholestasis. In the liver, the expression of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), increased noticeably in IF patients with cholestasis. In mice, we showed that oral antibiotics (gentamicin, GM or vancomycin, VCM) reduced colonic microbial diversity, with a decrease in both Gram-negative bacteria (GM affected Eubacterium and Bacteroides) and Gram-positive bacteria (VCM affected Clostridium, Bifidobacterium and Lactobacillus). Concomitantly, treatment with GM or VCM decreased secondary BAs in the colonic contents, with a simultaneous increase in primary BAs in plasma. Moreover, the changes in the colonic BA profile especially that of tauro-beta-muricholic acid (TβMCA), were predominantly associated with the inhibition of the FXR and further altered BA synthesis and transport. In conclusion, the administration of antibiotics significantly decreased the intestinal microbiota diversity and subsequently altered the BA composition. The alterations in BA composition contributed to cholestasis in IF patients by regulating FXR signaling. Using antibiotics during intestinal failure in children may lead to the development of liver disease. Microbiota in the gut play vital roles in balancing the digestive system, including transforming bile acids (BAs) secreted by the liver into forms that help us digest food. Wai Cai and Ying Wang at Shanghai Jiao Tong University in China and co-workers examined samples from 46 children treated with antibiotics for intestinal failure. The patients who also had cholestasis – disrupted production and flow of bile – had far fewer BA-transforming bacteria in their gut than those without cholestasis. They also had altered expression of a crucial BA receptor protein. Experiments on mice showed that treatment with two different antibiotics reduced microbiota diversity, which in turn influenced BA receptor signaling and altered BA composition, contributing to cholestasis.
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Affiliation(s)
- Yongtao Xiao
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Pediatric Research, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Kejun Zhou
- Shanghai Institute of Pediatric Research, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ying Lu
- Shanghai Institute of Pediatric Research, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Weihui Yan
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. .,Shanghai Institute of Pediatric Research, Shanghai, China. .,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Ying Wang
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. .,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
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Nagaoka S. Structure-function properties of hypolipidemic peptides. J Food Biochem 2018; 43:e12539. [PMID: 31353491 DOI: 10.1111/jfbc.12539] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 01/12/2018] [Accepted: 02/19/2018] [Indexed: 01/06/2023]
Abstract
This review addresses the structure-function properties of hypolipidemic peptides. The cholesterol-lowering peptide (lactostatin: IIAEK) operates via a new regulatory pathway in the calcium-channel-related mitogen-activated protein kinase (MAPK) signaling pathway of cholesterol degradation. The bile acid binding peptide (soystatin, VAWWMY) inhibits the micellar solubility of cholesterol in vitro and cholesterol absorption in vivo. VVYP is the most effective peptide having hypotriglyceridemic action in globin digests. The suppressive effect of globin digest on postprandial hyperlipidemia has been reported in humans. The ability of peptides (KRES, Apolipoprotein A-I mimetic peptides) to interact with lipids, remove LOOH and activate antioxidant enzymes associated with high-density lipoprotein determines their anti-inflammatory and anti-atherogenic properties. The β-conglycinin derived peptides KNPQLR, EITPEKNPQLR, and RKQEEDEDEEQQRE inhibit fatty acid synthase in vitro. These promising findings indicate the need for more conclusive molecular, cellular, and animal and human studies to design innovative new peptides that ameliorate cholesterol and lipid metabolism. PRACTICAL APPLICATIONS: Prevention and amelioration of hypercholesterolemia by dietary regulation are important. Dietary protein and peptides are very useful as regulators of serum cholesterol concentration. Diets low in saturated fat and cholesterol that include soy protein may reduce the risk of heart disease. In Japan, the concept of "food for specified health use" has been introduced for the prevention and treatment of life-style related disease. Thus, peptides derived from food proteins and sources other than food proteins such as peptide-rich functional foods and nutraceutical products, have considerable potential to prevent lifestyle-related diseases, especially hyperlipidemia, as discussed in this review. Furthermore, various strategies have been used for the efficient screening, development, and application of new hypolipidemic peptides. These include the use of phage display (for anti-obesity peptide), peptide mimetics (for anti-atherogenic peptide), and molecular targets such as CYP7A1 (for hypocholesterolemic peptide) and prohibitin (for anti-obesity peptide).
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Affiliation(s)
- Satoshi Nagaoka
- Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
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Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma. Sci Rep 2017; 7:6747. [PMID: 28751722 PMCID: PMC5532242 DOI: 10.1038/s41598-017-06439-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 06/13/2017] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to hepatocarcinoma. Tissue inhibitor of metalloproteinase 3 (Timp3) has a role in the pathogenesis of fatty liver disease associated with obesity and is silenced during metabolic disorders and liver cancer. We generated an hepatocyte-specific TIMP3 'gain-of-function' mouse model under the control of the Albumin promoter (AlbT3) and investigated its effects during high-fat diet (HFD). After 16 weeks of HFD, TIMP3 overexpression significantly improved glucose metabolism, hepatic fatty acid oxidation and cholesterol homeostasis. In AlbT3 mice CYP7A1, MDR3 and MRP2 gene expressions were observed, consistent with higher bile acid synthesis and export. Next, to evaluate the role of A Disintegrin and Metalloproteinase 17 (ADAM17), a crucial target of TIMP3, in these processes, we created mice deficient in Adam17 specifically in hepatocyte (A17LKO) or in myeloid lineage (A17MKO), founding that only A17LKO showed improvement in liver steatosis induced by HFD. Moreover, both, AlbT3 and A17LKO significantly reduced diethylnitrosamine-initiated, HFD-promoted hepatic tumorigenesis assessed by tumor multiplicity and total tumor area. Taken together, these data indicate that hepatic TIMP3 can slow progression of NAFLD, and tumorigenesis, at least in part, through the regulation of ADAM17 activity.
