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Lamm V, Huang K, Deng R, Cao S, Wang M, Soleymanjahi S, Promlek T, Rodgers R, Davis D, Nix D, Escudero GO, Xie Y, Chen CH, Gremida A, Rood RP, Liu TC, Baldridge MT, Deepak P, Davidson NO, Kaufman RJ, Ciorba MA. Tauroursodeoxycholic Acid (TUDCA) Reduces ER Stress and Lessens Disease Activity in Ulcerative Colitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.02.25322684. [PMID: 40236400 PMCID: PMC11998832 DOI: 10.1101/2025.04.02.25322684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Background and Aims In inflammatory bowel disease, protein misfolding in the endoplasmic reticulum (ER) potentiates epithelial barrier dysfunction and impairs mucosal healing. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, acts as a chemical chaperone to reduce protein aggregation and colitis severity in preclinical models. We conducted an open label trial evaluating oral TUDCA as therapy in patients with active ulcerative colitis (UC). Methods Patients with moderate-to-severely active UC (Mayo score ≥6, endoscopic subscore ≥1) received oral TUDCA at 1.75 or 2 g/day for 6 weeks. Exclusion criteria included known hepatic disorders or change in UC therapy within 60 days. Clinical disease activity questionnaires, endoscopy with biopsy, blood, and stool were collected at enrollment and after 6 weeks. The primary outcome measure was change in ER stress markers while safety, tolerability and change in UC disease activity were secondary outcomes. Results Thirteen participants completed the study with eleven evaluable for clinical response. TUDCA was well-tolerated with transient dyspepsia being the most common side effect. Mucosal biopsies revealed significant reductions in ER stress and inflammation as well as an increase in markers of epithelial restitution. Clinical, endoscopic, and histologic disease activity were significantly improved at week 6 (mean total Mayo Score: 9 to 4.5, p<0.001). Conclusions Six weeks of oral TUDCA treatment was well-tolerated in patients with active ulcerative colitis and promoted mucosal healing, lessened ER stress, and reduced clinical disease activity. A randomized controlled trial of adjunctive TUDCA therapy in patients with UC is warranted. Trial registration ClinicalTrials.gov (NCT04114292).
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Affiliation(s)
- Vladimir Lamm
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Katherine Huang
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Ruishu Deng
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Siyan Cao
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Miao Wang
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Saeed Soleymanjahi
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Thanyarat Promlek
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Rachel Rodgers
- Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Deanna Davis
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Darren Nix
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Guadalupe Oliva Escudero
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Yan Xie
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Chien-Huan Chen
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Anas Gremida
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Richard P Rood
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Ta-Chiang Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Megan T Baldridge
- Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Parakkal Deepak
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Nicholas O Davidson
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Randal J Kaufman
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Matthew A Ciorba
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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Tanaka M, Sato T, Gohda T, Kamei N, Murakoshi M, Ishiwata E, Endo K, Kawaharata W, Aida H, Nakata K, Akiyama Y, Kubota M, Sanuki M, Suzuki T, Suzuki Y, Furuhashi M. Urinary fatty acid-binding protein 4 is a promising biomarker for glomerular damage in patients with diabetes mellitus. J Diabetes Investig 2025; 16:670-679. [PMID: 39723798 PMCID: PMC11970305 DOI: 10.1111/jdi.14388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/28/2024] Open
Abstract
AIMS/INTRODUCTION Fatty acid-binding protein (FABP) 4, which acts as an adipokine secreted by adipocytes, macrophages, and capillary endothelial cells, is expressed in injured glomerular cells. It has been reported that urinary (U-) FABP4 is associated with renal dysfunction and proteinuria in several glomerular kidney diseases. However, the clinical significance of U-FABP4 in diabetic kidney disease (DKD) remains undetermined. MATERIALS AND METHODS Immunohistological analyses of FABP4 and FABP1 (liver-type FABP), an established biomarker for impaired proximal tubules, were performed in the kidneys of patients with DKD and nonobese diabetic mice (KK-Ta/Akita mice). The associations between U-FABP4 and U-FABP1 with kidney function and metabolic indices were also investigated in patients with type 1 diabetes (n = 57, mean age: 61 years) and patients with type 2 diabetes (n = 608, mean age: 65 years). RESULTS In both patients with diabetes and diabetic mice, FABP4 was expressed in injured glomeruli with increased markers of endoplasmic reticulum stress in addition to peritubular capillaries, whereas FABP1 was mainly expressed in proximal tubules. Levels of U-FABP4 and U-FABP1 were independently associated with each other, and both levels were independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) after adjustment of age, sex, type of diabetes, duration of diabetes, and systolic blood pressure in patients with diabetes. CONCLUSIONS Urinary level of FABP4 derived from injured glomeruli with increased endoplasmic reticulum stress is independently associated with eGFR and UACR, suggesting a promising biomarker for glomerular damage in patients with diabetes.
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Affiliation(s)
- Marenao Tanaka
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
- Tanaka Medical ClinicYoichiJapan
| | - Tatsuya Sato
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
- Department of Cellular Physiology and Signal TransductionSapporo Medical University School of MedicineSapporoJapan
| | - Tomohito Gohda
- Department of NephrologyJuntendo University Faculty of MedicineTokyoJapan
| | - Nozomu Kamei
- Department of Endocrinology and MetabolismHiroshima Red Cross Hospital & Atomic‐bomb Survivors HospitalHiroshimaJapan
- Institute for Clinical ResearchNHO Kure Medical Center and Chugoku Cancer CenterKureJapan
| | - Maki Murakoshi
- Department of NephrologyJuntendo University Faculty of MedicineTokyoJapan
| | - Erika Ishiwata
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Keisuke Endo
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Wataru Kawaharata
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Hiroki Aida
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Kei Nakata
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Yukinori Akiyama
- Department of NeurosurgerySapporo Medical University School of MedicineSapporoJapan
| | - Mitsunobu Kubota
- Department of Endocrinology and DiabetologyNHO Kure Medical Center and Chugoku Cancer CenterKureJapan
| | - Michiyoshi Sanuki
- Institute for Clinical ResearchNHO Kure Medical Center and Chugoku Cancer CenterKureJapan
| | - Toru Suzuki
- Natori Toru Internal Medicine and Diabetes ClinicNatoriJapan
| | - Yusuke Suzuki
- Department of NephrologyJuntendo University Faculty of MedicineTokyoJapan
| | - Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
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Mansoor T, Farrukh F, Khalid SN, Abramov D, Michos ED, Mehta A, Paul TK, Dani SS, Al Rifai M, Misra A, Nambi V, Virani SS, Minhas AMK. The future of hypertension pharmacotherapy: Ongoing and future clinical trials for hypertension. Curr Probl Cardiol 2025; 50:102922. [PMID: 39522662 DOI: 10.1016/j.cpcardiol.2024.102922] [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: 11/02/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Hypertension is among the most prevalent diagnoses across the world and increases the risk of many serious health problems, such as stroke, heart disease, and kidney disease. Pharmacological approaches to treat hypertension are often required and reduce blood pressure through mechanisms such as vasodilation, inhibition of the renin-angiotensin-aldosterone pathway, and increased urine output to reduce blood volume, among other mechanisms. Further research is ongoing to find novel pathways and mechanisms to treat hypertension, which we summarize in this review. We used clinicaltrials.gov to gather information about ongoing clinical trials of pharmacological hypertension therapy as of March 2024 and found 103 clinical trials that met our criteria. The interventions of these 103 clinical trials include novel and previously approved pharmacological and dietary supplement therapies for hypertension. We aim to use these clinical trials to provide insight into the future therapies and practices of hypertension treatment.
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Affiliation(s)
- Taha Mansoor
- Department of Internal Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA.
| | - Fatima Farrukh
- Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Subaina N Khalid
- Department of Internal Medicine, SUNY Upstate Medical University, Syracruse, NY, USA
| | - Dmitry Abramov
- Division of Cardiology, Department of Medicine, Loma Linda University Health, Loma Linda, CA, USA
| | - Erin D Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anurag Mehta
- Division of Cardiology, Virginia Commonwealth University, Richmond, VA, USA
| | - Timir K Paul
- Department of Cardiovascular Sciences, University of Tennessee Health Science Center- Nashville, TN, USA
| | - Sourbha S Dani
- Division of Cardiology, Lahey Hospital and Medical Center, Beth Israel Lahey Health, Burlington, MA, USA
| | | | - Arunima Misra
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Vijay Nambi
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA; Michael E. DeBakey Veterans Affair Medical Center, Houston, TX, USA
| | - Salim S Virani
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Abdul Mannan Khan Minhas
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA
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Congur I, Mingrone G, Guan K. Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy. Metabolism 2025; 162:156062. [PMID: 39515414 DOI: 10.1016/j.metabol.2024.156062] [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: 07/15/2024] [Revised: 09/02/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Endoplasmic reticulum (ER) is an essential organelle involved in vesicular transport, calcium handling, protein synthesis and folding, and lipid biosynthesis and metabolism. ER stress occurs when ER homeostasis is disrupted by the accumulation of unfolded and/or misfolded proteins in the ER lumen. Adaptive pathways of the unfolded protein response (UPR) are activated to maintain ER homeostasis. In obesity and type 2 diabetes mellitus (T2DM), accumulating data indicate that persistent ER stress due to maladaptive UPR interacts with insulin/leptin signaling, which may be the potential and central mechanistic link between obesity-/T2DM-induced metabolic dysregulation (chronic hyperglycemia, dyslipidemia and lipotoxicity in cardiomyocytes), insulin/leptin resistance and the development of diabetic cardiomyopathy (DiabCM). Meanwhile, these pathological conditions further exacerbate ER stress. However, their interrelationships and the underlying molecular mechanisms are not fully understood. A deeper understanding of ER stress-mediated pathways in DiabCM is needed to develop novel therapeutic strategies. The aim of this review is to discuss the crosstalk between ER stress and leptin/insulin signaling and their involvement in the development of DiabCM focusing on mitochondria-associated ER membranes and chronic inflammation. We also present the current direction of drug development and important considerations for translational research into targeting ER stress for the treatment of DiabCM.
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Affiliation(s)
- Irem Congur
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Germany
| | - Geltrude Mingrone
- Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, United Kingdom; Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Kaomei Guan
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Germany.
