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1
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Liu T, Han S, Yao Y, Zhang G. Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment. Cancer Manag Res 2023; 15:957-975. [PMID: 37693221 PMCID: PMC10487743 DOI: 10.2147/cmar.s421771] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 08/30/2023] [Indexed: 09/12/2023] Open
Abstract
In recent years, the abnormal glucose metabolism of tumor cells has attracted increasing attention. Abnormal glucose metabolism is closely related to the occurrence and development of tumors. Monocarboxylate transporters (MCTs) transport the sugar metabolites lactic acid and pyruvate, which affect glucose metabolism and tumor progression in a variety of ways. Thus, research has recently focused on MCTs and their potential functions in cancer. The MCT superfamily consists of 14 members. MCT1 and MCT4 play a crucial role in the maintenance of intracellular pH in tumor cells by transporting monocarboxylic acids (such as lactate, pyruvate and butyrate). MCT1 and MCT4 are highly expressed in a variety of tumor cells and are involved the proliferation, invasion and migration of tumor cells, which are closely related to the prognosis of cancer. Because of their important functions in tumor cells, MCT1 and MCT4 have become potential targets for cancer treatment. In this review, we focus on the structure, function and regulation of MCT1 and MCT4 and discuss the developed inhibitors of MCT1 and MCT4 to provide more comprehensive information that might aid in the development of strategies targeting MCTs in cancer.
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Affiliation(s)
- Tian Liu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Shangcong Han
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China
| | - Yu Yao
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Guiming Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
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2
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Peng K, Dong W, Luo T, Tang H, Zhu W, Huang Y, Yang X. Butyrate and obesity: Current research status and future prospect. Front Endocrinol (Lausanne) 2023; 14:1098881. [PMID: 36909336 PMCID: PMC9999029 DOI: 10.3389/fendo.2023.1098881] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/07/2023] [Indexed: 03/14/2023] Open
Abstract
Over the past few decades, increasing prevalence of obesity caused an enormous medical, social, and economic burden. As the sixth most important risk factor contributing to the overall burden of disease worldwide, obesity not only directly harms the human body, but also leads to many chronic diseases such as diabetes, cardiovascular diseases (CVD), nonalcoholic fatty liver disease (NAFLD), and mental illness. Weight loss is still one of the most effective strategies against obesity and related disorders. Recently, the link between intestinal microflora and metabolic health has been constantly established. Butyrate, a four-carbon short-chain fatty acid, is a major metabolite of the gut microbiota that has many beneficial effects on metabolic health. The anti-obesity activity of butyrate has been demonstrated, but its mechanisms of action have not been fully described. This review summarizes current knowledge of butyrate, including its production, absorption, distribution, metabolism, and the effect and mechanisms involved in weight loss and obesity-related diseases. The aim was to contribute to and advance our understanding of butyrate and its role in obesity. Further exploration of butyrate and its pathway may help to identify new anti-obesity.
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Affiliation(s)
- Ke Peng
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Wenjie Dong
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Taimin Luo
- Department of Pharmacy, Chengdu Seventh People’s Hospital, Chengdu, Sichuan, China
| | - Hui Tang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Wanlong Zhu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yilan Huang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xuping Yang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
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3
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Nickerson AJ, Rajendran VM. Aldosterone up-regulates basolateral Na + -K + -2Cl - cotransporter-1 to support enhanced large-conductance K + channel-mediated K + secretion in rat distal colon. FASEB J 2021; 35:e21606. [PMID: 33908679 PMCID: PMC9777186 DOI: 10.1096/fj.202100203r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/24/2021] [Accepted: 04/05/2021] [Indexed: 12/25/2022]
Abstract
Na+ -K+ -2Cl- cotransporter-1 (NKCC1) facilitates basolateral K+ and Cl- uptake, supporting their efflux across mucosal membranes of colonic epithelial cells. NKCC1 activity has also been shown to be critical for electrogenic K+ secretion induced by aldosterone, which is known to stimulate large-conductance K+ (BK) channel expression in mucosal membranes. This study was aimed to (1) identify whether aldosterone enhances NKCC1 expression specifically to support BK-mediated K+ secretion and (2) to determine whether increased NKCC1 supports electrogenic Cl- secretion in parallel to K+ secretion. Dietary Na+ depletion was used to induce secondary hyperaldosteronism in rats, or aldosterone was administered ex vivo to rat distal colonic mucosae. NKCC1-dependent electrogenic K+ or Cl- secretion was measured as a function of short circuit current (ISC ). qRT-PCR, western blot, and immunofluorescence analyses were performed using standard techniques. Aldosterone enhanced NKCC1 and BKα expression and electrogenic K+ secretion in the distal colon, which was inhibited by either serosal bumetanide (NKCC1 inhibitor) or mucosal iberiotoxin (IbTX; BK channel blocker), but not TRAM-34 (IK channel blocker). Expression of NKCC1 and BKα proteins was enhanced in crypt cells of hyper-aldosterone rats. However, neither NKCC1-dependent Cl- secretion nor CFTR (apical Cl- channel) expression was enhanced by aldosterone. We conclude that aldosterone enhances NKCC1 to support BK-mediated K+ secretion independently of Cl- secretion in the distal colon. The regulation of NKCC1 expression/K+ secretion by aldosterone may be a therapeutic target in treating gastrointestinal disorders associated with alterations in colonic K+ transport, such as colonic pseudo-obstruction, and hyperkalemia associated with renal disease.