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Guo J, Gao Y, Cao X, Zhang J, Chen W. Cholesterol-lowing effect of taurine in HepG2 cell. Lipids Health Dis 2017; 16:56. [PMID: 28302129 PMCID: PMC5356372 DOI: 10.1186/s12944-017-0444-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 03/07/2017] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND A number of studies indicate that taurine promotes cholesterol conversion to bile acids by upregulating CYP7A1 gene expression. Few in vitro studies are concerned the concentration change of cholesterol and its product of bile acids, and the molecular mechanism of CYP7A1 induction by taurine. METHODS The levels of intracellular total cholesterol (TC), free cholesterol (FC), cholesterol ester (EC), total bile acids (TBA) and medium TBA were determined after HepG2 cells were cultured for 24/48 h in DMEM supplemented with taurine at the final concentrations of 1/10/20 mM respectively. The protein expressions of CYP7A1, MEK1/2, c-Jun, p-c-Jun and HNF-4α were detected. RESULTS Taurine significantly reduced cellular TC and FC in dose -and time-dependent ways, and obviously increased intracellular/medium TBA and CYP7A1 expressions. There was no change in c-Jun expression, but the protein expressions of MEK1/2 and p-c-Jun were increased at 24 h and inhibited at 48 h by 20 mM taurine while HNF4α was induced after both of the 24 h and 48 h treatment. CONCLUSION Taurine could enhance CYP7A1 expression by inducing HNF4α and inhibiting MEK1/2 and p-c-Jun expressions to promote intracellular cholesterol metabolism.
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Affiliation(s)
- Junxia Guo
- Food Science Department, College of Biochemical Engineering, Beijing Union University, Fatou west 18#, Chaoyang District, Beijing, 100023, People's Republic of China.,Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, 100191, People's Republic of China
| | - Ya Gao
- Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, 100191, People's Republic of China
| | - Xuelian Cao
- Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, 100191, People's Republic of China
| | - Jing Zhang
- Food Science Department, College of Biochemical Engineering, Beijing Union University, Fatou west 18#, Chaoyang District, Beijing, 100023, People's Republic of China.,Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, 100191, People's Republic of China
| | - Wen Chen
- Food Science Department, College of Biochemical Engineering, Beijing Union University, Fatou west 18#, Chaoyang District, Beijing, 100023, People's Republic of China. .,Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, 100191, People's Republic of China.
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Suárez-García S, del Bas JM, Caimari A, Escorihuela RM, Arola L, Suárez M. Impact of a cafeteria diet and daily physical training on the rat serum metabolome. PLoS One 2017; 12:e0171970. [PMID: 28192465 PMCID: PMC5305073 DOI: 10.1371/journal.pone.0171970] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 01/27/2017] [Indexed: 12/18/2022] Open
Abstract
Regular physical activity and healthy dietary patterns are commonly recommended for the prevention and treatment of metabolic syndrome (MetS), which is diagnosed at an alarmingly increasing rate, especially among adolescents. Nevertheless, little is known regarding the relevance of physical exercise on the modulation of the metabolome in healthy people and those with MetS. We have previously shown that treadmill exercise ameliorated different symptoms of MetS. The aim of this study was to investigate the impact of a MetS-inducing diet and different intensities of aerobic training on the overall serum metabolome of adolescent rats. For 8 weeks, young rats were fed either standard chow (ST) or cafeteria diet (CAF) and were subjected to a daily program of training on a treadmill at different speeds. Non-targeted metabolomics was used to identify changes in circulating metabolites, and a combination of multivariate analysis techniques was implemented to achieve a holistic understanding of the metabolome. Among all the identified circulating metabolites influenced by CAF, lysophosphatidylcholines were the most represented family. Serum sphingolipids, bile acids, acylcarnitines, unsaturated fatty acids and vitamin E and A derivatives also changed significantly in CAF-fed rats. These findings suggest that an enduring systemic inflammatory state is induced by CAF. The impact of physical training on the metabolome was less striking than the impact of diet and mainly altered circulating bile acids and glycerophospholipids. Furthermore, the serum levels of monocyte chemoattractant protein-1 were increased in CAF-fed rats, and C-reactive protein was decreased in trained groups. The leptin/adiponectin ratio, a useful marker of MetS, was increased in CAF groups, but decreased in proportion to training intensity. Multivariate analysis revealed that ST-fed animals were more susceptible to exercise-induced changes in metabolites than animals with MetS, in which moderate-intensity seems more effective than high-intensity training. Our results indicate that CAF has a strong negative impact on the metabolome of animals that is difficult to reverse by daily exercise.
