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bile acids and their effects on diabetes

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Frontiers of Medicine 2018年第6期12卷 608-623页

作者： Cynthia Rajani Wei Jia University of Hawaii Cancer Center HonoluluHI 96813USA Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine Shanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai 200233China

Diabetes is a widespread, rapidly increasing metabolic disease that is driven by hyperglycemia. Early glycemic control is of primary importance to avoid vascular complications including development of retinal disorders leading to blindness, end-stage renal disease, and accelerated atherosclerosis with a higher risk of myocardial infarction, stroke and limb amputations. Even after hyperglycemia has been brought under control, “metabolic memory,” a cluster of irreversible metabolic changes that allow diabetes to progress, may persist depending on the duration of hyperglycemia. Manipulation of bile acid (BA) receptors and the BA pool have been shown to be useful in establishing glycemic control in diabetes due to their ability to regulate energy metabolism by binding and activating nuclear transcription factors such as farnesoid X receptor (FXR) in liver and intestine as well as the G-protein coupled receptor, TGR5, in enteroendocrine cells and pancreatic β-cells. The downstream targets of BA activated FXR, FGF15/21, are also important for glucose/insulin homeostasis. In this review we will discuss the effect of BAs on glucose and lipid metabolism and explore recent research on establishing glycemic control in diabetes through the manipulation of BAs and their receptors in the liver, intestine and pancreas, alteration of the enterohepatic circulation, bariatric surgery and alignment of circadian rhythms.

关键词： bile acids metabolic memory diabetes circadian rhythm bariatric surgery

bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease

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World Journal of Gastroenterology 2023年第27期29卷 4252-4270页

作者： Xiong-Quan Long Ming-Zhu Liu Zi-Hao Liu Lv-Zhou Xia Shi-Peng Lu Xiao-Ping Xu Ming-Hao Wu Department of Gastroenterology The First Affiliated Hospital of Hunan Normal University(Hunan Provincial People's Hospital)Changsha 410005Hunan ProvinceChina

Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel *** a result of the interaction between the liver and the gut microbiota,bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food *** the development of genomics and metabolomics,more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their *** acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora,epithelial barrier function,and intestinal *** bowel disease can be treated in new ways by using these potential *** paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic *** addition,we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.

关键词： bile acids Inflammatory bowel disease Intestinal immunology bile acid receptors bile acid metabolism Gut microbiota

bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells

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World Journal of Gastroenterology 2024年第5期30卷 485-498页

作者： Chu-Xuan Liu Ying Gao Xiu-Fang Xu Xin Jin Yun Zhang Qian Xu Huan-Xin Ding Bing-Jun Li Fang-Ke Du Lin-Chuan Li Ming-Wei Zhong Jian-Kang Zhu Guang-Yong Zhang Department of General Surgery Shandong Provincial Qianfoshan HospitalShandong UniversityJinan 250014Shandong ProvinceChina Department of General Surgery Linyi People's HospitalLinyi 276034Shandong ProvinceChina Department of Nursing Huantai TCM HospitalZibo 256400Shandong ProvinceChina Center for Translational medical Research The First Affiliated Hospital of Shandong First Medical UniversityJinan 250014Shandong ProvinceChina Department of General Surgery The First Affiliated Hospital of Shandong First Medical UniversityJinan 250014Shandong ProvinceChina

BACKGROUND Gastric cancer(GC)is associated with high mortality *** acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains *** GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic *** confers additional cancer phenotypes,including ferroptosis *** is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant ***,it is not fully defined if BAs can influence GC progression by modulating *** To reveal the mechanism of BAs regulation in ferroptosis of GC *** In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to *** used gain and loss of function assays to examine the impacts of farnesoid X receptor(FXR)and BTB and CNC homology 1(BACH1)overexpression and knockdown to obtain further insights into the molecular mechanism *** Our data suggested that BAs could reverse erastin-induced ferroptosis in GC *** effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression ***,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and ***,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and ***,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis *** This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC *** work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

关键词： Gastric cancer Ferroptosis bile acids Chenodeoxycholic acid Farnesoid X receptor Glutathione

bile acids as endogenous etiologic agents in gastrointestinal cancer

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World Journal of Gastroenterology 2009年第27期15卷 3329-3340页

作者： Harris Bernstein Carol Bernstein Claire M Payne Katerina Dvorak Department of Cell Biology and Anatomy College of Medicine and Arizona Cancer Center University of ArizonaTucson Arizona 85724 United States Department of Cell Biology and Anatomy College of Medicine University of ArizonaTucson Arizona 85724 United States Hematology/Oncology Southern Arizona Veterans Affairs Health Care System Tucson Arizona 85723 United States

bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.

关键词： bile acids Cancer Adenocarcinoma Esophagus Stomach Small intestine Pancreas Colon Apoptosis DNA damage

bile acids and microbes in metabolic disease

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World Journal of Gastroenterology 2022年第48期28卷 6846-6866页

作者： Dhiraj Kumar Sah Archana Arjunan Sun Young Park Young Do Jung Department of Biochemistry Chonnam National UniversityGwangju 501190South Korea Department of Internal Medicine Chonnam National UniversityGwangju 501190South Korea

bile acids(BAs)serve as physiological detergents that enable the intestinal absorption and transportation of nutrients,lipids and *** are primarily produced by humans to catabolize cholesterol and play crucial roles in gut metabolism,microbiota habitat regulation and cell ***-activated nuclear receptors regulate the enterohepatic circulation of BAs which play a role in energy,lipid,glucose,and drug *** gut microbiota plays an essential role in the biotransformation of BAs and regulates BAs composition and ***,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 *** and their metabolites are used to treat altered gut microbiota and metabolic *** review explores the increasing body of evidence that links alterations of gut microbial activity and BAs with the pathogenesis of metabolic ***,we summarize existing research on gut microbes and BAs in relation to intracellular pathways pertinent to metabolic ***,we discuss how therapeutic interventions using BAs can facilitate microbiome functioning and ease metabolic diseases.