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Affiliation(s)
- Andrew J. Nickerson
- Department of Physiology, Pharmacology and Neuroscience, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Vazhaikkurichi M. Rajendran
- Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia
- Departments of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia
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4
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Wang C, Cao S, Shen Z, Hong Q, Feng J, Peng Y, Hu C. Effects of dietary tributyrin on intestinal mucosa development, mitochondrial function and AMPK-mTOR pathway in weaned pigs. J Anim Sci Biotechnol 2019; 10:93. [PMID: 31788241 PMCID: PMC6876078 DOI: 10.1186/s40104-019-0394-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 09/11/2019] [Indexed: 02/08/2023] Open
Abstract
Background The objective of this experiment was to investigate the influence of dietary tributyrin on intestinal mucosa development, oxidative stress, mitochondrial function and AMPK-mTOR signaling pathway. Methods Seventy-two pigs were divided into two treatments and received either a basal diet or the same diet supplemented with 750 mg/kg tributyrin. Each treatment has six replicates of six pigs. After 14 days, 6 pigs from each treatment were selected and the jejunal samples were collected. Results Results showed that supplemental tributyrin increased (P < 0.05) villus height and villus height: crypt depth of weaned pigs. Pigs fed tributyrin had greater (P < 0.05) RNA/DNA and protein/DNA ratios than pigs on the control group. The mRNA levels of sodium glucose transport protein-1 and glucose transporter-2 in the jejunum were upregulated (P < 0.05) in pigs fed the tributyrin diet. Dietary tributyrin supplementation lowered (P < 0.05) the malondialdehyde and hydrogen peroxide (H2O2) content in jejunum, enhanced (P < 0.05) the mitochondrial function, as demonstrated by decreased (P < 0.05) reactive oxygen species level and increased (P < 0.05) mitochondrial membrane potential. Furthermore, tributyrin increased (P < 0.05) mitochondrial DNA content and the mRNA abundance of genes related to mitochondrial functions, including peroxisomal proliferator-activated receptor-γ coactivator-1α, mitochondrial transcription factor A, nuclear respiratory factor-1 in the jejunum. Supplementation with tributyrin elevated (P < 0.05) the phosphorylation level of AMPK and inhibited (P < 0.05) the phosphorylation level of mTOR in jejunum compared with the control group. Conclusions These findings suggest that dietary supplementation with tributyrin promotes intestinal mucosa growth, extenuates oxidative stress, improves mitochondrial function and modulates the AMPK-mTOR signal pathway of weaned pigs.