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Affiliation(s)
- Susana Suárez-García
- Departament de Bioquímica i Biotecnologia, Nutrigenomics Research Group, Universitat Rovira i Virgili, Tarragona, Spain
| | - Josep M. del Bas
- Technological Unit of Nutrition and Health, EURECAT-Technological Center of Catalonia, Reus, Spain
| | - Antoni Caimari
- Technological Unit of Nutrition and Health, EURECAT-Technological Center of Catalonia, Reus, Spain
| | - Rosa M. Escorihuela
- Institut de Neurociències, Departament de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Lluís Arola
- Departament de Bioquímica i Biotecnologia, Nutrigenomics Research Group, Universitat Rovira i Virgili, Tarragona, Spain
- Technological Unit of Nutrition and Health, EURECAT-Technological Center of Catalonia, Reus, Spain
| | - Manuel Suárez
- Departament de Bioquímica i Biotecnologia, Nutrigenomics Research Group, Universitat Rovira i Virgili, Tarragona, Spain
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Valanejad L, Nadolny C, Shiffka S, Chen Y, You S, Deng R. Differential Feedback Regulation of Δ4-3-Oxosteroid 5β-Reductase Expression by Bile Acids. PLoS One 2017; 12:e0170960. [PMID: 28125709 PMCID: PMC5268776 DOI: 10.1371/journal.pone.0170960] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 01/14/2017] [Indexed: 02/08/2023] Open
Abstract
Δ4-3-oxosteroid 5β-reductase is member D1 of the aldo-keto reductase family 1 (AKR1D1), which catalyzes 5β-reduction of molecules with a 3-oxo-4-ene structure. Bile acid intermediates and most of the steroid hormones carry the 3-oxo-4-ene structure. Therefore, AKR1D1 plays critical roles in both bile acid synthesis and steroid hormone metabolism. Currently our understanding on transcriptional regulation of AKR1D1 under physiological and pathological conditions is very limited. In this study, we investigated the regulatory effects of primary bile acids, chenodeoxycholic acid (CDCA) and cholic acid (CA), on AKR1D1 expression. The expression levels of AKR1D1 mRNA and protein in vitro and in vivo following bile acid treatments were determined by real-time PCR and Western blotting. We found that CDCA markedly repressed AKR1D1 expression in vitro in human hepatoma HepG2 cells and in vivo in mice. On the contrary, CA significantly upregulated AKR1D1 expression in HepG2 cells and in mice. Further mechanistic investigations revealed that the farnesoid x receptor (FXR) signaling pathway was not involved in regulating AKR1D1 by bile acids. Instead, CDCA and CA regulated AKR1D1 through the mitogen-activated protein kinases/c-Jun N-terminal kinases (MAPK/JNK) signaling pathway. Inhibition of the MAPK/JNK pathway effectively abolished CDCA and CA-mediated regulation of AKR1D1. It was thus determined that AKR1D1 expression was regulated by CDCA and CA through modulating the MAPK/JNK signaling pathway. In conclusion, AKR1D1 expression was differentially regulated by primary bile acids through negative and positive feedback mechanisms. The findings indicated that both bile acid concentrations and compositions play important roles in regulating AKR1D1 expression, and consequently bile acid synthesis and steroid hormone metabolism.
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Affiliation(s)
- Leila Valanejad
- Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, United States of America
| | - Christina Nadolny
- Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, United States of America
| | - Stephanie Shiffka
- Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, United States of America
| | - Yuan Chen
- Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, United States of America
| | - Sangmin You
- Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, United States of America
| | - Ruitang Deng
- Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, United States of America
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Henkel AS, LeCuyer B, Olivares S, Green RM. Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in Mice. Cell Mol Gastroenterol Hepatol 2016; 3:261-271. [PMID: 28275692 PMCID: PMC5331781 DOI: 10.1016/j.jcmgh.2016.11.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/01/2016] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Cholestasis promotes endoplasmic reticulum (ER) stress in the liver, however, the effect of ER stress on hepatic bile acid metabolism is unknown. We aim to determine the effect of ER stress on hepatic bile acid synthesis and transport in mice. METHODS ER stress was induced pharmacologically in C57BL/6J mice and human hepatoma (HepG2) cells. The hepatic expression of genes controlling bile acid synthesis and transport was determined. To measure the activity of the primary bile acid synthetic pathway, the concentration of 7α-hydroxy-4-cholesten-3-1 was measured in plasma. RESULTS Induction of ER stress in mice and HepG2 cells rapidly suppressed the hepatic expression of the primary bile acid synthetic enzyme, cholesterol 7α-hydroxylase. Plasma levels of 7α-hydroxy-4-cholesten-3-1 were reduced in mice subjected to ER stress, indicating impaired bile acid synthesis. Induction of ER stress in mice and HepG2 cells increased expression of the bile salt export pump (adenosine triphosphate binding cassette [Abc]b11) and a bile salt efflux pump (Abcc3). The observed regulation of Cyp7a1, Abcb11, and Abcc3 occurred in the absence of hepatic inflammatory cytokine activation and was not dependent on activation of hepatic small heterodimer partner or intestinal fibroblast growth factor 15. Consistent with suppressed bile acid synthesis and enhanced bile acid export from hepatocytes, prolonged ER stress decreased the hepatic bile acid content in mice. CONCLUSIONS Induction of ER stress in mice suppresses bile acid synthesis and enhances bile acid removal from hepatocytes independently of established bile acid regulatory pathways. These data show a novel function of the ER stress response in regulating bile acid metabolism.
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Key Words
- 7α-Hydroxy-4-Cholesten-3-1
- ABC, adenosine triphosphate binding cassette
- Bile Acid Synthesis
- C4, 7α-hydroxy-4-cholesten-3-1
- CYP7A1, cholesterol 7α-hydroxylase
- Cyp7a1
- DMEM, Dulbecco's modified Eagle medium
- DMSO, dimethyl sulfoxide
- ER, endoplasmic reticulum
- ERK, extracellular signaling-regulated kinase
- FGF, fibroblast growth factor
- FXR, farnesoid X receptor
- IL, interleukin
- IRE1α, inositol requiring enzyme 1α
- JNK, c-Jun-N-terminal kinase
- NTCP, sodium/taurocholate cotransporter
- RIDD, regulated inositol requiring enzyme 1α–dependent messenger RNA decay
- SHP, small heterodimer partner
- UPR, unfolded protein response
- Unfolded Protein Response
- mRNA, messenger RNA
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Affiliation(s)
- Anne S. Henkel
- Correspondence Address correspondence to: Anne S. Henkel, MD, 320 East Superior Street, Tarry 15-705, Chicago, Illinois 60611. fax: (312) 908-9032.320 East Superior StreetTarry 15-705ChicagoIllinois 60611
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Fusakio ME, Willy JA, Wang Y, Mirek ET, Al Baghdadi RJT, Adams CM, Anthony TG, Wek RC. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol Biol Cell 2016; 27:1536-51. [PMID: 26960794 PMCID: PMC4850040 DOI: 10.1091/mbc.e16-01-0039] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/03/2016] [Indexed: 12/22/2022] Open
Abstract
Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins-PERK (PEK/EIF2AK3), IRE1, and ATF6-is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole-body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera.