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Huang N, Ge M, Liu X, Tian X, Yin P, Bao Z, Cao F, Shyh-Chang N, Dong B, Dai L, Gan Z, Hu P, Qu J, Wang S, Wang H, Xiao Q, Yue R, Yue J, Zhang L, Zhang Y, Zhang H, Zhang W, Liu GH, Pei G, Liu Y, Zhu D, Dong B. A framework of biomarkers for skeletal muscle aging: a consensus statement by the Aging Biomarker Consortium. LIFE MEDICINE 2024; 3:lnaf001. [PMID: 40008206 PMCID: PMC11851484 DOI: 10.1093/lifemedi/lnaf001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/24/2025] [Indexed: 02/27/2025]
Abstract
The skeletal muscle is an important organ for movement and metabolism in human body, and its physiological aging underlies the occurrence of muscle atrophy and sarcopenia. China has the largest aging population in the world and is facing a grand challenge with how to prevent and treat skeletal muscle aging-related diseases. To address this difficult problem, the Aging Biomarker Consortium (ABC) of China has reached an expert consensus on biomarkers of skeletal muscle aging by synthesizing literatures and insights from scientists and clinicians. This consensus attempts to provide a comprehensive assessment of biomarkers associated with skeletal muscle aging, and proposes a systematic framework to classify them into three dimensions: functional, structural, and humoral. Within each dimension, the experts recommend clinically relevant biomarkers for skeletal muscle aging. This consensus aims to lay the foundation for future research on skeletal muscle aging, facilitating precise prediction, diagnosis, and treatment of skeletal muscle aging and sarcopenia. It is anticipated to make significant contributions to healthy aging of skeletal muscle in the elderly population in China and around the world as well.
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Affiliation(s)
| | - Ning Huang
- The Center of Gerontology and Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Meiling Ge
- The Center of Gerontology and Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaolei Liu
- The Center of Gerontology and Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xu Tian
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China
| | - Pengbin Yin
- Department of Orthopedics, Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Zhijun Bao
- Department of Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Feng Cao
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing 100853, China
| | - Ng Shyh-Chang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Biao Dong
- National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Sichuan Real and Best Biotech Co., Ltd., Chengdu 610041, China
| | - Lunzhi Dai
- National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhenji Gan
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Department of Spine Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University Medical School, Nanjing University, Nanjing 210061, China
| | - Ping Hu
- Spine Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200072, China
- Guangzhou Laboratory, Guangzhou 510005, China
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510005, China
- The Tenth People’s Hospital Affiliated to Tongji University, Shanghai 200072, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Institute for Stem Cell and Regenerative Medicine, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Si Wang
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
| | - Huating Wang
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Department of Orthopedics and Traumatology, Prince of Wales Hospital, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Qian Xiao
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Rui Yue
- Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University, Shanghai 200092, China
| | - Jirong Yue
- The Center of Gerontology and Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Licheng Zhang
- Department of Orthopaedic Trauma, the Fourth Medical Center, National Clinical Research Center for Orthopaedics & Sports Rehabilitation in China, Chinese PLA General Hospital, Beijing 100853, China
| | - Yong Zhang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Hongbo Zhang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China
- The SYSU-YSG Joint Laboratory for Skin Health Research, Sun Yat-sen University, Guangzhou 510080, China
- Advanced Medical Technology Center, The First Afiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| | - Gang Pei
- The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai 200070, China
| | - Yong Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; TaiKang Center for Life and Medical Sciences; the Institute for Advanced Studies; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China
| | - Dahai Zhu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Birong Dong
- The Center of Gerontology and Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
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Liu Y, Xu C, Gu R, Han R, Li Z, Xu X. Endoplasmic reticulum stress in diseases. MedComm (Beijing) 2024; 5:e701. [PMID: 39188936 PMCID: PMC11345536 DOI: 10.1002/mco2.701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/28/2024] Open
Abstract
The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.
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Affiliation(s)
- Yingying Liu
- Department of Aviation Clinical Medicine, Air Force Medical CenterPLABeijingChina
| | - Chunling Xu
- School of Pharmaceutical SciencesTsinghua UniversityBeijingChina
| | - Renjun Gu
- School of Chinese MedicineNanjing University of Chinese MedicineNanjingChina
- Department of Gastroenterology and HepatologyJinling HospitalMedical School of Nanjing UniversityNanjingChina
| | - Ruiqin Han
- State Key Laboratory of Medical Molecular BiologyDepartment of Biochemistry and Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ziyu Li
- School of Acupuncture and TuinaSchool of Regimen and RehabilitationNanjing University of Chinese MedicineNanjingChina
| | - Xianrong Xu
- Department of Aviation Clinical Medicine, Air Force Medical CenterPLABeijingChina
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Zhen J, Zhang Y, Li Y, Zhou Y, Cai Y, Huang G, Xu A. The gut microbiota intervenes in glucose tolerance and inflammation by regulating the biosynthesis of taurodeoxycholic acid and carnosine. Front Cell Infect Microbiol 2024; 14:1423662. [PMID: 39206042 PMCID: PMC11351283 DOI: 10.3389/fcimb.2024.1423662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/15/2024] [Indexed: 09/04/2024] Open
Abstract
Objective This study aims to investigate the pathogenesis of hyperglycemia and its associated vasculopathy using multiomics analyses in diabetes and impaired glucose tolerance, and validate the mechanism using the cell experiments. Methods In this study, we conducted a comprehensive analysis of the metagenomic sequencing data of diabetes to explore the key genera related to its occurrence. Subsequently, participants diagnosed with impaired glucose tolerance (IGT), and healthy subjects, were recruited for fecal and blood sample collection. The dysbiosis of the gut microbiota (GM) and its associated metabolites were analyzed using 16S rDNA sequencing and liquid chromatograph mass spectrometry, respectively. The regulation of gene and protein expression was evaluated through mRNA sequencing and data-independent acquisition technology, respectively. The specific mechanism by which GM dysbiosis affects hyperglycemia and its related vasculopathy was investigated using real-time qPCR, Western blotting, and enzyme-linked immunosorbent assay techniques in HepG2 cells and neutrophils. Results Based on the published data, the key alterable genera in the GM associated with diabetes were identified as Blautia, Lactobacillus, Bacteroides, Prevotella, Faecalibacterium, Bifidobacterium, Ruminococcus, Clostridium, and Lachnoclostridium. The related metabolic pathways were identified as cholate degradation and L-histidine biosynthesis. Noteworthy, Blautia and Faecalibacterium displayed similar alterations in patients with IGT compared to those observed in patients with diabetes, and the GM metabolites, tauroursodeoxycholic acid (TUDCA) and carnosine (CARN, a downstream metabolite of histidine and alanine) were both found to be decreased, which in turn regulated the expression of proteins in plasma and mRNAs in neutrophils. Subsequent experiments focused on insulin-like growth factor-binding protein 3 and interleukin-6 due to their impact on blood glucose regulation and associated vascular inflammation. Both proteins were found to be suppressed by TUDCA and CARN in HepG2 cells and neutrophils. Conclusion Dysbiosis of the GM occurred throughout the entire progression from IGT to diabetes, characterized by an increase in Blautia and a decrease in Faecalibacterium, leading to reduced levels of TUDCA and CARN, which alleviated their inhibition on the expression of insulin-like growth factor-binding protein 3 and interleukin-6, contributing to the development of hyperglycemia and associated vasculopathy.
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Affiliation(s)
| | | | | | | | | | - Guangrui Huang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Anlong Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Wang L, Liu H, Zhou L, Zheng P, Li H, Zhang H, Liu W. Association of Obstructive Sleep Apnea with Nonalcoholic Fatty Liver Disease: Evidence, Mechanism, and Treatment. Nat Sci Sleep 2024; 16:917-933. [PMID: 39006248 PMCID: PMC11244635 DOI: 10.2147/nss.s468420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 06/22/2024] [Indexed: 07/16/2024] Open
Abstract
Obstructive sleep apnea (OSA), a common sleep-disordered breathing condition, is characterized by intermittent hypoxia (IH) and sleep fragmentation and has been implicated in the pathogenesis and severity of nonalcoholic fatty liver disease (NAFLD). Abnormal molecular changes mediated by IH, such as high expression of hypoxia-inducible factors, are reportedly involved in abnormal pathophysiological states, including insulin resistance, abnormal lipid metabolism, cell death, and inflammation, which mediate the development of NAFLD. However, the relationship between IH and NAFLD remains to be fully elucidated. In this review, we discuss the clinical correlation between OSA and NAFLD, focusing on the molecular mechanisms of IH in NAFLD progression. We meticulously summarize clinical studies evaluating the therapeutic efficacy of continuous positive airway pressure treatment for NAFLD in OSA. Additionally, we compile potential molecular biomarkers for the co-occurrence of OSA and NAFLD. Finally, we discuss the current research progress and challenges in the field of OSA and NAFLD and propose future directions and prospects.
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Affiliation(s)
- Lingling Wang
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Huiguo Liu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Ling Zhou
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Pengdou Zheng
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Hai Li
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Huojun Zhang
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Wei Liu
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
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9
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Chu NHS, Chow E, Chan JCN. The Therapeutic Potential of the Specific Intestinal Microbiome (SIM) Diet on Metabolic Diseases. BIOLOGY 2024; 13:498. [PMID: 39056692 PMCID: PMC11273990 DOI: 10.3390/biology13070498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/02/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024]
Abstract
Exploring the intricate crosstalk between dietary prebiotics and the specific intestinal microbiome (SIM) is intriguing in explaining the mechanisms of current successful dietary interventions, including the Mediterranean diet and high-fiber diet. This knowledge forms a robust basis for developing a new natural food therapy. The SIM diet can be measured and evaluated to establish a reliable basis for the management of metabolic diseases, such as diabetes, metabolic (dysfunction)-associated fatty liver disease (MAFLD), obesity, and metabolic cardiovascular disease. This review aims to delve into the existing body of research to shed light on the promising developments of possible dietary prebiotics in this field and explore the implications for clinical practice. The exciting part is the crosstalk of diet, microbiota, and gut-organ interactions facilitated by producing short-chain fatty acids, bile acids, and subsequent metabolite production. These metabolic-related microorganisms include Butyricicoccus, Akkermansia, and Phascolarctobacterium. The SIM diet, rather than supplementation, holds the promise of significant health consequences via the prolonged reaction with the gut microbiome. Most importantly, the literature consistently reports no adverse effects, providing a strong foundation for the safety of this dietary therapy.
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Affiliation(s)
- Natural H. S. Chu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; (E.C.); (J.C.N.C.)
| | - Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; (E.C.); (J.C.N.C.)
| | - Juliana C. N. Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; (E.C.); (J.C.N.C.)
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
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10
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Qian Q, Li M, Zhang Z, Davis SW, Rahmouni K, Norris AW, Cao H, Ding WX, Hotamisligil GS, Yang L. Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression. Cell Metab 2024; 36:1550-1565.e9. [PMID: 38718793 PMCID: PMC11222033 DOI: 10.1016/j.cmet.2024.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 03/05/2024] [Accepted: 04/17/2024] [Indexed: 07/05/2024]
Abstract
Obesity alters levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, dysregulation of which leads to nonalcoholic fatty liver disease (NAFLD). However, the impact of obesity on intra-pituitary homeostasis is largely unknown. Here, we uncovered a blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice and humans. Furthermore, we found that obesity inflames the pituitary gland, leading to impaired pituitary inositol-requiring enzyme 1α (IRE1α)-X-box-binding protein 1 (XBP1) UPR branch, which is essential for protecting against pituitary endocrine defects and NAFLD progression. Intriguingly, pituitary IRE1-deletion resulted in hypothyroidism and suppressed the thyroid hormone receptor B (THRB)-mediated activation of Xbp1 in the liver. Conversely, activation of the hepatic THRB-XBP1 axis improved NAFLD in mice with pituitary UPR defect. Our study provides the first evidence and mechanism of obesity-induced intra-pituitary cellular defects and the pathophysiological role of pituitary-liver UPR communication in NAFLD progression.