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Affiliation(s)
- Chunchun Wang
- 1Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Animal Science College, Zhejiang University, Yu Hang Tang Rd No. 866, Hangzhou, 310058 People's Republic of China
| | - Shuting Cao
- 1Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Animal Science College, Zhejiang University, Yu Hang Tang Rd No. 866, Hangzhou, 310058 People's Republic of China
| | - Zhuojun Shen
- 1Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Animal Science College, Zhejiang University, Yu Hang Tang Rd No. 866, Hangzhou, 310058 People's Republic of China
| | - Qihua Hong
- 1Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Animal Science College, Zhejiang University, Yu Hang Tang Rd No. 866, Hangzhou, 310058 People's Republic of China
| | - Jie Feng
- 1Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Animal Science College, Zhejiang University, Yu Hang Tang Rd No. 866, Hangzhou, 310058 People's Republic of China
| | - Yan Peng
- Shanghai Menon Animal Nutrition Technology Co. Ltd., Shanghai, 201807 China
| | - Caihong Hu
- 1Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Animal Science College, Zhejiang University, Yu Hang Tang Rd No. 866, Hangzhou, 310058 People's Republic of China
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Buret AG, Motta JP, Allain T, Ferraz J, Wallace JL. Pathobiont release from dysbiotic gut microbiota biofilms in intestinal inflammatory diseases: a role for iron? J Biomed Sci 2019; 26:1. [PMID: 30602371 PMCID: PMC6317250 DOI: 10.1186/s12929-018-0495-4] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/21/2018] [Indexed: 02/06/2023] Open
Abstract
Gut microbiota interacting with an intact mucosal surface are key to the maintenance of homeostasis and health. This review discusses the current state of knowledge of the biofilm mode of growth of these microbiota communities, and how in turn their disruptions may cause disease. Beyond alterations of relative microbial abundance and diversity, the aim of the review is to focus on the disruptions of the microbiota biofilm structure and function, the dispersion of commensal bacteria, and the mechanisms whereby these dispersed commensals may become pathobionts. Recent findings have linked iron acquisition to the expression of virulence factors in gut commensals that have become pathobionts. Causal studies are emerging, and mechanisms common to enteropathogen-induced disruptions, as well as those reported for Inflammatory Bowel Disease and colo-rectal cancer are used as examples to illustrate the great translational potential of such research. These new observations shed new light on our attempts to develop new therapies that are able to protect and restore gut microbiota homeostasis in the many disease conditions that have been linked to microbiota dysbiosis.
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Affiliation(s)
- Andre Gerald Buret
- Departments of Biological Sciences, and Pharmacology and Therapeutics, Inflammation Research Network, University of Calgary, 2500 University Dr. N.W, Calgary, T2N 1N4, Canada.
| | - Jean-Paul Motta
- Departments of Biological Sciences, and Pharmacology and Therapeutics, Inflammation Research Network, University of Calgary, 2500 University Dr. N.W, Calgary, T2N 1N4, Canada.,Institute of Digestive Health Research, INSERM UMR1220, Université Toulouse Paul Sabatier, Toulouse, France
| | - Thibault Allain
- Departments of Biological Sciences, and Pharmacology and Therapeutics, Inflammation Research Network, University of Calgary, 2500 University Dr. N.W, Calgary, T2N 1N4, Canada
| | - Jose Ferraz
- Division of Gastroenterology, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4, Canada
| | - John Lawrence Wallace
- Departments of Biological Sciences, and Pharmacology and Therapeutics, Inflammation Research Network, University of Calgary, 2500 University Dr. N.W, Calgary, T2N 1N4, Canada
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Xu H, Ghishan FK, Kiela PR. SLC9 Gene Family: Function, Expression, and Regulation. Compr Physiol 2018; 8:555-583. [PMID: 29687889 DOI: 10.1002/cphy.c170027] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The Slc9 family of Na+ /H+ exchangers (NHEs) plays a critical role in electroneutral exchange of Na+ and H+ in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na+ and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid-base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na+ /H+ exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na+ /H+ exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na+ /H+ exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na+ /H+ exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555-583, 2018.