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Affiliation(s)
- Michael E Fusakio
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Jeffrey A Willy
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Yongping Wang
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901
| | - Emily T Mirek
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901
| | | | - Christopher M Adams
- Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa, and Iowa City Veterans Affairs Medical Center, Iowa City, IA 52246
| | - Tracy G Anthony
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901
| | - Ronald C Wek
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
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Guan D, Zhao L, Chen D, Yu B, Yu J. Regulation of fibroblast growth factor 15/19 and 21 on metabolism: in the fed or fasted state. J Transl Med 2016; 14:63. [PMID: 26931208 PMCID: PMC4774037 DOI: 10.1186/s12967-016-0821-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 02/23/2016] [Indexed: 12/26/2022] Open
Abstract
Fibroblast growth factor (FGF) 15/19 and FGF21 are two atypical members of FGF19 subfamily that function as hormones. Exogenous FGF15/19 and FGF21 have pharmacological effects, and endogenous FGF15/19 and FGF21 play vital roles in the maintenance of energy homeostasis. Recent reports have expanded the effects of FGF15/19 and FGF21 on carbohydrate and lipid metabolism. However, the regulations of FGF15/19 and FGF21 on metabolism are different. FGF15/19 is mainly secreted from the small intestine in response to feeding, and FGF21 is secreted from the liver in response to extended fasting and from the liver and adipose tissue in response to feeding. In this work, we reviewed the regulatory effects of FGF15/19 and FGF21 on metabolism in the fast and fed states. This information may provide some insight into the metabolic regulation of FGF15/19 and FGF21 in different physiological condition.
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Affiliation(s)
- Dandan Guan
- Animal Nutrition Institute, Sichuan Agricultural University, No. 211 Huimin Road, Wenjiang District, Chengdu, 611130, China.
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, 611130, China.
| | - Lidan Zhao
- Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA.
| | - Daiwen Chen
- Animal Nutrition Institute, Sichuan Agricultural University, No. 211 Huimin Road, Wenjiang District, Chengdu, 611130, China.
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, 611130, China.
| | - Bing Yu
- Animal Nutrition Institute, Sichuan Agricultural University, No. 211 Huimin Road, Wenjiang District, Chengdu, 611130, China.
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, 611130, China.
| | - Jie Yu
- Animal Nutrition Institute, Sichuan Agricultural University, No. 211 Huimin Road, Wenjiang District, Chengdu, 611130, China.
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, 611130, China.
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Zhang H, Wang J, Liu Y, Gong L, Sun B. Rice bran proteins and their hydrolysates modulate cholesterol metabolism in mice on hypercholesterolemic diets. Food Funct 2016; 7:2747-53. [DOI: 10.1039/c6fo00044d] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The hypolipidemic properties of defatted rice bran protein (DRBP), fresh rice bran protein (FRBP), DRBP hydrolysates (DRBPH), and FRBP hydrolysates (FRBPH) were determined in mice on high fat diets for four weeks.
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Affiliation(s)
- Huijuan Zhang
- Innovation Center for Food Nutrition and Human Health
- Beijing Technology & Business University (BTBU)
- Beijing 100048
- China
| | - Jing Wang
- Innovation Center for Food Nutrition and Human Health
- Beijing Technology & Business University (BTBU)
- Beijing 100048
- China
- Key Laboratory of Space Nutrition and Food Engineering
| | - Yingli Liu
- Innovation Center for Food Nutrition and Human Health
- Beijing Technology & Business University (BTBU)
- Beijing 100048
- China
| | - Lingxiao Gong
- Innovation Center for Food Nutrition and Human Health
- Beijing Technology & Business University (BTBU)
- Beijing 100048
- China
| | - Baoguo Sun
- Innovation Center for Food Nutrition and Human Health
- Beijing Technology & Business University (BTBU)
- Beijing 100048
- China
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Geng T, Xia L, Russo S, Kamara D, Cowart LA. Prosteatotic genes are associated with unsaturated fat suppression of saturated fat-induced hepatic steatosis in C57BL/6 mice. Nutr Res 2015; 35:812-822. [PMID: 26277244 PMCID: PMC5520982 DOI: 10.1016/j.nutres.2015.06.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 06/21/2015] [Accepted: 06/30/2015] [Indexed: 01/01/2023]
Abstract
Both high sugar and fat diets can induce prosteatotic genes, leading to obesity and obesity-associated diseases, including hepatic steatosis. Unsaturated fat/fatty acid (USFA) reduces high sugar-induced hepatic steatosis by inhibiting the induced prosteatotic genes. In contrast, it is still unclear how USFA ameliorates saturated fat/fatty acid (SFA)-induced hepatic steatosis. As sugar and fat have different transport and metabolic pathways, we hypothesized that USFA suppressed SFA-induced hepatic steatosis via a different set of prosteatotic genes. To test this, we implemented high SFA vs USFA diets and a control diet in C57BL/6 mice for 16 weeks. Severe hepatic steatosis was induced in mice fed the SFA diet. Among a nearly complete set of prosteatotic genes, only the stearoyl-coenzyme a desaturase 1 (Scd1), cluster of differentiation 36 (Cd36), and peroxisome proliferator-activated receptor γ (Pparγ) genes that were differentially expressed in the liver could contribute to SFA-induced steatosis or the alleviative effect of USFA. That is, the SFA diet induced the expression of Cd36 and Pparγ but not Scd1, and the USFA diet suppressed Scd1 expression and the induction of Cd36 and Pparγ. These findings were mainly recapitulated in cultured hepatocytes. The essential roles of SCD1 and CD36 were confirmed by the observation that the suppression of SCD1 and CD36 with small interfering RNA or drug treatment ameliorated SFA-induced lipid accumulation in hepatocytes. We thus concluded that SCD1, CD36, and PPARγ were essential to the suppression of SFA-induced hepatic steatosis by main dietary USFA, which may provide different therapeutic targets for reducing high-fat vs sugar-induced hepatic steatosis.