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Affiliation(s)
- Qingwen Qian
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Mark Li
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Zeyuan Zhang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Shannon W Davis
- Department of Biological Sciences, College of Arts and Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Kamal Rahmouni
- Department of Neuroscience and Pharmacology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Andrew W Norris
- Division of Endocrinology and Diabetes, Department of Pediatrics, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Huojun Cao
- Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA 52242, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Gökhan S Hotamisligil
- Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
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11
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Simões BES, Muniz MRR, Araujo TD, Magalhães Carneiro E, Simionato AVC. Evaluation of tauroursodeoxycholic acid in liver cells' cultures by MEKC: Initial hints to comprehend its role in diabetes mellitus of obese individuals. Electrophoresis 2024; 45:1252-1264. [PMID: 38775263 DOI: 10.1002/elps.202300223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 07/13/2024]
Abstract
Genetic factors, diet, lifestyle, and other factors lead to various complications in the body, such as obesity and other chronic diseases. The inflammatory state caused by excessive accumulation of body fat affects the pathways related to the control of glycemic homeostasis, leading to a high demand for insulin, to subsequent failure of stressed β cells, and development of type 2 diabetes mellitus (T2DM). The study of new endocrine signalers, such as bile acids (BAs), becomes necessary as it allows the development of alternatives for T2DM treatment. In this work, a methodology was developed to quantify tauroursodeoxycholic BA (TUDCA) in liver cells of the HepG2 strain treated in hyperlipidic medium. This BA helps to improve insulin clearance by increasing the expression of the insulin-degrading enzyme, restoring sensitivity to this hormone, and making it viable for treating T2DM. Herein, a targeted metabolomic method for TUDCA determination in extracellular medium of hepatocyte matrices by micellar electrokinetic chromatography-UV was optimized, validated, and applied. The optimized background electrolyte was composed of 40 mmol/L sodium cholate and 30 mmol/L sodium tetraborate at pH 9.0. The following figures of merit were evaluated: linearity, limit of quantification, limit of detection, accuracy, and precision. Data obtained with the validated electrophoretic method showed a self-stimulation of TUDCA production in media supplemented only with BA. On the other hand, TUDCA concentration was reduced in the hyperlipidic medium. This suggests that, in these media, the effect of TUDCA is reduced, such as self-stimulated production and consequent regulation of glycemic homeostasis. Therefore, the results reinforce the need for investigating TUDCA as a potential T2DM biomarker as well as its use to treat several comorbidities, such as obesity and diabetes mellitus.
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Affiliation(s)
- Bruna Eduarda Santos Simões
- Laboratory of Analysis of Biomolecules Tiselius, Institute of Chemistry, Universidade Estadual de Campinas, Campinas, Brazil
| | | | | | | | - Ana Valéria Colnaghi Simionato
- Laboratory of Analysis of Biomolecules Tiselius, Institute of Chemistry, Universidade Estadual de Campinas, Campinas, Brazil
- National Institute of Science and Technology for Bioanalytics, Campinas, Brazil
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12
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Zito E, Lescure A, Borgese N. Chemical chaperones in metabolic fitness beyond protein folding. Trends Endocrinol Metab 2024; 35:572-575. [PMID: 38664151 DOI: 10.1016/j.tem.2024.04.006] [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: 03/18/2024] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 07/11/2024]
Abstract
Chemical chaperones are small molecules that improve protein folding, alleviating aberrant pathological phenotypes due to protein misfolding. Recent reports suggest that, in parallel with their role in relieving endoplasmic reticulum (ER) stress, chemical chaperones rescue mitochondrial function and insulin signaling. These effects may underlie their pharmacological action on metabolically demanding tissues.
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Affiliation(s)
- Ester Zito
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
| | - Alain Lescure
- University of Strasbourg, CNRS, Architecture and Reactivity of RNA, Strasbourg, France
| | - Nica Borgese
- Consiglio Nazionale delle Ricerche Neuroscience Institute, 20854 Vedano al Lambro, Italy
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13
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Pereira S, Castellani LN, Kowalchuk C, Alganem K, Zhang X, Ryan WG, Singh R, Wu S, Au E, Asgariroozbehani R, Agarwal SM, Giacca A, Mccullumsmith RE, Hahn MK. Olanzapine's effects on hypothalamic transcriptomics and kinase activity. Psychoneuroendocrinology 2024; 163:106987. [PMID: 38340539 PMCID: PMC10947847 DOI: 10.1016/j.psyneuen.2024.106987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 01/12/2024] [Accepted: 02/04/2024] [Indexed: 02/12/2024]
Abstract
Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.
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Affiliation(s)
- Sandra Pereira
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada
| | | | | | - Khaled Alganem
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
| | - Xiaolu Zhang
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - William G Ryan
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
| | | | - Sally Wu
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Emily Au
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada
| | - Roshanak Asgariroozbehani
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Sri Mahavir Agarwal
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Banting & Best Diabetes Centre, Toronto, ON, Canada
| | - Adria Giacca
- Department of Physiology, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Banting & Best Diabetes Centre, Toronto, ON, Canada
| | - Robert E Mccullumsmith
- Department of Neurosciences, University of Toledo, Toledo, OH, USA; ProMedica, Neuroscience Institute, Toledo, OH, USA
| | - Margaret K Hahn
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Banting & Best Diabetes Centre, Toronto, ON, Canada.
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14
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Germani S, Van Ho AT, Cherubini A, Varone E, Chernorudskiy A, Renna GM, Fumagalli S, Gobbi M, Lucchetti J, Bolis M, Guarrera L, Craparotta I, Rastelli G, Piccoli G, de Napoli C, Nogara L, Poggio E, Brini M, Cattaneo A, Bachi A, Simmen T, Calì T, Quijano-Roy S, Boncompagni S, Blaauw B, Ferreiro A, Zito E. SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA. Cell Rep Med 2024; 5:101439. [PMID: 38402623 PMCID: PMC10982971 DOI: 10.1016/j.xcrm.2024.101439] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 12/06/2023] [Accepted: 01/31/2024] [Indexed: 02/27/2024]
Abstract
Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, including Ca2+ levels and bioenergetics, thus reversing diaphragmatic weakness. The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss. Importantly, muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression, and TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics. These findings point to ERO1A as a biomarker and a viable target for intervention and to TUDCA as a pharmacological treatment for SEPN1-RM.
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Affiliation(s)
- Serena Germani
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Andrew Tri Van Ho
- Basic and Translational Myology Laboratory, Université Paris, BFA, UMR 8251, CNRS, 75013 Paris, France
| | | | - Ersilia Varone
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | | | | | | | - Marco Gobbi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Jacopo Lucchetti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Marco Bolis
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Bioinformatics Core Unit, Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland
| | - Luca Guarrera
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | | | - Giorgia Rastelli
- CAST, Center for Advanced Studies and Technology & DNICS, Department of Neuroscience, Imaging and Clinical Sciences, University G. D'Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Giorgia Piccoli
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Cosimo de Napoli
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Leonardo Nogara
- Department of Biomedical Sciences, University of Padua, Padua, Italy; Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
| | - Elena Poggio
- Department of Biology, University of Padova, Padova, Italy
| | - Marisa Brini
- Department of Pharmaceutical Sciences, University of Padova, Padova, Italy; Department of Biology, University of Padova, Padova, Italy; Study Center for Neurodegeneration (CESNE), University of Padova, Padova, Italy
| | | | - Angela Bachi
- IFOM-ETS AIRC Institute of Molecular Oncology, Milan, Italy
| | - Thomas Simmen
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Tito Calì
- Department of Biomedical Sciences, University of Padua, Padua, Italy; Study Center for Neurodegeneration (CESNE), University of Padova, Padova, Italy; Padova Neuroscience Center, University of Padova, Padova, Italy
| | - Susana Quijano-Roy
- APHP-Université Paris-Saclay, Reference Center for Neuromuscular Disorders Nord-Est-Ile de France, FILNEMUS, ERN-Euro-NMD, Creteil, France; Pediatric Neurology and ICU Department, DMU Santé Enfant Adolescent (SEA), Raymond Poincaré University Hospital, Garches, France
| | - Simona Boncompagni
- CAST, Center for Advanced Studies and Technology & DNICS, Department of Neuroscience, Imaging and Clinical Sciences, University G. D'Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Bert Blaauw
- Department of Biomedical Sciences, University of Padua, Padua, Italy; Venetian Institute of Molecular Medicine, Padova, Italy.
| | - Ana Ferreiro
- Basic and Translational Myology Laboratory, Université Paris, BFA, UMR 8251, CNRS, 75013 Paris, France; APHP, Reference Center for Neuromuscular Disorders Nord-Est-Ile de France, Neuromyology Department, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
| | - Ester Zito
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
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15
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Liu Y, Huang K, Zhang Y, Cao H, Guan X. Dietary polyphenols maintain homeostasis via regulating bile acid metabolism: a review of possible mechanisms. Food Funct 2023; 14:9486-9505. [PMID: 37815149 DOI: 10.1039/d3fo02471g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
The synthesis and metabolism of bile acids (BAs) have been implicated in various metabolic diseases, including obesity and diabetes. Dietary polyphenols, as natural antioxidants, play a vital role in synthesizing and metabolizing bile acids. This paper reviews the mechanism of dietary polyphenols involved in bile acid (BA) synthesis and metabolism. The impact of different gut microorganisms on BA profiles is discussed in detail. The regulation of BA metabolism by dietary polyphenols can be divided into two modes: (1) dietary polyphenols directly activate/inhibit farnesol X receptor (FXR) and Takeda G protein-coupled receptor (TGR5); (2) dietary polyphenols regulate BA synthesis and metabolism through changes in intestinal microorganisms. Research on direct activation/inhibition of FXR and TGR5 by polyphenols should be ramped up. In addition, the effect of dietary polyphenols on intestinal microorganisms has been paid more and more attention and has become a target that cannot be ignored.
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Affiliation(s)
- Yongyong Liu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
| | - Kai Huang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, PR China
| | - Yu Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, PR China
| | - Hongwei Cao
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, PR China
| | - Xiao Guan
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, PR China
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16
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Kuang J, Wang J, Li Y, Li M, Zhao M, Ge K, Zheng D, Cheung KCP, Liao B, Wang S, Chen T, Zhang Y, Wang C, Ji G, Chen P, Zhou H, Xie C, Zhao A, Jia W, Zheng X, Jia W. Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis. Cell Metab 2023; 35:1752-1766.e8. [PMID: 37591244 DOI: 10.1016/j.cmet.2023.07.011] [Citation(s) in RCA: 103] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/19/2023] [Accepted: 07/24/2023] [Indexed: 08/19/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1. Additionally, HDCA significantly increased abundances of probiotic species such as Parabacteroides distasonis, which enhances lipid catabolism through fatty acid-hepatic peroxisome proliferator-activated receptor alpha (PPARα) signaling, which in turn upregulates hepatic FXR. These findings suggest that HDCA has therapeutic potential for treating NAFLD, with a unique mechanism of simultaneously activating hepatic CYP7B1 and PPARα.