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Affiliation(s)
- Hua Xu
- Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, Arizona, USA
| | - Fayez K Ghishan
- Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, Arizona, USA
| | - Pawel R Kiela
- Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, Arizona, USA.,Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
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Changes in the Luminal Environment of the Colonic Epithelial Cells and Physiopathological Consequences. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:476-486. [PMID: 28082121 DOI: 10.1016/j.ajpath.2016.11.015] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 11/21/2016] [Accepted: 11/23/2016] [Indexed: 12/28/2022]
Abstract
Evidence, mostly from experimental models, has accumulated, indicating that modifications of bacterial metabolite concentrations in the large intestine luminal content, notably after changes in the dietary composition, may have important beneficial or deleterious consequences for the colonic epithelial cell metabolism and physiology in terms of mitochondrial energy metabolism, reactive oxygen species production, gene expression, DNA integrity, proliferation, and viability. Recent data suggest that for some bacterial metabolites, like hydrogen sulfide and butyrate, the extent of their oxidation in colonocytes affects their capacity to modulate gene expression in these cells. Modifications of the luminal bacterial metabolite concentrations may, in addition, affect the colonic pH and osmolarity, which are known to affect colonocyte biology per se. Although the colonic epithelium appears able to face, up to some extent, changes in its luminal environment, notably by developing a metabolic adaptive response, some of these modifications may likely affect the homeostatic process of colonic epithelium renewal and the epithelial barrier function. The contribution of major changes in the colonocyte luminal environment in pathological processes, like mucosal inflammation, preneoplasia, and neoplasia, although suggested by several studies, remains to be precisely evaluated, particularly in a long-term perspective.
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8
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Enzymatically modified starch up-regulates expression of incretins and sodium-coupled monocarboxylate transporter in jejunum of growing pigs. Animal 2016; 11:1180-1188. [PMID: 27927266 DOI: 10.1017/s1751731116002615] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Dietary effects on the host are mediated via modulation of the intestinal mucosal responses. The present study investigated the effect of an enzymatically modified starch (EMS) product on the mucosal expression of genes related to starch digestion, sugar and short-chain fatty acid (SCFA) absorption and incretins in the jejunum and cecum in growing pigs. Moreover, the impact of the EMS on hepatic expression of genes related to glucose and lipid metabolism, and postprandial serum metabolites were assessed. Barrows (n=12/diet; initial BW 29 kg) were individually fed three times daily with free access to a diet containing either EMS or waxy corn starch as control (CON) for 10 days. The enzymatic modification led to twice as many α-1,6-glycosidic bonds (~8%) in the amylopectin fraction in the EMS in comparison with the non-modified native waxy corn starch (4% α-1,6-glycosidic bonds). Linear discriminant analysis revealed distinct clustering of mucosal gene expression for EMS and CON diets in jejunum. Compared with the CON diet, the EMS intake up-regulated jejunal expression of sodium-coupled monocarboxylate transporter (SMCT), glucagon-like peptide-1 (GLP1) and gastric inhibitory polypeptide (GIP) (P<0.05) and intestinal alkaline phosphatase (ALPI) (P=0.08), which may be related to greater luminal SCFA availability, whereas cecal gene expression was unaffected by diet. Hepatic peroxisome proliferator-activated receptor γ (PPARγ) expression tended (P=0.07) to be down-regulated in pigs fed the EMS diet compared with pigs fed the CON diet, which may explain the trend (P=0.08) of 30% decrease in serum triglycerides in pigs fed the EMS diet. Furthermore, pigs fed the EMS diet had a 50% higher (P=0.03) serum urea concentration than pigs fed the CON diet potentially indicating an increased use of glucogenic amino acids for energy acquisition in these pigs. Present findings suggested the jejunum as the target site to influence the intestinal epithelium and altered lipid and carbohydrate metabolism by EMS feeding.
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Uchiyama K, Sakiyama T, Hasebe T, Musch MW, Miyoshi H, Nakagawa Y, He TC, Lichtenstein L, Naito Y, Itoh Y, Yoshikawa T, Jabri B, Stappenbeck T, Chang EB. Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development. Sci Rep 2016; 6:32094. [PMID: 27561676 PMCID: PMC4999796 DOI: 10.1038/srep32094] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 08/01/2016] [Indexed: 12/13/2022] Open
Abstract
Proliferation and spatial development of colonic epithelial cells are highly regulated along the crypt vertical axis, which, when perturbed, can result in aberrant growth and carcinogenesis. In this study, two key factors were identified that have important and counterbalancing roles regulating these processes: pericrypt myofibroblast-derived Wnt-5a and the microbial metabolite butyrate. Cultured YAMC cell proliferation and heat shock protein induction were analzyed after butryate, conditioned medium with Wnt5a activity, and FrzB containing conditioned medium. In vivo studies to modulate Hsp25 employed intra-colonic wall Hsp25 encoding lentivirus. To silence Wnt-5a in vivo, intra-colonic wall Wnt-5a silencing RNA was used. Wnt-5a, secreted by stromal myofibroblasts of the lower crypt, promotes proliferation through canonical β-catenin activation. Essential to this are two key requirements: (1) proteolytic conversion of the highly insoluble ~40 kD Wnt-5a protein to a soluble 36 mer amino acid peptide that activates epithelial β-catenin and cellular proliferation, and (2) the simultaneous inhibition of butyrate-induced Hsp25 by Wnt-5a which is necessary to arrest the proliferative process in the upper colonic crypt. The interplay and spatial gradients of these factors insures that crypt epithelial cell proliferation and development proceed in an orderly fashion, but with sufficient plasticity to adapt to physiological perturbations including inflammation.