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Affiliation(s)
- Tuoyu Geng
- Institute of Epigenetics and Epigenomics, Yangzhou University, 48 Wenhui East Road, Yangzhou, Jiangsu 225009, China; College of Animal Science and Technology, Yangzhou University, 48 Wenhui East Road, Yangzhou, Jiangsu 225009, China; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425, USA.
| | - Lili Xia
- College of Animal Science and Technology, Yangzhou University, 48 Wenhui East Road, Yangzhou, Jiangsu 225009, China
| | - Sarah Russo
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425, USA
| | - Davida Kamara
- Union Hospital of Cecil County, 106 Bow St, Elkton, MD 21921, USA
| | - Lauren Ashley Cowart
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425, USA; Ralph H Johnson Veteran's Affairs Medical Center, 109 Bee St, 29403, Charleston, SC, USA
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Tan Y, Bi W, Zhang GX. Role and molecular mechanism of farnesoid X receptor in obstructive jaundice. Shijie Huaren Xiaohua Zazhi 2015; 23:2574-2581. [DOI: 10.11569/wcjd.v23.i16.2574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Obstructive jaundice is a common and frequently occurring disease, which can result in multiple organ dysfunction syndrome in serious conditions due to the abnormal accumulation of bile acids in blood. Farnesoid X receptor (FXR), a nuclear receptor for bile acid, plays a significant role in bile acid metabolism. Recent research demonstrates that FXR also participates in the regulation of the pathological and physiological processes during obstructive jaundice. In this article, we review the latest research about the role and molecular mechanism of FXR in obstructive jaundice, in order to explore new methods and strategies for curing the disease.
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Marangoni A, Fiorino E, Gilardi F, Aldini R, Scotti E, Nardini P, Foschi C, Donati M, Montagnani M, Cevenini M, Franco P, Roda A, Crestani M, Cevenini R. Chlamydia pneumoniae acute liver infection affects hepatic cholesterol and triglyceride metabolism in mice. Atherosclerosis 2015; 241:471-9. [PMID: 26086356 DOI: 10.1016/j.atherosclerosis.2015.05.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 05/15/2015] [Accepted: 05/25/2015] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Chlamydia pneumoniae has been linked to atherosclerosis, strictly associated with hyperlipidemia. The liver plays a central role in the regulation of lipid metabolism. Since in animal models C. pneumoniae can be found at hepatic level, this study aims to elucidate whether C. pneumoniae infection accelerates atherosclerosis by affecting lipid metabolism. METHODS Thirty Balb/c mice were challenged intra-peritoneally with C. pneumoniae elementary bodies and thirty with Chlamydia trachomatis, serovar D. Thirty mice were injected with sucrose-phosphate-glutamate buffer, as negative controls. Seven days after infection, liver samples were examined both for presence of chlamydia and expression of genes involved in inflammation and lipid metabolism. RESULTS C. pneumoniae was isolated from 26 liver homogenates, whereas C. trachomatis was never re-cultivated (P < 0.001). C. pneumoniae infected mice showed significantly increased serum cholesterol and triglycerides levels compared both with negative controls (P < 0.001 and P = 0.0197, respectively) and C. trachomatis infected mice (P < 0.001). Liver bile acids were significantly reduced in C. pneumoniae compared to controls and C. trachomatis infected mice. In C. pneumoniae infected livers, cholesterol 7α-hydroxylase (Cyp7a1) and low-density lipoprotein receptor (Ldlr) mRNA levels were reduced, while inducible degrader of the low-density lipoprotein receptor (Idol) expression was increased. Hypertriglyceridemia was associated to reduced expression of hepatic carnitine palmitoyltransferase-1a (Cpt1a) and medium chain acyl-Coenzyme A dehydrogenase (Acadm). Pro-inflammatory cytokines gene expression was increased compared to negative controls. Conversely, in C. trachomatis infected animals, normal serum lipid levels were associated with elevated pro-inflammatory cytokines gene expression, linked to only a mild disturbance of lipid regulatory genes. CONCLUSION Our results indicate that C. pneumoniae mouse liver infection induces dyslipidemic effects with significant modifications of genes involved in lipid metabolism.
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Affiliation(s)
- Antonella Marangoni
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi di Bologna, Bologna, Italy
| | - Erika Fiorino
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Federica Gilardi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Rita Aldini
- Dipartimento di Farmacia e Biotecnologie, Università degli Studi di Bologna, Bologna, Italy
| | - Elena Scotti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Paola Nardini
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi di Bologna, Bologna, Italy
| | - Claudio Foschi
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi di Bologna, Bologna, Italy
| | - Manuela Donati
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi di Bologna, Bologna, Italy
| | - Marco Montagnani
- Dipartimento di Scienze Mediche e Chirurgiche, Università degli studi di Bologna, Bologna, Italy
| | - Monica Cevenini
- Dipartimento di Scienze Mediche e Chirurgiche, Università degli studi di Bologna, Bologna, Italy
| | - Placido Franco
- Dipartimento di Chimica "G. Ciamician", Università degli Studi di Bologna, Bologna, Italy
| | - Aldo Roda
- Dipartimento di Chimica "G. Ciamician", Università degli Studi di Bologna, Bologna, Italy
| | - Maurizio Crestani
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
| | - Roberto Cevenini
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi di Bologna, Bologna, Italy
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Abstract
While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.