关键词： bile acids Metabolic diseases Gut microbe Diabetic mellitus Obesity Hypercholesterolemia

Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids

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Acta Pharmaceutica Sinica B 2015年第2期5卷 129-134页

作者： Courtney B.Ferrebee Paul A.Dawson Department of Pediatrics Division of Gastroenterology Hepatology and Nutrition Emory University Molecular Medicine Graduate Program Wake Forest School of Medicine

The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).

关键词： bile acids Liver Intestine Transporters Lipid metabolism Energy homeostasis

Bioactivities,Mechanisms,Production,and Potential Application of bile acids in Preventing and Treating Infectious Diseases

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Engineering 2024年第7期38卷 13-26页

作者： Shuang Liu Shuo Yang Biljana Blazekovic Lu Li Jidan Zhang Yi Wang Experimental Research Center China Academy of Chinese Medical SciencesBeijing 100700China Faculty of Pharmacy and Biochemistry University of ZagrebZagreb 10000Croatia

Infectious diseases are a global public health problem,with emerging and re-emerging infectious diseases on the rise ***,their prevention and treatment are still major *** acids are common metabolites in both hosts and microorganisms that play a significant role in controlling the metabolism of lipids,glucose,and *** acids have historically been utilized as first-line,valuable therapeutic agents for related metabolic and hepatobiliary ***,bile acids are the major active ingredients of cow bezoar and bear bile,which are commonly used traditional Chinese medicines(TCMs)with the therapeutic effects of clearing heat,detoxification,and relieving wind and *** recent years,the promising performance of bile acids against infectious diseases has attracted attention from the scientific *** paper reviews for the first time the biological activities,possible mechanisms,production routes,and potential applications of bile acids in the treatment and prevention of infectious *** with previous reviews,we comprehensively summarize existing studies on the use of bile acids against infectious diseases caused by pathogenic microorganisms that are leading causes of global morbidity and *** addition,to ensure a stable supply of bile acids at affordable prices,it is necessary to clarify the biosynthesis of bile acids in vivo,which will assist scientists in elucidating the accumulation of bile acids and discovering how to engineer various bile acids by means of chemosynthesis,biosynthesis,and chemoenzymatic ***,we explore the current challenges in the field and recommend a development strategy for bile-acid-based drugs and the sustainable production of bile *** presented studies suggest that bile acids are potential novel therapeutic agents for managing infectious diseases and can be artificially synthesized in a sustainable way.

关键词： bile acids Infectious diseases Bioactivities Mechanisms Anti-infective agents

Suppressing FXR promotes antiviral effects of bile acids via enhancing the interferon transcription

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3513-3527页

作者： Xue Liang Kunpeng Liu Xin Jia Cuiqin Cheng Meiqi Zhang Lingdong Kong Qiqi Li Zhe Liu Min Li Junliang Li Yao Wang Anlong Xu School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China Guangxi Key Laboratory of Special Biomedicine School of MedicineGuangxi UniversityNanning 530004China Beijing Academy of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 100029China Beijing Research Institute of Chinese Medicine Beijing University of Chinese MedicineBeijing 100029China

bile acids(BAs)are natural metabolites in mammals and have the potential to function as drugs against viral ***,the limited understanding of chenodeoxycholic acid(CDCA)receptors and downstream signaling,along with its lower suppression efficiency in inhibiting virus infection limits its clinical *** this study,we demonstrate that farnesoid X receptor(FXR),the receptor of CDCA,negatively regulates interferon signaling,thereby contributing to the reduced effectiveness of CDCA against virus *** deficiency or pharmacological inhibition enhances interferon signaling activation to suppress virus ***,FXR impairs the DNA binding and transcriptional abilities of activated interferon regulatory factor 3(IRF3)through *** IRF3 transcriptional activity by FXReIRF3 interaction significantly undermines the expression of Interferon Beta 1(IFNB1)and the antiviral response of cells,especially upon the CDCA *** FXR-deficient cells,or when combined with Z-guggulsterone(GUGG)treatment,CDCA exhibits a more potent ability to restrict virus ***,these findings suggest that FXR serves as a limiting factor for CDCA in inhibiting virus replication,which can be attributed to the“signaling-brake”roles of FXR in interferon *** FXR inhibition represents a promising pharmaceutical strategy for the clinical application of BAs metabolites as antiviral drugs.

关键词： bile acids FXR IRF3 Interferon transcription RNA virus Z-guggulsterone Broad-spectrum antiviral activity Synergistic inhibitory effect

High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids

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World Journal of Gastroenterology 2012年第9期18卷 923-929页

作者： Lotta K Stenman Reetta Holma Riitta Korpela Institute of Biomedicine PharmacologyUniversity of Helsinki

AIM： To investigate whether high-fat-feeding is associ- ated with increased intestinal permeability via altera- tions in bile acid metabolism.METHODS： Male C57BI/6J mice were fed on a high-fat （n = 26） or low-fat diet （n = 24） for 15 wk. Intestinal permeability was measured from duodenum, jejunum, ileum and colon in an Ussing chamber system using 4 kDa FITC-labeled dextran as an indicator. Fecal bile ac- ids were analyzed with gas chromatography. Segments of jejunum and colon were analyzed for the expression of farnesoid X receptor （FXR） and tumor necrosis factor

关键词： bile acids bile salts Diet-induced obesity Farnesoid X-activated receptor Intestinal permeability Ursodeoxycholic acid