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Affiliation(s)
- Junliang Kuang
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Jieyi Wang
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yitao Li
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Mengci Li
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Mingliang Zhao
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Kun Ge
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Dan Zheng
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Kenneth C P Cheung
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Boya Liao
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Shouli Wang
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Tianlu Chen
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yinan Zhang
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Congrong Wang
- Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Peng Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510655, China
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Aihua Zhao
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Weiping Jia
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Xiaojiao Zheng
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Wei Jia
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
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17
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Di Conza G, Ho PC, Cubillos-Ruiz JR, Huang SCC. Control of immune cell function by the unfolded protein response. Nat Rev Immunol 2023; 23:546-562. [PMID: 36755160 DOI: 10.1038/s41577-023-00838-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2023] [Indexed: 02/10/2023]
Abstract
Initiating and maintaining optimal immune responses requires high levels of protein synthesis, folding, modification and trafficking in leukocytes, which are processes orchestrated by the endoplasmic reticulum. Importantly, diverse extracellular and intracellular conditions can compromise the protein-handling capacity of this organelle, inducing a state of 'endoplasmic reticulum stress' that activates the unfolded protein response (UPR). Emerging evidence shows that physiological or pathological activation of the UPR can have effects on immune cell survival, metabolism, function and fate. In this Review, we discuss the canonical role of the adaptive UPR in immune cells and how dysregulation of this pathway in leukocytes contributes to diverse pathologies such as cancer, autoimmunity and metabolic disorders. Furthermore, we provide an overview as to how pharmacological approaches that modulate the UPR could be harnessed to control or activate immune cell function in disease.
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Affiliation(s)
- Giusy Di Conza
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Ping-Chih Ho
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
- Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
| | - Stanley Ching-Cheng Huang
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
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18
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Dantas Machado AC, Ramos SF, Gauglitz JM, Fassler AM, Petras D, Aksenov AA, Kim UB, Lazarowicz M, Barnard Giustini A, Aryafar H, Vodkin I, Warren C, Dorrestein PC, Zarrinpar A, Zarrinpar A. Portosystemic shunt placement reveals blood signatures for the development of hepatic encephalopathy through mass spectrometry. Nat Commun 2023; 14:5303. [PMID: 37652904 PMCID: PMC10471626 DOI: 10.1038/s41467-023-40741-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 08/09/2023] [Indexed: 09/02/2023] Open
Abstract
Elective transjugular intrahepatic portosystemic shunt (TIPS) placement can worsen cognitive dysfunction in hepatic encephalopathy (HE) patients due to toxins, including possible microbial metabolites, entering the systemic circulation. We conducted untargeted metabolomics on a prospective cohort of 22 patients with cirrhosis undergoing elective TIPS placement and followed them up to one year post TIPS for HE development. Here we suggest that pre-existing intrahepatic shunting predicts HE severity post-TIPS. Bile acid levels decrease in the peripheral vein post-TIPS, and the abundances of three specific conjugated di- and tri-hydroxylated bile acids are inversely correlated with HE grade. Bilirubins and glycerophosphocholines undergo chemical modifications pre- to post-TIPS and based on HE grade. Our results suggest that TIPS-induced metabolome changes can impact HE development, and that pre-existing intrahepatic shunting could be used to predict HE severity post-TIPS.
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Affiliation(s)
| | - Stephany Flores Ramos
- Division of Gastroenterology and Hepatology, University of California, San Diego, La Jolla, CA, USA
- Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Julia M Gauglitz
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Anne-Marie Fassler
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Daniel Petras
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
- CMFI Cluster of Excellence, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany
| | - Alexander A Aksenov
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
- Department of Chemistry, University of Connecticut, Storrs, CT, USA
| | - Un Bi Kim
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Michael Lazarowicz
- Department of Radiology, Division of Interventional Radiology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Abbey Barnard Giustini
- Division of Gastroenterology and Hepatology, University of California, San Diego, La Jolla, CA, USA
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sounds Health Care System, Seattle, WA, USA
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Hamed Aryafar
- San Diego Imaging, San Diego, CA, USA
- Departments of Radiology, University of California San Diego Medical Center, La Jolla, CA, USA
| | - Irine Vodkin
- Division of Gastroenterology and Hepatology, University of California, San Diego, La Jolla, CA, USA
| | - Curtis Warren
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA
- Center for Computational Mass Spectrometry, University of California, San Diego, La Jolla, CA, USA
| | - Ali Zarrinpar
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
- J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, USA.
| | - Amir Zarrinpar
- Division of Gastroenterology and Hepatology, University of California, San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA.
- Jennifer Moreno Department of Veterans Affairs Medical Center, La Jolla, CA, USA.
- Institute of Diabetes and Metabolic Health, University of California, San Diego, La Jolla, CA, USA.
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19
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Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol (Lausanne) 2023; 14:1169624. [PMID: 37560311 PMCID: PMC10407565 DOI: 10.3389/fendo.2023.1169624] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/05/2023] [Indexed: 08/11/2023] Open
Abstract
The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.
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Affiliation(s)
| | - Van B. Lu
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
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20
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Beals JW, Kayser BD, Smith GI, Schweitzer GG, Kirbach K, Kearney ML, Yoshino J, Rahman G, Knight R, Patterson BW, Klein S. Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes. Nat Metab 2023; 5:1221-1235. [PMID: 37365374 PMCID: PMC10515726 DOI: 10.1038/s42255-023-00829-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/24/2023] [Indexed: 06/28/2023]
Abstract
The additional therapeutic effects of regular exercise during a dietary weight loss program in people with obesity and prediabetes are unclear. Here, we show that whole-body (primarily muscle) insulin sensitivity (primary outcome) was 2-fold greater (P = 0.006) after 10% weight loss induced by calorie restriction plus exercise training (Diet+EX; n = 8, 6 women) than 10% weight loss induced by calorie restriction alone (Diet-ONLY; n = 8, 4 women) in participants in two concurrent studies. The greater improvement in insulin sensitivity was accompanied by increased muscle expression of genes involved in mitochondrial biogenesis, energy metabolism and angiogenesis (secondary outcomes) in the Diet+EX group. There were no differences between groups in plasma branched-chain amino acids or markers of inflammation, and both interventions caused similar changes in the gut microbiome. Few adverse events were reported. These results demonstrate that regular exercise during a diet-induced weight loss program has profound additional metabolic benefits in people with obesity and prediabetes.Trial Registration: ClinicalTrials.gov (NCT02706262 and NCT02706288).
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Affiliation(s)
- Joseph W Beals
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - Brandon D Kayser
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
- Genentech, South San Francisco, CA, USA
| | - Gordon I Smith
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - George G Schweitzer
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - Kyleigh Kirbach
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - Monica L Kearney
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
- Department of Kinesiology, Nutrition, & Recreation, Southeast Missouri State University, Cape Girardeau, MO, USA
| | - Jun Yoshino
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Gibraan Rahman
- Department of Pediatrics, University of California, San Diego, CA, USA
- Department of Computer Science and Engineering, University of California, San Diego, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California, San Diego, CA, USA
- Department of Computer Science and Engineering, University of California, San Diego, CA, USA
| | - Bruce W Patterson
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA.
- Sansum Diabetes Research Institute, Santa Barbara, CA, USA.
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21
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Ajmal N, Bogart MC, Khan P, Max-Harry IM, Nunemaker CS. Emerging Anti-Diabetic Drugs for Beta-Cell Protection in Type 1 Diabetes. Cells 2023; 12:1472. [PMID: 37296593 PMCID: PMC10253164 DOI: 10.3390/cells12111472] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 06/12/2023] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not halt disease progression. Thus, an effective therapy may require beta-cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can halt T1D. Within the National Clinical Trial (NCT) database, a vast majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on non-insulin pharmacological therapies. Many investigational new drugs fall under the category of immunomodulators, such as the recently FDA-approved CD-3 monoclonal antibody teplizumab. Four intriguing candidate drugs fall outside the category of immunomodulators, which are the focus of this review. Specifically, we discuss several non-immunomodulators that may have more direct action on beta cells, such as verapamil (a voltage-dependent calcium channel blocker), gamma aminobutyric acid (GABA, a major neurotransmitter with effects on beta cells), tauroursodeoxycholic acid (TUDCA, an endoplasmic reticulum chaperone), and volagidemab (a glucagon receptor antagonist). These emerging anti-diabetic drugs are expected to provide promising results in both beta-cell restoration and in suppressing cytokine-derived inflammation.
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Affiliation(s)
- Nida Ajmal
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (N.A.); (P.K.); (I.M.M.-H.)
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, OH 45701, USA
| | | | - Palwasha Khan
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (N.A.); (P.K.); (I.M.M.-H.)
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, OH 45701, USA
| | - Ibiagbani M. Max-Harry
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (N.A.); (P.K.); (I.M.M.-H.)
- Molecular and Cellular Biology Graduate Program, Ohio University, Athens, OH 45701, USA
| | - Craig S. Nunemaker
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (N.A.); (P.K.); (I.M.M.-H.)
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, OH 45701, USA
- Molecular and Cellular Biology Graduate Program, Ohio University, Athens, OH 45701, USA
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22
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Li N, Zhang X, Li M, Liu M, Jin Y, Xu H. Simultaneous determination of UDCA and its major metabolites in human plasma with surrogate matrix by a rapid and specific LC-MS/MS method. J Chromatogr B Analyt Technol Biomed Life Sci 2023; 1223:123726. [PMID: 37148852 DOI: 10.1016/j.jchromb.2023.123726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/17/2023] [Accepted: 04/21/2023] [Indexed: 05/08/2023]
Abstract
A rapid, convenient, and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of ursodeoxycholic acid (UDCA), and its major metabolites, glycoursodeoxycholic acid (GUDCA) and tauroursodeoxycholic acid (TUDCA) in human plasma. Methanol was chosen as surrogate matrix for preparation the calibrators to establish calibration curves. Isotope internal standard was used for each analyte. After plasma samples were deproteinized with methanol, the post-treatment samples were analyzed on a ZORBAX SB-C18 column (2.1 × 50 mm, 1.8 μm) with 2 mM ammonium acetate and acetonitrile as mobile phase at a flow rate of 0.5 mL/min. Detection was performed on a triple quadrupole mass spectrometer operating in multiple reaction monitoring (MRM) employing negative ESI interface using API5500 triple quadrupole tandem mass spectrometer system, with the transitions set at m/z 391.4 → m/z 391.4, m/z 448.3 → m/z 73.9, m/z 498.4 → m/z 80.1, m/z 395.3 → m/z 395.3, m/z 453.3 → m/z 74.0, and m/z 503.2 → m/z 79.9 for UDCA, GUDCA, TUDCA, UDCA-d4, GUDCA-d5, and TUDCA-d5, respectively. The calibration curve ranges were 5.00-2500 ng/mL for UDCA and GUDCA and 0.500-250 ng/mL for TUDCA. The intra- and inter-day precision was within 7.00% in terms of relative standard deviation (RSD%) and the accuracy within 11.75% in terms of relative error. The selectivity, sensitivity, extraction recovery, matrix effect, dilution reliability, and stability were within the acceptable range. The method was successfully applied to a pharmacokinetic study in 12 healthy Chinese volunteers after oral administration of 250 mg UDCA.