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Affiliation(s)
- Steven A. Kliewer
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX USA,Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX USA,Address correspondence to SAK () and DJM ()
| | - David J. Mangelsdorf
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX USA,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX USA,Address correspondence to SAK () and DJM ()
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Shih DM, Wang Z, Lee R, Meng Y, Che N, Charugundla S, Qi H, Wu J, Pan C, Brown JM, Vallim T, Bennett BJ, Graham M, Hazen SL, Lusis AJ. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J Lipid Res 2014; 56:22-37. [PMID: 25378658 DOI: 10.1194/jlr.m051680] [Citation(s) in RCA: 248] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
We performed silencing and overexpression studies of flavin containing monooxygenase (FMO) 3 in hyperlipidemic mouse models to examine its effects on trimethylamine N-oxide (TMAO) levels and atherosclerosis. Knockdown of hepatic FMO3 in LDL receptor knockout mice using an antisense oligonucleotide resulted in decreased circulating TMAO levels and atherosclerosis. Surprisingly, we also observed significant decreases in hepatic lipids and in levels of plasma lipids, ketone bodies, glucose, and insulin. FMO3 overexpression in transgenic mice, on the other hand, increased hepatic and plasma lipids. Global gene expression analyses suggested that these effects of FMO3 on lipogenesis and gluconeogenesis may be mediated through the PPARα and Kruppel-like factor 15 pathways. In vivo and in vitro results were consistent with the concept that the effects were mediated directly by FMO3 rather than trimethylamine/TMAO; in particular, overexpression of FMO3 in the human hepatoma cell line, Hep3B, resulted in significantly increased glucose secretion and lipogenesis. Our results indicate a major role for FMO3 in modulating glucose and lipid homeostasis in vivo, and they suggest that pharmacologic inhibition of FMO3 to reduce TMAO levels would be confounded by metabolic interactions.
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Affiliation(s)
- Diana M Shih
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Zeneng Wang
- Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, OH
| | | | - Yonghong Meng
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Nam Che
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Sarada Charugundla
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Hannah Qi
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Judy Wu
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Calvin Pan
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - J Mark Brown
- Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, OH
| | - Thomas Vallim
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Brian J Bennett
- Department of Genetics, University of North Carolina, Chapel Hill, NC
| | | | - Stanley L Hazen
- Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, OH
| | - Aldons J Lusis
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA Departments of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
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Tavares-Sanchez OL, Rodriguez C, Gortares-Moroyoqui P, Estrada MI. Hepatocyte nuclear factor-4α, a multifunctional nuclear receptor associated with cardiovascular disease and cholesterol catabolism. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2014; 25:126-139. [PMID: 24848804 DOI: 10.1080/09603123.2014.915015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Cardiovascular diseases (CVDs), the leading cause of death worldwide, are associated with high plasma cholesterol levels. The conversion of cholesterol to bile acids (BAs) accounts for about 50% of total cholesterol elimination from the body. This phenomenon occurs in the liver and is regulated by nuclear receptors such as hepatocyte nuclear factor-4α (HNF-4α). Therefore, special emphasis is given to HNF-4α properties and its multifunctional role, particularly in the conversion of cholesterol to BAs. HNF-4α is a highly conserved transcription factor that has the potential capacity to transactivate a vast number of genes, including CYP7 which codes for cholesterol 7α-hydroxylase (CYP7A1; EC 1.14.13.17), the rate-limiting enzyme of BA biosynthesis. The fact that HNF-4α transactivation potential can be modulated via phosporylation is of particular interest. Additional findings on structural and functional characteristics of HNF-4α may eventually present alternatives to control the levels of cholesterol in the body and consequently reduce the risk of CVDs.
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Affiliation(s)
- Olga Lidia Tavares-Sanchez
- a Departamento de Biotecnología y Ciencias Alimentarias , Instituto Tecnológico de Sonora , Ciudad Obregón , Mexico
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Liu X, Qi Y, Tian B, Chen D, Gao H, Xi C, Xing Y, Yuan Z. Maternal protein restriction induces alterations in hepatic tumor necrosis factor-α/CYP7A1 signaling and disorders regulation of cholesterol metabolism in the adult rat offspring. J Clin Biochem Nutr 2014; 55:40-7. [PMID: 25120278 PMCID: PMC4078062 DOI: 10.3164/jcbn.13-100] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 02/02/2014] [Indexed: 12/19/2022] Open
Abstract
It is well recognized that adverse events in utero impair fetal development and lead to the development of obesity and metabolic syndrome in adulthood. To investigate the mechanisms linking impaired fetal growth to increased cholesterol, an important clinical risk factor characterizing the metabolic syndrome and cardiovascular disease, we examined the impact of maternal undernutrition on tumor necrosis factor-α (TNF-α)/c-jun N-terminal kinase (JNK) signaling pathway and the cholesterol 7α-hydroxylase (CYP7A1) expression in the livers of the offspring with a protein restriction model. The male offspring with intrauterine growth restriction (IUGR) caused by the isocaloric low-protein diet showed decreased liver weight at birth and augmented circulation and hepatic cholesterol levels at 40 weeks of age. Maternal undernutrition significantly upregulated cytokine TNF-α expression and JNK phospholytion levels in the livers from fetal age to adulthood. Elevated JNK phospholytion could be linked to downregulated hepatocyte nuclear factor-4α and CYP7A1 expression, subsequently led to higher hepatic cholesterol. This work demonstrated that intrauterine malnutrition-induced IUGR might result in intrinsic disorder in hepatic TNF-α/CYP7A1 signaling, and contribute to the development of hypercholesterolemia in later life.