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Affiliation(s)
- Kazuhiko Uchiyama
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA.,Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan
| | - Toshio Sakiyama
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA.,Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 8908520; Japan
| | - Takumu Hasebe
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
| | - Mark W Musch
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
| | - Hiroyuki Miyoshi
- Department of Pathology, Washington University at St. Louis, St. Louis, MO, USA
| | - Yasushi Nakagawa
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
| | - Tong-Chuan He
- Department of Surgery, University of Chicago; Chicago, IL 60637; USA
| | - Lev Lichtenstein
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA.,Department of Gastroenterology, Soroka University Medical Center, Beer-Sheva 84101; Israel
| | - Yuji Naito
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan
| | - Toshikazu Yoshikawa
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan
| | - Bana Jabri
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
| | | | - Eugene B Chang
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
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Dames P, Bergann T, Fromm A, Bücker R, Barmeyer C, Krug SM, Fromm M, Schulzke JD. Interleukin-13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity. J Physiol 2015; 593:5269-82. [PMID: 26365358 DOI: 10.1113/jp271156] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 08/28/2015] [Indexed: 12/13/2022] Open
Abstract
KEY POINTS Interleukin-13 (IL-13) causes intestinal epithelial barrier dysfunction, and is implicated in the pathogenesis of Th2-driven intestinal inflammation (e.g. ulcerative colitis). However, it is unclear whether the epithelial sodium channel (ENaC) - the main limiting factor for sodium absorption in the distal colon - is also influenced by IL-13 and if so, by what mechanism(s). We demonstrate in an intestinal cell model as well as in mouse distal colon that IL-13 causes reduced ENaC activity. We show that IL-13 impairs ENaC-dependent sodium transport by activating the JAK1/2-STAT6 signalling pathway. These results improve our understanding of the mechanisms through which IL-13 functions as a key effector cytokine in ulcerative colitis, thereby contributing to the distinct pathology of this disease. ABSTRACT Interleukin-13 (IL-13) has been strongly implicated in the pathogenesis of ulcerative colitis, possibly by disrupting epithelial integrity. In the distal colon, the epithelial sodium channel (ENaC) is an important factor in the regulation of sodium absorption, and therefore plays a critical role in minimizing intestinal sodium and water losses. In the present study, we investigated whether IL-13 also acts as a potent modulator of epithelial sodium transport via ENaC, and the signalling components involved. The effect of IL-13 on ENaC was examined in HT-29/B6-GR/MR human colon cells, as well as in mouse distal colon, by measuring amiloride-sensitive short-circuit current (ISC ) in Ussing chambers. The expression levels of ENaC subunits and the cellular components that contribute to ENaC activity were analysed by qRT-PCR and promoter gene assay. We show that IL-13, in both the cell model and in native intestinal tissue, impaired epithelial sodium absorption via ENaC (JNa ) as a result of decreased transcription levels of β- and γ-ENaC subunits and SGK1, a post-translational regulator of ENaC activity, due to impaired promoter activity. The reduction in JNa was prevented by inhibition of JAK1/2-STAT6 signalling. This inhibition also affected the IL-13-induced decrease in p38 MAPK phosphorylation. The contribution of STAT6 to IL-13-mediated ENaC inactivation was confirmed in a STAT6(-/-) mouse model. In conclusion, these results indicate that IL-13, the levels of which are elevated in ulcerative colitis, contributes to impaired ENaC activity via modulation of the STAT6/p38 MAPK pathways.