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Affiliation(s)
- Ning Li
- Department of Pharmaceutical Analysis, Pharmacy School, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xue Zhang
- Department of Pharmaceutical Analysis, Pharmacy School, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Mengxin Li
- Department of Pharmaceutical Analysis, Pharmacy School, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Mengmeng Liu
- Department of Pharmaceutical Analysis, Pharmacy School, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yi Jin
- Department of Pharmaceutical Analysis, Pharmacy School, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Haiyan Xu
- Department of Pharmaceutical Analysis, Pharmacy School, Shenyang Pharmaceutical University, Shenyang 110016, China.
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23
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Ji C. Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors. Int J Mol Sci 2023; 24:ijms24097938. [PMID: 37175645 PMCID: PMC10178330 DOI: 10.3390/ijms24097938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.
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Affiliation(s)
- Cheng Ji
- Research Center for Liver Disease, GI/Liver Division, Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90089, USA
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24
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Albaugh VL, Axelrod C, Belmont KP, Kirwan JP. Physiology Reconfigured: How Does Bariatric Surgery Lead to Diabetes Remission? Endocrinol Metab Clin North Am 2023; 52:49-64. [PMID: 36754497 DOI: 10.1016/j.ecl.2022.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Bariatric surgery improves glucose homeostasis and glycemic control in patients with type 2 diabetes. Over the past 20 years, a breadth of studies has been conducted in humans and rodents aimed to identify the regulatory nodes responsible for surgical remission of type 2 diabetes. The review herein discusses central mechanisms of type 2 diabetes remission associated with weight loss and surgical modification of the gastrointestinal tract.
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Affiliation(s)
- Vance L Albaugh
- Metamor Institute, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA; Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA
| | - Christopher Axelrod
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA
| | - Kathryn P Belmont
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA
| | - John P Kirwan
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
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25
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Cha KY, Cho W, Park S, Ahn J, Park H, Baek I, Lee M, Lee S, Arai Y, Lee SH. Generation of bioactive MSC-EVs for bone tissue regeneration by tauroursodeoxycholic acid treatment. J Control Release 2023; 354:45-56. [PMID: 36586671 DOI: 10.1016/j.jconrel.2022.12.053] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/24/2022] [Accepted: 12/26/2022] [Indexed: 01/02/2023]
Abstract
Extracellular vesicles (EVs) are nano-sized carriers that reflect the parent cell's information and are known to mediate cell-cell communication. In order to overcome the disadvantages of mesenchymal stem cells (MSCs) in cell therapy, such as unexpected differentiation leading to tumorization, immune rejection, and other side effects, EVs derived from MSCs (MSC-EVs) with the tissue regenerative function have been studied as new cell-free therapeutics. However, therapeutic applications of EVs require overcoming several challenges. First, the production efficiency of MSC-EVs should be increased at least as much as the quantity of them are required to their clinical application; second, MSC-EVs needs to show various functionality further, thereby increasing tissue regeneration efficiency. In this study, we treated tauroursodeoxycholic acid (TUDCA), a biological derivative known to regulate cholesterol, to MSCs and investigated whether TUDCA treatment would be able to increase EV production efficiency and tissue regenerative capacity of EVs. Indeed, it appears that TUDCA priming to MSC increases the yield of MSC-EVs >2 times by reducing the cellular cholesterol level in MSCs and increasing the exocytosis-related CAV1 expression. Interestingly, it was found that the EVs derived from TUDCA-primed MSCs (T-EV) contained higher amounts of anti-inflammatory cytokines (IL1RN, IL6, IL10, and IL11) and osteogenic proteins (ALP, RUNX2, BMP2, BMPR1, and BMPR2) than those in control MSC-EVs (C-EV). Besides, it was shown that T-EV not only regulated M1/M2 macrophages differentiation of monocytes, also effectively increased the osteogenic differentiation of MSCs as well as bone tissue regeneration in a bone defect rat model. Based on these results, it is concluded that TUDCA treatment to MSC as a new approach endows EV with high-yield production and functionality. Thus, we strongly believe T-EV would be a powerful therapeutic material for bone tissue regeneration and potentially could be expanded to other types of tissue regeneration for clinical applications.
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Affiliation(s)
- Kyung-Yup Cha
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Woongjin Cho
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Sunghyun Park
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Jinsung Ahn
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Hyoeun Park
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Inho Baek
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Minju Lee
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Sunjun Lee
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Yoshie Arai
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea.
| | - Soo-Hong Lee
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea.
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26
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Ajoolabady A, Kaplowitz N, Lebeaupin C, Kroemer G, Kaufman RJ, Malhi H, Ren J. Endoplasmic reticulum stress in liver diseases. Hepatology 2023; 77:619-639. [PMID: 35524448 PMCID: PMC9637239 DOI: 10.1002/hep.32562] [Citation(s) in RCA: 154] [Impact Index Per Article: 77.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 02/02/2023]
Abstract
The endoplasmic reticulum (ER) is an intracellular organelle that fosters the correct folding of linear polypeptides and proteins, a process tightly governed by the ER-resident enzymes and chaperones. Failure to shape the proper 3-dimensional architecture of proteins culminates in the accumulation of misfolded or unfolded proteins within the ER, disturbs ER homeostasis, and leads to canonically defined ER stress. Recent studies have elucidated that cellular perturbations, such as lipotoxicity, can also lead to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to reestablish ER homeostasis ("adaptive UPR"), or, conversely, to provoke cell death when ER stress is overwhelmed and sustained ("maladaptive UPR"). It is well documented that ER stress contributes to the onset and progression of multiple hepatic pathologies including NAFLD, alcohol-associated liver disease, viral hepatitis, liver ischemia, drug toxicity, and liver cancers. Here, we review key studies dealing with the emerging role of ER stress and the UPR in the pathophysiology of liver diseases from cellular, murine, and human models. Specifically, we will summarize current available knowledge on pharmacological and non-pharmacological interventions that may be used to target maladaptive UPR for the treatment of nonmalignant liver diseases.
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Affiliation(s)
- Amir Ajoolabady
- Department of Cardiology, Shanghai Institute for Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China
| | - Neil Kaplowitz
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- USC Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Cynthia Lebeaupin
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Randal J. Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Jun Ren
- Department of Cardiology, Shanghai Institute for Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA
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Sun L, Li F, Tan W, Zhao W, Li Y, Zhu X, Gao P, Shu G, Wang S, Jiang Q, Wang L. Lithocholic acid promotes skeletal muscle regeneration through the TGR5 receptor. Acta Biochim Biophys Sin (Shanghai) 2023; 55:51-61. [PMID: 36647725 PMCID: PMC10157625 DOI: 10.3724/abbs.2022201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
<p indent="0mm">Lithocholic acid (LCA) is a classical secondary bile acid formed by the metabolism of gut microbiota. The TGR5 receptor (also known as G protein-coupled receptor 1, GPBAR1) is an important bile acid membrane receptor that mediates a variety of metabolic processes <italic>in vivo</italic>. In recent years, most studies have focused on the role of bile acid receptors in the intestine and liver. However, there are few reports on its effect on skeletal muscle regeneration, and the specific mechanism remains unclear. Therefore, it is necessary to investigate the mechanism of the TGR5 receptor in the regulation of skeletal muscle regeneration. The results demonstrate that muscle injection with LCA significantly reduces the necrosis rate of injured muscle and improves muscle injury. Moreover, treatment of C2C12 cells with LCA significantly increases AKT/mTOR/FoxO3 phosphorylation through the TGR5 receptor, enhances MyoG transcription and reduces FBXO32 transcription. These findings indicate that LCA can activate the TGR5/AKT signaling pathway, inhibit protein degradation and promote protein synthesis to enhance the myogenic process and promote skeletal muscle regeneration. </p>.
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Dantas Machado AC, Ramos SF, Gauglitz JM, Carpenter AM, Petras D, Aksenov AA, Kim UB, Lazarowicz M, Giustini AB, Aryafar H, Vodkin I, Warren C, Dorrestein PC, Zarrinpar A, Zarrinpar A. Pre- and Post-Portosystemic Shunt Placement Metabolomics Reveal Molecular Signatures for the Development of Hepatic Encephalopathy. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.01.02.22281374. [PMID: 36711444 PMCID: PMC9882439 DOI: 10.1101/2023.01.02.22281374] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Hepatic encephalopathy (HE) is a common complication of advanced liver disease causing brain dysfunction. This is likely due to the accumulation of unfiltered toxins within the bloodstream. A known risk factor for developing or worsening HE is the placement of a transjugular intrahepatic portosystemic shunt (TIPS), which connects the pre-hepatic and post-hepatic circulation allowing some blood to bypass the dysfunctional liver and decreases portal hypertension. To better understand the pathophysiology of post-TIPS HE, we conducted a multi-center prospective cohort study employing metabolomic analyses on hepatic vein and peripheral vein blood samples from participants with cirrhosis undergoing elective TIPS placement, measuring chemical modifications and changes in concentrations of metabolites resulting from TIPS placement. In doing so, we identified numerous alterations in metabolites, including bile acids, glycerophosphocholines, and bilirubins possibly implicated in the development and severity of HE.
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Feris F, McRae A, Kellogg TA, McKenzie T, Ghanem O, Acosta A. Mucosal and hormonal adaptations after Roux-en-Y gastric bypass. Surg Obes Relat Dis 2023; 19:37-49. [PMID: 36243547 PMCID: PMC9797451 DOI: 10.1016/j.soard.2022.08.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 01/12/2023]
Abstract
The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.
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Affiliation(s)
- Fauzi Feris
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Alison McRae
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Todd A Kellogg
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Travis McKenzie
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Omar Ghanem
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Andres Acosta
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
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Sah DK, Arjunan A, Park SY, Jung YD. Bile acids and microbes in metabolic disease. World J Gastroenterol 2022; 28:6846-6866. [PMID: 36632317 PMCID: PMC9827586 DOI: 10.3748/wjg.v28.i48.6846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/01/2022] [Accepted: 12/05/2022] [Indexed: 12/26/2022] Open
Abstract
Bile acids (BAs) serve as physiological detergents that enable the intestinal absorption and transportation of nutrients, lipids and vitamins. BAs are primarily produced by humans to catabolize cholesterol and play crucial roles in gut metabolism, microbiota habitat regulation and cell signaling. BA-activated nuclear receptors regulate the enterohepatic circulation of BAs which play a role in energy, lipid, glucose, and drug metabolism. The gut microbiota plays an essential role in the biotransformation of BAs and regulates BAs composition and metabolism. Therefore, altered gut microbial and BAs activity can affect human metabolism and thus result in the alteration of metabolic pathways and the occurrence of metabolic diseases/syndromes, such as diabetes mellitus, obesity/hypercholesterolemia, and cardiovascular diseases. BAs and their metabolites are used to treat altered gut microbiota and metabolic diseases. This review explores the increasing body of evidence that links alterations of gut microbial activity and BAs with the pathogenesis of metabolic diseases. Moreover, we summarize existing research on gut microbes and BAs in relation to intracellular pathways pertinent to metabolic disorders. Finally, we discuss how therapeutic interventions using BAs can facilitate microbiome functioning and ease metabolic diseases.