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Affiliation(s)
- Xiaomei Liu
- Key Laboratory of Health Ministry for Congenital Malformations, Shengjing Hospital of China Medical University, 36th, Sanhao Street, Heping district, Shenyang 110004, China
| | - Ying Qi
- Virus Laboratory, Shengjing Hospital of China Medical University, 36th, Sanhao Street, Heping district, Shenyang 110004, China
| | - Baoling Tian
- Department of Pathology, Shengjing Hospital of China Medical University, 36th, Sanhao Street, Heping district, Shenyang 110004, China
| | - Dong Chen
- Key Laboratory of Health Ministry for Congenital Malformations, Shengjing Hospital of China Medical University, 36th, Sanhao Street, Heping district, Shenyang 110004, China
| | - Hong Gao
- Key Laboratory of Health Ministry for Congenital Malformations, Shengjing Hospital of China Medical University, 36th, Sanhao Street, Heping district, Shenyang 110004, China
| | - Chunyan Xi
- Department of Pediatrics, Shengjing Hospital of China Medical University, 36th, Sanhao Street, Heping district, Shenyang 110004, China
| | - Yanlin Xing
- Department of Pediatrics, Shengjing Hospital of China Medical University, 36th, Sanhao Street, Heping district, Shenyang 110004, China
| | - Zhengwei Yuan
- Key Laboratory of Health Ministry for Congenital Malformations, Shengjing Hospital of China Medical University, 36th, Sanhao Street, Heping district, Shenyang 110004, China
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Lou G, Ma X, Fu X, Meng Z, Zhang W, Wang YD, Van Ness C, Yu D, Xu R, Huang W. GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells. PLoS One 2014; 9:e93567. [PMID: 24755711 PMCID: PMC3995640 DOI: 10.1371/journal.pone.0093567] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 03/06/2014] [Indexed: 12/21/2022] Open
Abstract
GPBAR1/TGR5 is a novel plasma membrane-bound G protein–coupled bile acid (BA) receptor. BAs are known to induce the expression of inflammatory cytokines in the liver with unknown mechanism. Here we show that without other external stimuli, TGR5 activation alone induced the expression of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) in murine macrophage cell line RAW264.7 or murine Kupffer cells. The TGR5-mediated increase of pro-inflammatory cytokine expression was suppressed by JNK inhibition. Moreover, the induced pro-inflammatory cytokine expression in mouse liver by 1% cholic acid (CA) diet was blunted in JNK−/− mice. TGR5 activation by its ligands enhanced the phosphorylation levels, DNA-binding and trans-activities of c-Jun and ATF2 transcription factors. Finally, the induced pro-inflammatory cytokine expression in Kupffer cells by TGR5 activation correlated with the suppression of Cholesterol 7α-hydroxylase (Cyp7a1) expression in murine hepatocytes. These results suggest that TGR5 mediates the BA-induced pro-inflammatory cytokine production in murine Kupffer cells through JNK-dependent pathway. This novel role of TGR5 may correlate to the suppression of Cyp7a1 expression in hepatocytes and contribute to the delicate BA feedback regulation.
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Affiliation(s)
- Guiyu Lou
- Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China; Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Xiaoxiao Ma
- Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America; Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Xianghui Fu
- Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Zhipeng Meng
- Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America; Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Wenyu Zhang
- Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Yan-Dong Wang
- Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Carl Van Ness
- Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Donna Yu
- Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Rongzhen Xu
- Department of Hematology and Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wendong Huang
- Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
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Babeu JP, Boudreau F. Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks. World J Gastroenterol 2014; 20:22-30. [PMID: 24415854 PMCID: PMC3886012 DOI: 10.3748/wjg.v20.i1.22] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/12/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte nuclear factor 4-alpha (HNF4-α) is a nuclear receptor regulating metabolism, cell junctions, differentiation and proliferation in liver and intestinal epithelial cells. Mutations within the HNF4A gene are associated with human diseases such as maturity-onset diabetes of the young. Recently, HNF4A has also been described as a susceptibility gene for ulcerative colitis in genome-wide association studies. In addition, specific HNF4A genetic variants have been identified in pediatric cohorts of Crohn’s disease. Results obtained from knockout mice supported that HNF4-α can protect the intestinal mucosae against inflammation. However, the exact molecular links behind HNF4-α and inflammatory bowel diseases remains elusive. In this review, we will summarize the current knowledge about the role of HNF4-α and its isoforms in inflammation. Specific nature of HNF4-α P1 and P2 classes of isoforms will be summarized. HNF4-α role as a hepatocyte mediator for cytokines relays during liver inflammation will be integrated based on documented examples of the literature. Conclusions that can be made from these earlier liver studies will serve as a basis to extrapolate correlations and divergences applicable to intestinal inflammation. Finally, potential functional roles for HNF4-α isoforms in protecting the intestinal mucosae from chronic and pathological inflammation will be presented.
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Abstract
Enterohepatic circulation is responsible for the capture of bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver. Bile acids are secreted from the liver in the form of mixed micelles that also contain phosphatidylcholines and cholesterol that facilitate the uptake of fats and vitamins from the diet due to the surfactant properties of bile acids and lipids. Bile acids are synthesized in the liver from cholesterol by a cascade of enzymes that carry out oxidation and conjugation reactions, and transported to the bile duct and gall bladder where they are stored before being released into the intestine. Bile flow from the gall bladder to the small intestine is triggered by food intake in accordance with its role in lipid and vitamin absorption from the diet. Bile acids are further metabolized by gut bacteria and are transported back to the circulation. Metabolites produced in the liver are termed primary bile acids or primary conjugated bile salts, while the metabolites generated by bacterial are called secondary bile acids. About 95% of bile acids are reabsorbed in the proximal and distal ileum into the hepatic portal vein and then into the liver sinusoids, where they are efficiently transported into the liver with little remaining in circulation. Each bile acid is reabsorbed about 20 times on average before being eliminated. Enterohepatic circulation is under tight regulation by nuclear receptor signaling, notably by the farnesoid X receptor (FXR).
