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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： bariatric surgery bile acids circadian rhythm diabetes metabolic memory

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 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

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

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

Role of farnesoid X receptor and bile acids in alcoholic liver disease

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Acta Pharmaceutica Sinica B 2015年第2期5卷 158-167页

作者： Sharon Manley Wenxing Ding Department of Pharmacology Toxicology and Therapeutics the University of Kansas Medical Center

Alcoholic liver disease(ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover,ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor(FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, Fox O3a(forkhead box-containing protein class O3a) and PPARα(peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.

关键词： Farnesoid X receptor bile acids Autophagy Alcoholic liver disease FoxO3

Fatty liver diseases,bile acids,and FXR

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Acta Pharmaceutica Sinica B 2016年第5期6卷 409-412页

作者： Yan Zhu Hongxia Liu Min Zhang Grace L.Guo Beijing Mentougou District Hospital School of Nursing Beijing University of Chinese Medicine Children's Liver Diseases Center 302 Military Hospital of China Department of Pharmacology and Toxicology Earnest Mario School of Pharmacy & Environmental and Occupational Health Science InstituteRutgers University

The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even to hepatocellular carcinoma (HCC). A comprehensive understanding of the mechanism(s) of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved. An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH. Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury. The bile acid homeostasis is critically regulated by the farnesoid X receptor (FXR) that is activated by bile acids. FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport. Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver. Therefore, the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

关键词： Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Liver metabolism bile acids Farnesoid X receptor

The direct and gut microbiota-mediated effects of dietary bile acids on the improvement of gut barriers in largemouth bass(Micropterus salmoides)

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Animal Nutrition 2023年第3期14卷 32-42页

作者： Rui Xia Qingshuang Zhang Dongmei Xia Qiang Hao Qianwen Ding Chao Ran Yalin Yang Aizhi Cao Zhen Zhang Zhigang Zhou China-Norway Joint Lab on Fish Gut Microbiota Institute of Feed ResearchChinese Academy of Agricultural SciencesBeijing 100081China Norway-China Joint Lab on Fish Gut Microbiota Institute of BiologyNorwegian University of Science and TechnologyTrondheimNorway Key Laboratory for Feed Biotechnology of the Ministry of Agriculture and Rural Affairs Institute of Feed ResearchChinese Academy of Agricultural SciencesBeijing 100081China Shandong Longchang Animal Health Care Co. Ltd.Jinan 251100China Institute of Animal Husbandry and Veterinary Jiangxi Academy of Agricultural ScienceJiangxi 330000China

Fish gut barrier damage under intensive culture model is a significant concern for aquaculture *** study aimed to investigate the effects of bile acids(BAs)on gut barriers in Micropterus salmoides.A germ-free(GF)zebrafish model was employed to elucidate the effects of the direct stimulation of BAs and the indirect regulations mediated by the gut microbiota on gut barrier *** diets were formulated with BAs supplemented at 0,150,300 and 450 mg/kg,and these 4 diets were defined as control,BA150,BA300 and BA450,*** 5 weeks of feeding experiment,the survival rate of fish fed with BA300 diet was increased(P0.05).The results of the gut microbiota transferring experiment demonstrated an upregulation of gut barrier-related genes,including immunoglobulin Z/T(Ig Z/T),IL-6,IL-1βand IL-10,by the gut microbiota transferred from the BA300 group compared with the control(P<0.05).Feeding the BA300 diet directly to GF zebrafish resulted in enhanced expression of Ig M,Ig Z/T,lysozyme

关键词： bile acids Gut barrier Gut microbiota Largemouth bass Germ-free zebrafish