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Affiliation(s)
- Dhiraj Kumar Sah
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
| | - Archana Arjunan
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
| | - Sun Young Park
- Department of Internal Medicine, Chonnam National University, Gwangju 501190, South Korea
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
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31
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Deka D, D'Incà R, Sturniolo GC, Das A, Pathak S, Banerjee A. Role of ER Stress Mediated Unfolded Protein Responses and ER Stress Inhibitors in the Pathogenesis of Inflammatory Bowel Disease. Dig Dis Sci 2022; 67:5392-5406. [PMID: 35318552 DOI: 10.1007/s10620-022-07467-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 02/28/2022] [Indexed: 01/05/2023]
Abstract
Previous investigations have increased the knowledge about the pathological processes of inflammatory bowel diseases. Besides the complex organization of immune reactions, the mucosal epithelial lining has been recognized as a crucial regulator in the commencement and persistence of intestinal inflammation. As the intestinal epithelium is exposed to various environmental factors, the intestinal epithelial cells are confronted with diverse cellular stress conditions. In eukaryotic cells, an imbalance in the endoplasmic reticulum (ER) might cause aggregation of unfolded or misfolded proteins in the lumen of ER, a condition known as endoplasmic reticulum stress. This cellular mechanism stimulates the unfolded protein response (UPR), which elevates the potential of the endoplasmic reticulum protein folding, improves protein production and its maturation, and also stimulates ER-associated protein degradation. Current analyses reported that in the epithelium, the ER stress might cause the pathogenesis of inflammatory bowel disease that affects the synthesis of protein, inducing the apoptosis of the epithelial cell and stimulating the proinflammatory reactions in the gut. There have been significant efforts to develop small molecules or molecular chaperones that will be potent in ameliorating ER stress. The restoration of UPR balance in the endoplasmic reticulum via pharmacological intervention might be a novel therapeutic approach for the treatment of inflammatory bowel diseases (IBDs). This review provides novel insights into the role of chemical chaperone UPR modulators to modify ER stress levels. We further discuss the future directions/challenges in the development of therapeutic strategies for IBDs by targeting the ER stress. Figure depicting the role of endoplasmic reticulum stress-mediated inflammatory bowel disease and the therapeutic role of endoplasmic reticulum stress inhibitors in alleviating the diseased condition.
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Affiliation(s)
- Dikshita Deka
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Renata D'Incà
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128, Padua, Italy
| | - Giacomo Carlo Sturniolo
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128, Padua, Italy
| | - Alakesh Das
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India.
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Zhang Y, Cheng Y, Liu J, Zuo J, Yan L, Thring RW, Ba X, Qi D, Wu M, Gao Y, Tong H. Tauroursodeoxycholic acid functions as a critical effector mediating insulin sensitization of metformin in obese mice. Redox Biol 2022; 57:102481. [PMID: 36148770 PMCID: PMC9493383 DOI: 10.1016/j.redox.2022.102481] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/28/2022] Open
Abstract
Metformin is widely used to surmount insulin resistance (IR) and type 2 diabetes. Accumulating evidence suggests that metformin may improve IR through regulating gut microbiota and bile acids. However, the underlying mechanisms remain unclear. Our metabolomic analysis showed that metformin significantly increased the accumulation of tauroursodeoxycholic acid (TUDCA) in intestine and liver from high-fat diet (HFD)-induced IR mice. TUDCA also alleviated IR, and reduced oxidative stress and intestinal inflammation in ob/ob mice. TUDCA blocked KEAP1 to bind with Nrf2, resulting in Nrf2 translocation into nuclear and initiating the transcription of antioxidant genes, which eventually reduced intracellular ROS accumulation and improved insulin signaling. Analysis of gut microbiota further revealed that metformin reduced the relative abundance of Bifidobacterium, which produces bile salt hydrolase (BSH). The reduction in BSH was probably crucial for the accumulation of TUDCA. Metformin also increased the proportion of Akkermanisia muciniphlia in gut microbiota of ob/ob mice via TUDCA. These beneficial effects of metformin in remodeling gut microbiota, reducing oxidative stress and improving insulin sensitivity were partly due to the accumulation of TUDCA, suggesting that TUDCA may be a potential therapy for metabolic syndrome.
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Affiliation(s)
- Ya Zhang
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China; Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Yang Cheng
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Jian Liu
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Jihui Zuo
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Liping Yan
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Ronald W Thring
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Xueqing Ba
- Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University, Changchun, Jilin, China
| | - Dake Qi
- College of Pharmacy, University of Manitoba, Winnipeg, Canada
| | - Mingjiang Wu
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Yitian Gao
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China.
| | - Haibin Tong
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China.
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The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis. Nat Commun 2022; 13:6068. [PMID: 36241650 PMCID: PMC9568547 DOI: 10.1038/s41467-022-33609-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 09/23/2022] [Indexed: 12/24/2022] Open
Abstract
Diurnal (i.e., 24-hour) oscillations of the gut microbiome have been described in various species including mice and humans. However, the driving force behind these rhythms remains less clear. In this study, we differentiate between endogenous and exogenous time cues driving microbial rhythms. Our results demonstrate that fecal microbial oscillations are maintained in mice kept in the absence of light, supporting a role of the host's circadian system rather than representing a diurnal response to environmental changes. Intestinal epithelial cell-specific ablation of the core clock gene Bmal1 disrupts rhythmicity of microbiota. Targeted metabolomics functionally link intestinal clock-controlled bacteria to microbial-derived products, in particular branched-chain fatty acids and secondary bile acids. Microbiota transfer from intestinal clock-deficient mice into germ-free mice altered intestinal gene expression, enhanced lymphoid organ weights and suppressed immune cell recruitment. These results highlight the importance of functional intestinal clocks for microbiota composition and function, which is required to balance the host's gastrointestinal homeostasis.
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34
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Li H, Perino A, Huang Q, Von Alvensleben GVG, Banaei-Esfahani A, Velazquez-Villegas LA, Gariani K, Korbelius M, Bou Sleiman M, Imbach J, Sun Y, Li X, Bachmann A, Goeminne LJE, Gallart-Ayala H, Williams EG, Ivanisevic J, Auwerx J, Schoonjans K. Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis. Cell Metab 2022; 34:1594-1610.e4. [PMID: 36099916 PMCID: PMC9534359 DOI: 10.1016/j.cmet.2022.08.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 06/22/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022]
Abstract
Bile acids (BAs) are complex and incompletely understood enterohepatic-derived hormones that control whole-body metabolism. Here, we profiled postprandial BAs in the liver, feces, and plasma of 360 chow- or high-fat-diet-fed BXD male mice and demonstrated that both genetics and diet strongly influence BA abundance, composition, and correlation with metabolic traits. Through an integrated systems approach, we mapped hundreds of quantitative trait loci that modulate BAs and identified both known and unknown regulators of BA homeostasis. In particular, we discovered carboxylesterase 1c (Ces1c) as a genetic determinant of plasma tauroursodeoxycholic acid (TUDCA), a BA species with established disease-preventing actions. The association between Ces1c and plasma TUDCA was validated using data from independent mouse cohorts and a Ces1c knockout mouse model. Collectively, our data are a unique resource to dissect the physiological importance of BAs as determinants of metabolic traits, as underscored by the identification of CES1C as a master regulator of plasma TUDCA levels.
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Affiliation(s)
- Hao Li
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Alessia Perino
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Qingyao Huang
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Giacomo V G Von Alvensleben
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Amir Banaei-Esfahani
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Laura A Velazquez-Villegas
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Karim Gariani
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Melanie Korbelius
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Maroun Bou Sleiman
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Jéromine Imbach
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Yu Sun
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Xiaoxu Li
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Alexis Bachmann
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Ludger J E Goeminne
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Hector Gallart-Ayala
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland
| | - Evan G Williams
- Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
| | - Julijana Ivanisevic
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
| | - Kristina Schoonjans
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
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Zhou R, He M, Fan J, Li R, Zuo Y, Li B, Gao G, Sun T. The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review. Front Neurosci 2022; 16:947295. [PMID: 36188456 PMCID: PMC9523121 DOI: 10.3389/fnins.2022.947295] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/29/2022] [Indexed: 11/21/2022] Open
Abstract
Schizophrenia (SCZ) is a serious mental illness that affects 1% of people worldwide. SCZ is associated with a higher risk of developing metabolic disorders such as obesity. Antipsychotics are the main treatment for SCZ, but their side effects include significant weight gain/obesity. Despite extensive research, the underlying mechanisms by which SCZ and antipsychotic treatment induce weight gain/obesity remain unclear. Hypothalamic endoplasmic reticulum (ER) stress is one of the most important pathways that modulates inflammation, neuronal function, and energy balance. This review aimed to investigate the role of hypothalamic ER stress in SCZ and antipsychotic-induced weight gain/obesity. Preliminary evidence indicates that SCZ is associated with reduced dopamine D2 receptor (DRD2) signaling, which significantly regulates the ER stress pathway, suggesting the importance of ER stress in SCZ and its related metabolic disorders. Antipsychotics such as olanzapine activate ER stress in hypothalamic neurons. These effects may induce decreased proopiomelanocortin (POMC) processing, increased neuropeptide Y (NPY) and agouti-related protein (AgRP) expression, autophagy, and leptin and insulin resistance, resulting in hyperphagia, decreased energy expenditure, and central inflammation, thereby causing weight gain. By activating ER stress, antipsychotics such as olanzapine activate hypothalamic astrocytes and Toll-like receptor 4 signaling, thereby causing inflammation and weight gain/obesity. Moreover, evidence suggests that antipsychotic-induced ER stress may be related to their antagonistic effects on neurotransmitter receptors such as DRD2 and the histamine H1 receptor. Taken together, ER stress inhibitors could be a potential effective intervention against SCZ and antipsychotic-induced weight gain and inflammation.