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Affiliation(s)
- Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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Gerbal-Chaloin S, Iankova I, Maurel P, Daujat-Chavanieu M. Nuclear receptors in the cross-talk of drug metabolism and inflammation. Drug Metab Rev 2013; 45:122-44. [PMID: 23330545 DOI: 10.3109/03602532.2012.756011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammation and infection have long been known to affect the activity and expression of enzymes involved in hepatic and extrahepatic drug clearance. Significant advances have been made to elucidate the molecular mechanisms underlying the complex cross-talk between inflammation and drug-metabolism alterations. The emergent role of ligand-activated transcriptional regulators, belonging to the nuclear receptor (NR) superfamily, is now well established. The NRs, pregnane X receptor, constitutive androstane receptor, retinoic X receptor, glucocorticoid receptor, and hepatocyte nuclear factor 4, and the basic helix-loop-helix/Per-ARNT-Sim family member, aryl hydrocarbon receptor, are the main regulators of the detoxification function. According to the panel of mediators secreted during inflammation, a cascade of numerous signaling pathways is activated, including nuclear factor kappa B, mitogen-activated protein kinase, and the Janus kinase/signal transducer and activator of transcription pathways. Complex cross-talk is established between these signaling pathways regulating either constitutive or induced gene expression. In most cases, a mutual antagonism between xenosensor and inflammation signaling occurs. This review focuses on the molecular and cellular mechanisms implicated in this cross-talk.
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Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol 2013; 368:17-29. [PMID: 22609541 PMCID: PMC3491147 DOI: 10.1016/j.mce.2012.05.004] [Citation(s) in RCA: 294] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 04/18/2012] [Accepted: 05/08/2012] [Indexed: 02/07/2023]
Abstract
Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption back into the circulation and reuptake to the liver. This process is under tight regulation by nuclear receptor signaling. Bile acids, produced from cholesterol, can alter gene expression in the liver and small intestine via activating the nuclear receptors farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G protein coupled receptor TGR5, and other cell signaling pathways (JNK1/2, AKT and ERK1/2). Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and a crucial control element for maintaining bile acid homeostasis. FXR has a high affinity for several major endogenous bile acids, notably cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid. By responding to excess bile acids, FXR is a bridge between the liver and small intestine to control bile acid levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and gut, relative to other tissues, and contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters. FXR activation also affects lipid and glucose metabolism, and can influence drug metabolism.
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Affiliation(s)
- Tsutomu Matsubara
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Fei Li
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
- Correspondence: Frank J. Gonzalez, Laboratory of Metabolism, National Cancer Institute, Building 37, Room 3106, Bethesda, MD 20892, Tel: 301-496-9067, Fax: 301-496-8419,
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Ferrari A, Fiorino E, Giudici M, Gilardi F, Galmozzi A, Mitro N, Cermenati G, Godio C, Caruso D, De Fabiani E, Crestani M. Linking epigenetics to lipid metabolism: focus on histone deacetylases. Mol Membr Biol 2012; 29:257-66. [PMID: 23095054 DOI: 10.3109/09687688.2012.729094] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
A number of recent studies revealed that epigenetic modifications play a central role in the regulation of lipid and of other metabolic pathways such as cholesterol homeostasis, bile acid synthesis, glucose and energy metabolism. Epigenetics refers to aspects of genome functions regulated in a DNA sequence-independent fashion. Chromatin structure is controlled by epigenetic mechanisms through DNA methylation and histone modifications. The main modifications are histone acetylation and deacetylation on specific lysine residues operated by two different classes of enzymes: Histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. The interaction between these enzymes and histones can activate or repress gene transcription: Histone acetylation opens and activates chromatin, while deacetylation of histones and DNA methylation compact chromatin making it transcriptionally silent. The new evidences on the importance of HDACs in the regulation of lipid and other metabolic pathways will open new perspectives in the comprehension of the pathophysiology of metabolic disorders.
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Affiliation(s)
- Alessandra Ferrari
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italia
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Kir S, Zhang Y, Gerard RD, Kliewer SA, Mangelsdorf DJ. Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo. J Biol Chem 2012; 287:41334-41. [PMID: 23038264 PMCID: PMC3510831 DOI: 10.1074/jbc.m112.421834] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Fibroblast growth factor 19 (FGF19) is a postprandial enterokine induced by the nuclear bile acid receptor, FXR, in ileum. FGF19 inhibits bile acid synthesis in liver through transcriptional repression of cholesterol 7α-hydroxylase (CYP7A1) via a mechanism involving the nuclear receptor SHP. Here, in a series of loss-of-function studies, we show that the nuclear receptors HNF4α and LRH-1 have dual roles in regulating Cyp7a1 in vivo. First, they cooperate in maintaining basal Cyp7a1 expression. Second, they enable SHP binding to the Cyp7a1 promoter and facilitate FGF19-mediated repression of bile acid synthesis. HNF4α and LRH-1 promote active transcription histone marks on the Cyp7a1 promoter that are reversed by FGF19 in a SHP-dependent manner. These findings demonstrate that both HNF4α and LRH-1 are important regulators of Cyp7a1 transcription in vivo.
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Affiliation(s)
- Serkan Kir
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
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