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Affiliation(s)
- Ruqin Zhou
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Meng He
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
- *Correspondence: Meng He,
| | - Jun Fan
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Ruoxi Li
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yufeng Zuo
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Benben Li
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Guanbin Gao
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, China
- Guanbin Gao,
| | - Taolei Sun
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
- Taolei Sun,
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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Liu Y, Xu D, Wang L, Du W, Zhang L, Xiang X. MBTPS2 exacerbates albuminuria in streptozotocin-induced type I diabetic nephropathy by promoting endoplasmic reticulum stress-mediated renal damage. Arch Physiol Biochem 2022; 128:1050-1057. [PMID: 32255378 DOI: 10.1080/13813455.2020.1749084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The membrane-bound transcription factor protease site 2 (MBTPS2) is an intramembranous metalloprotease involved in the regulation of ER stress response, however, whether it is associated with DN is unknown. RESULTS We report that MBTPS2 expression is upregulated in the renal cortex of diabetic mice induced by streptozotocin (STZ), a murine model of insulinopenic type 1 DN. Functionally, in vivo, MBTPS2 overexpression exacerbates and its knockdown attenuates albuminuria, which indicate a detrimental role of MBTPS2 played in albuminuria development in DN mice. We further show that MBTPS2 promotes ER stress and renal damage in DN mice, and that reducing ER stress via a chemical chaperone 4-phenylbutyric acid (4-PBA) markedly rescues MBTPS2-exacerbated renal damage and albuminuria severity. CONCLUSIONS Collectively, our study associates the function of MBTPS2 in DN albuminuria with ER stress regulation, thus underscoring the notorious role of maladaptive ER response in influencing DN albuminuria.
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Affiliation(s)
- Yongliang Liu
- Central of Translation Medicine, Zibo Central Hospital, Shandong University, Zibo, China
| | - Dayu Xu
- Department of Urology, Zibo Central Hospital, Shandong University, Zibo, China
| | - Linping Wang
- Central of Translation Medicine, Zibo Central Hospital, Shandong University, Zibo, China
| | - Wenyan Du
- Central of Translation Medicine, Zibo Central Hospital, Shandong University, Zibo, China
| | - Limei Zhang
- Department of Endocrinology, Zibo Central Hospital, Shandong University, Zibo, China
| | - Xinxin Xiang
- Central of Translation Medicine, Zibo Central Hospital, Shandong University, Zibo, China
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Sahin E, Saglam N, Erdem S, Alvuroglu E, Abidin I, Yulug E, Alver A. 7,8-Dihydroxyflavone alleviates Endoplasmic Reticulum Stress in cafeteria diet-induced metabolic syndrome. Life Sci 2022; 306:120781. [PMID: 35835252 DOI: 10.1016/j.lfs.2022.120781] [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: 06/17/2022] [Revised: 06/29/2022] [Accepted: 07/01/2022] [Indexed: 10/17/2022]
Abstract
AIMS Prolonged Endoplasmic Reticulum Stress (ERS) is involved in the pathogenesis of metabolic syndrome, including type-2 diabetes mellitus, cardiovascular diseases, atherosclerosis, obesity, and fatty liver disease. There have been significant efforts to discover molecules to treat ERS and/or to ameliorate associate symptoms. In this study, we investigated the effect of 7,8-Dihydroxyflavone (7,8-DHF) on ERS in liver and pancreas tissues in a cafeteria (CAF) diet induced metabolic syndrome model. MAIN METHODS Male C57BL/6 mice were fed CAF diet for 16 weeks and 7,8-DHF was administered intraperitoneally (5 mg/kg/day) for last four weeks. 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) in liver and pancreas tissues, insulin and interleukin-1β (IL-1β) in serum were analyzed by ELISA method and serum biochemistry parameters were analyzed with autoanalyzer. GRP78 and CHOP gene expression levels were determined by qRT-PCR. In addition, histopathological analyzes were performed on liver and pancreas tissues. KEY FINDINGS Findings revealed that CAF diet caused metabolic abnormalities, insulin resistance and inflammation in serum and triggered ERS in pancreas and liver tissues. 7,8-DHF treatment significantly reduced metabolic abnormalities by reducing serum biochemical parameters, HOMO-IR and IL-1β levels. qRT-PCR and ELISA results indicated that 7,8-DHF treatment down-regulated GRP78 and CHOP expression and protein levels in the liver and GRP78 expression in pancreas. Efficiency of 7,8-DHF in these tissues was also demonstrated by histopathological tests. SIGNIFICANCE In conclusion, CAF diet-induced metabolic syndrome model, 7,8-DHF suppressed ERS and ERS-induced metabolic disorders in both liver and pancreas. Therefore, 7,8-DHF may potentially be a novel therapeutic compound to ameliorate ERS and related metabolic symptoms.
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Affiliation(s)
- Elif Sahin
- Department of Medical Biochemistry, Graduate School of Medical Science, Karadeniz Technical University, Trabzon, Turkiye.
| | - Neslihan Saglam
- Department of Medical Biochemistry, Graduate School of Medical Science, Karadeniz Technical University, Trabzon, Turkiye
| | - Seniz Erdem
- Department of Medical Biochemistry, Graduate School of Medical Science, Karadeniz Technical University, Trabzon, Turkiye
| | - Elif Alvuroglu
- Department of Histology and Embryology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkiye
| | - Ismail Abidin
- Department of Biophysics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkiye
| | - Esin Yulug
- Department of Histology and Embryology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkiye
| | - Ahmet Alver
- Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkiye
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Ismail HM, Evans-Molina C. Does the Gut Microbiome Play a Role in Obesity in Type 1 Diabetes? Unanswered Questions and Review of the Literature. Front Cell Infect Microbiol 2022; 12:892291. [PMID: 35873174 PMCID: PMC9304930 DOI: 10.3389/fcimb.2022.892291] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/16/2022] [Indexed: 11/18/2022] Open
Abstract
Evidence suggests that type 1 diabetes (T1D) risk and progression are associated with gut bacterial imbalances. Children with either T1D or islet antibody positivity exhibit gut dysbiosis (microbial imbalance) characterized by lower gram-positive to gram-negative gut bacterial ratios compared to healthy individuals, leading to a pro-inflammatory milieu. In addition, specific gut microbiome changes, including increased virulence factors, elevated phage, prophage, and motility genes, and higher amplitude stress responses, have been identified in individuals who have or are progressing towards T1D. Additionally, gut microbiome differences are associated with and thought to contribute to obesity, a comorbidity that is increasingly prevalent among persons with T1D. Obesity in T1D is problematic because individuals with obesity progress faster to T1D, have reduced insulin sensitivity compared to their lean counterparts, and have higher risk of complications. Animal and human studies suggest higher relative abundance of bacterial taxa associated with changes in bile acid and short chain fatty acid biosynthesis in obesity. However, it is unknown to what extent the gut microbiome plays a role in obesity in T1D and these worse outcomes. In this review, we aim to evaluate potential gut microbiome changes and associations in individuals with T1D who are obese, highlighting the specific gut microbiome changes associated with obesity and with T1D development. We will identify commonalities and differences in microbiome changes and examine potential microbiota-host interactions and the metabolic pathways involved. Finally, we will explore interventions that may be of benefit to this population, in order to modify disease and improve outcomes.
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Affiliation(s)
- Heba M. Ismail
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
- *Correspondence: Heba M. Ismail, ; Carmella Evans-Molina,
| | - Carmella Evans-Molina
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Richard L. Roudebush Veterans Affairs (VA) Medical Center, Indiana University School of Informatics and Computing, Indianapolis, IN, United States
- *Correspondence: Heba M. Ismail, ; Carmella Evans-Molina,
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40
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Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 2022; 19:432-450. [PMID: 35165436 DOI: 10.1038/s41575-021-00566-7] [Citation(s) in RCA: 208] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2021] [Indexed: 02/06/2023]
Abstract
Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.
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41
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Tauroursodeoxycholic acid improves glucose tolerance and reduces adiposity in normal protein and malnourished mice fed a high-fat diet. Food Res Int 2022; 156:111331. [DOI: 10.1016/j.foodres.2022.111331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 11/19/2022]
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Ferrulli A, Terruzzi I, Senesi P, Succi M, Cannavaro D, Luzi L. Turning the clock forward: New pharmacological and non pharmacological targets for the treatment of obesity. Nutr Metab Cardiovasc Dis 2022; 32:1320-1334. [PMID: 35354547 DOI: 10.1016/j.numecd.2022.02.016] [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: 11/30/2021] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 11/26/2022]
Abstract
AIMS Obesity and its main metabolic complication, type 2 diabetes, have attained the status of a global pandemic; there is need for novel strategies aimed at treating obesity and preventing the development of diabetes. A healthy diet and exercise are basic for treatment of obesity but often not enough. Pharmacotherapy can be helpful in maintaining compliance, ameliorating obesity-related health risks, and improving quality of life. In the last two decades, the knowledge of central and peripheral mechanisms underlying homeostatic and hedonic aspects of food intake has significantly increased. Dysregulation of one or more of these components could lead to obesity. DATA SYNTHESIS In order to better understand how potential innovative treatment options can affect obesity, homeostatic and reward mechanisms that regulate energy balance has been firstly illustrated. Then, an overview of potential therapeutic targets for obesity, distinguished according to the level of regulation of feeding behavior, has been provided. Moreover, several non-drug therapies have been recently tested in obesity, such as non-invasive neurostimulation: Transcranial Magnetic Stimulation or Transcranial Direct Current Stimulation. All of them are promising for obesity treatment and are almost devoid of side effects, constituting a potential resource for the prevention of metabolic diseases. CONCLUSIONS The plethora of current anti-obesity therapies creates the unique challenge for physicians to customize the intervention, according to the specific obesity characteristics and the intervention side effect profiles; moreover, it allows multimodal approaches addressed to treat obesity and metabolic adaptation with complementary mechanisms.
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Affiliation(s)
- Anna Ferrulli
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Ileana Terruzzi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Pamela Senesi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Massimiliano Succi
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Daniele Cannavaro
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Livio Luzi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
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43
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Angelidi AM, Belanger MJ, Kokkinos A, Koliaki CC, Mantzoros CS. Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy. Endocr Rev 2022; 43:507-557. [PMID: 35552683 PMCID: PMC9113190 DOI: 10.1210/endrev/bnab034] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Indexed: 02/08/2023]
Abstract
Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed.
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Affiliation(s)
- Angeliki M Angelidi
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Matthew J Belanger
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Chrysi C Koliaki
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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44
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Kny M, Fielitz J. Hidden Agenda - The Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammation-Induced Muscle Wasting. Front Immunol 2022; 13:878755. [PMID: 35615361 PMCID: PMC9124858 DOI: 10.3389/fimmu.2022.878755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body. It adapts rapidly in response to physiological as well as pathological stress, such as inactivity, immobilization, and inflammation. In response to a reduced workload or inflammation muscle atrophy develops. Recent work suggests that adaptive or maladaptive processes in the endoplasmic reticulum (ER), also known as sarcoplasmic reticulum, contributes to this process. In muscle cells, the ER is a highly specialized cellular organelle that assures calcium homeostasis and therefore muscle contraction. The ER also assures correct folding of proteins that are secreted or localized to the cell membrane. Protein folding is a highly error prone process and accumulation of misfolded or unfolded proteins can cause ER stress, which is counteracted by the activation of a signaling network known as the unfolded protein response (UPR). Three ER membrane residing molecules, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1a (IRE1a), and activating transcription factor 6 (ATF6) initiate the UPR. The UPR aims to restore ER homeostasis by reducing overall protein synthesis and increasing gene expression of various ER chaperone proteins. If ER stress persists or cannot be resolved cell death pathways are activated. Although, ER stress-induced UPR pathways are known to be important for regulation of skeletal muscle mass and function as well as for inflammation and immune response its function in ICUAW is still elusive. Given recent advances in the development of ER stress modifying molecules for neurodegenerative diseases and cancer, it is important to know whether or not therapeutic interventions in ER stress pathways have favorable effects and these compounds can be used to prevent or treat ICUAW. In this review, we focus on the role of ER stress-induced UPR in skeletal muscle during critical illness and in response to predisposing risk factors such as immobilization, starvation and inflammation as well as ICUAW treatment to foster research for this devastating clinical problem.
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Affiliation(s)
- Melanie Kny
- Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Jens Fielitz
- Department of Molecular Cardiology, DZHK (German Center for Cardiovascular Research), Partner Site, Greifswald, Germany
- Department of Internal Medicine B, Cardiology, University Medicine Greifswald, Greifswald, Germany
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45
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Chakaroun R, Massier L, Musat N, Kovacs P. New Paradigms for Familiar Diseases: Lessons Learned on Circulatory Bacterial Signatures in Cardiometabolic Diseases. Exp Clin Endocrinol Diabetes 2022; 130:313-326. [PMID: 35320847 DOI: 10.1055/a-1756-4509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Despite the strongly accumulating evidence for microbial signatures in metabolic tissues, including the blood, suggesting a novel paradigm for metabolic disease development, the notion of a core blood bacterial signature in health and disease remains a contentious concept. Recent studies clearly demonstrate that under a strict contamination-free environment, methods such as 16 S rRNA gene sequencing, fluorescence in-situ hybridization, transmission electron microscopy, and several more, allied with advanced bioinformatics tools, allow unambiguous detection and quantification of bacteria and bacterial DNA in human tissues. Bacterial load and compositional changes in the blood have been reported for numerous disease states, suggesting that bacteria and their components may partially induce systemic inflammation in cardiometabolic disease. This concept has been so far primarily based on measurements of surrogate parameters. It is now highly desirable to translate the current knowledge into diagnostic, prognostic, and therapeutic approaches.This review addresses the potential clinical relevance of a blood bacterial signature pertinent to cardiometabolic diseases and outcomes and new avenues for translational approaches. It discusses pitfalls related to research in low bacterial biomass while proposing mitigation strategies for future research and application approaches.
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Affiliation(s)
- Rima Chakaroun
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.,Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, Sweden
| | - Lucas Massier
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.,Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden
| | - Niculina Musat
- Department of Isotope Biogeochemistry, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany
| | - Peter Kovacs
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.,Deutsches Zentrum für Diabetesforschung eV, Neuherberg, Germany
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46
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Zhu L, Ye C, Hu B, Xia H, Bian Q, Liu Y, Kong M, Zhou S, Liu H. Regulation of gut microbiota and intestinal metabolites by Poria cocos oligosaccharides improves glycolipid metabolism disturbance in high-fat diet-fed mice. J Nutr Biochem 2022; 107:109019. [DOI: 10.1016/j.jnutbio.2022.109019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 01/04/2022] [Accepted: 03/18/2022] [Indexed: 01/03/2023]
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47
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McNally BD, Ashley DF, Hänschke L, Daou HN, Watt NT, Murfitt SA, MacCannell ADV, Whitehead A, Bowen TS, Sanders FWB, Vacca M, Witte KK, Davies GR, Bauer R, Griffin JL, Roberts LD. Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle. Nat Commun 2022; 13:1748. [PMID: 35365625 PMCID: PMC8975934 DOI: 10.1038/s41467-022-29363-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/09/2022] [Indexed: 12/14/2022] Open
Abstract
The endoplasmic reticulum (ER) regulates cellular protein and lipid biosynthesis. ER dysfunction leads to protein misfolding and the unfolded protein response (UPR), which limits protein synthesis to prevent cytotoxicity. Chronic ER stress in skeletal muscle is a unifying mechanism linking lipotoxicity to metabolic disease. Unidentified signals from cells undergoing ER stress propagate paracrine and systemic UPR activation. Here, we induce ER stress and lipotoxicity in myotubes. We observe ER stress-inducing lipid cell non-autonomous signal(s). Lipidomics identifies that palmitate-induced cell stress induces long-chain ceramide 40:1 and 42:1 secretion. Ceramide synthesis through the ceramide synthase 2 de novo pathway is regulated by UPR kinase Perk. Inactivation of CerS2 in mice reduces systemic and muscle ceramide signals and muscle UPR activation. The ceramides are packaged into extracellular vesicles, secreted and induce UPR activation in naïve myotubes through dihydroceramide accumulation. This study furthers our understanding of ER stress by identifying UPR-inducing cell non-autonomous signals.
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Affiliation(s)
- Ben D McNally
- Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK
| | - Dean F Ashley
- Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK
| | - Lea Hänschke
- Life & Medical Sciences Institute (LIMES) Development, Genetics & Molecular Physiology Unit, University of Bonn, Carl-Troll-Straße, 31, 53115, Bonn, Germany
| | - Hélène N Daou
- School of Medicine, University of Leeds, Leeds, LS2 9JT, UK
| | - Nicole T Watt
- School of Medicine, University of Leeds, Leeds, LS2 9JT, UK
| | - Steven A Murfitt
- Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK
| | | | - Anna Whitehead
- School of Medicine, University of Leeds, Leeds, LS2 9JT, UK
| | - T Scott Bowen
- Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
| | | | - Michele Vacca
- Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK.,Clinica Medica "Frugoni", Interdisciplinar Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Klaus K Witte
- School of Medicine, University of Leeds, Leeds, LS2 9JT, UK
| | - Graeme R Davies
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Reinhard Bauer
- Life & Medical Sciences Institute (LIMES) Development, Genetics & Molecular Physiology Unit, University of Bonn, Carl-Troll-Straße, 31, 53115, Bonn, Germany
| | - Julian L Griffin
- Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK.,Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Lee D Roberts
- School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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48
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Xie AJ, Mai CT, Zhu YZ, Liu XC, Xie Y. Bile acids as regulatory molecules and potential targets in metabolic diseases. Life Sci 2021; 287:120152. [PMID: 34793769 DOI: 10.1016/j.lfs.2021.120152] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/06/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023]
Abstract
Bile acids are important hydroxylated steroids that are synthesized in the liver from cholesterol for intestinal absorption of lipids and other fatty-nutrient. They also display remarkable and immense functions such as regulating immune responses, managing the apoptosis of cells, participating in glucose metabolism, and so on. Some bile acids were used for the treatment or prevention of diseases such as gallstones, primary biliary cirrhosis, and colorectal cancer. Meanwhile, the accumulation of toxic bile acids leads to apoptosis, necrosis, and inflammation. Alteration of bile acids metabolism, as well as the gut microbiota that interacted with bile acids, contributes to the pathogenesis of metabolic diseases. Therefore, the purpose of this review is to summarize the current functions and pre-clinical or clinical applications of bile acids, and to further discuss the alteration of bile acids in metabolic disorders as well as the manipulation of bile acids metabolism as potential therapeutic targets.
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Affiliation(s)
- Ai-Jin Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Chu-Tian Mai
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Yi-Zhun Zhu
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Xian-Cheng Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
| | - Ying Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau.
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49
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Shahzad K, Fatima S, Al-Dabet MM, Gadi I, Khawaja H, Ambreen S, Elwakiel A, Klöting N, Blüher M, Nawroth PP, Mertens PR, Michel S, Jaschinski F, Klar R, Isermann B. CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease. J Am Soc Nephrol 2021; 32:3066-3079. [PMID: 34479965 PMCID: PMC8638397 DOI: 10.1681/asn.2021040431] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/21/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Maladaptive endoplasmic reticulum stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell-death-promoting transcription factor C/EBP homologous protein (CHOP). Here, we determined whether locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorate experimental DKD. METHODS We determined the efficacy of CHOP-ASO in the early and late stages of experimental DKD (in 8- or 16-week-old db/db mice, respectively) alone or with an angiotensin-converting enzyme inhibitor (ACEi), after an in vivo dose-escalation study. We used renal functional parameters and morphologic analyses to assess the effect of CHOP-ASO and renal gene-expression profiling to identify differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells. RESULTS CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at the early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. CHOP-ASO affected a significantly larger number of genes and disease pathways, including reduced sodium-glucose transport protein 2 (Slc5a2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented death of human kidney cells in vitro . CONCLUSIONS The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi, particularly at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.
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Affiliation(s)
- Khurrum Shahzad
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Sameen Fatima
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany,Institute of Experimental Internal Medicine, Department of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Moh’d Mohanad Al-Dabet
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany,Department of Medical Laboratories, American University of Madaba, Amman, Jordan
| | - Ihsan Gadi
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Hamzah Khawaja
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Saira Ambreen
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Ahmed Elwakiel
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Nora Klöting
- Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany,Medical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Peter P. Nawroth
- Internal Medicine I and Clinical Chemistry, German Diabetes Center, Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany
| | - Peter R. Mertens
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Department of Internal Medicine, Otto-von-Guericke University, Magdeburg, Germany
| | - Sven Michel
- Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
| | | | - Richard Klar
- Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
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Mastrototaro L, Roden M. Insulin resistance and insulin sensitizing agents. Metabolism 2021; 125:154892. [PMID: 34563556 DOI: 10.1016/j.metabol.2021.154892] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/08/2021] [Accepted: 09/20/2021] [Indexed: 02/06/2023]
Abstract
Insulin resistance is a common feature of obesity and type 2 diabetes, but novel approaches of diabetes subtyping (clustering) revealed variable degrees of insulin resistance in people with diabetes. Specifically, the severe insulin resistant diabetes (SIRD) subtype not only exhibits metabolic abnormalities, but also bears a higher risk for cardiovascular, renal and hepatic comorbidities. In humans, insulin resistance comprises dysfunctional adipose tissue, lipotoxic insulin signaling followed by glucotoxicity, oxidative stress and low-grade inflammation. Recent studies show that aside from metabolites (free fatty acids, amino acids) and signaling proteins (myokines, adipokines, hepatokines) also exosomes with their cargo (proteins, mRNA and microRNA) contribute to altered crosstalk between skeletal muscle, liver and adipose tissue during the development of insulin resistance. Reduction of fat mass mainly, but not exclusively, explains the success of lifestyle modification and bariatric surgery to improve insulin sensitivity. Moreover, some older antihyperglycemic drugs (metformin, thiazolidinediones), but also novel therapeutic concepts (new peroxisome proliferator-activated receptor agonists, incretin mimetics, sodium glucose cotransporter inhibitors, modulators of energy metabolism) can directly or indirectly reduce insulin resistance. This review summarizes molecular mechanisms underlying insulin resistance including the roles of exosomes and microRNAs, as well as strategies for the management of insulin resistance in humans.
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Affiliation(s)
- Lucia Mastrototaro
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
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