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Affiliation(s)
- Petra Dames
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Theresa Bergann
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Anja Fromm
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Roland Bücker
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Christian Barmeyer
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Susanne M Krug
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Michael Fromm
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Jörg-Dieter Schulzke
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
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11
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Encarnação JC, Abrantes AM, Pires AS, Botelho MF. Revisit dietary fiber on colorectal cancer: butyrate and its role on prevention and treatment. Cancer Metastasis Rev 2015. [DOI: 10.1007/s10555-015-9578-9] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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12
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IWANAGA T, KISHIMOTO A. Cellular distributions of monocarboxylate transporters: a review . Biomed Res 2015; 36:279-301. [DOI: 10.2220/biomedres.36.279] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Toshihiko IWANAGA
- Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University
| | - Ayuko KISHIMOTO
- Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University
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13
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Bergann T, Fromm A, Borden SA, Fromm M, Schulzke JD. Glucocorticoid receptor is indispensable for physiological responses to aldosterone in epithelial Na+ channel induction via the mineralocorticoid receptor in a human colonic cell line. Eur J Cell Biol 2011; 90:432-9. [PMID: 21354648 DOI: 10.1016/j.ejcb.2011.01.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2010] [Revised: 12/17/2010] [Accepted: 01/05/2011] [Indexed: 11/26/2022] Open
Abstract
The epithelial Na+ channel (ENaC) plays a crucial role in electrogenic Na(+) absorption in the distal colon. ENaC induction via the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) is differentially regulated by modulatory components. As most existing epithelial cell lines including colonic epithelial cell lines miss the co-expression of functional GR and MR, signaling on ENaC is only poorly characterized regarding the interplay of glucocorticoids and mineralocorticoids. In the present study, we show that GR expression and activity are indispensable for MR-dependent induction of ENaC-mediated Na(+) transport. Cooperativity of the two receptors has been studied in the highly differentiated, epithelial colonic cell line HT-29/B6-GR/MR which is equipped with the complete receptor repertoire of both GR and MR due to stable transfection. In contrast to HT-29/B6 cells solely expressing the MR, this cell line displays a physiological response to aldosterone regarding ENaC induction. To achieve this, a pre-incubation step with the GR agonist dexamethasone was required to allow for the subsequent stimulation of ENaC by aldosterone. As a result of cooperative effects between the activated GR and the MR, MR protein levels were elevated and MR-dependent transcription of ENaC subunits β and γ was increased. As an additional mechanism involved, transcription of SGK-1 (serum- and glucocorticoid-induced kinase 1) and GILZ (glucocorticoid-induced leucin zipper)--both essential for the insertion of ENaC into the apical enterocyte membrane--were also augmented by the activated MR.
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Affiliation(s)
- Theresa Bergann
- Department of General Medicine, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
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Gonçalves P, Araújo JR, Martel F. Characterization of Butyrate Uptake by Nontransformed Intestinal Epithelial Cell Lines. J Membr Biol 2011; 240:35-46. [DOI: 10.1007/s00232-011-9340-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Accepted: 01/02/2011] [Indexed: 10/18/2022]
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Bergann T, Plöger S, Fromm A, Zeissig S, Borden SA, Fromm M, Schulzke JD. A colonic mineralocorticoid receptor cell model expressing epithelial Na+ channels. Biochem Biophys Res Commun 2009; 382:280-5. [DOI: 10.1016/j.bbrc.2009.03.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Accepted: 03/04/2009] [Indexed: 11/27/2022]
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Gonçalves P, Araújo JR, Pinho MJ, Martel F. Modulation of butyrate transport in Caco-2 cells. Naunyn Schmiedebergs Arch Pharmacol 2008; 379:325-36. [PMID: 19023563 DOI: 10.1007/s00210-008-0372-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2008] [Accepted: 10/30/2008] [Indexed: 02/06/2023]
Abstract
The aim of this study was to investigate the putative influence of some pharmacological agents and drugs of abuse upon the apical uptake of butyrate (BT) into Caco-2 cells. The apical uptake of (14)C-BT by Caco-2 cells was (1) time and concentration dependent, (2) pH dependent, (3) Na(+) independent and Cl(-) dependent, (4) energy dependent, (5) inhibited by several BT structural analogues (acetate, propionate, alpha-ketobutyrate, pyruvate, lactate), (6) insensitive to the anion exchange inhibitors DIDS and SITS and (7) inhibited by the monocarboxylate transport (MCT) inhibitors NPPB and pCMB. These characteristics are compatible with an involvement of MCT1-mediated transport. Acutely, uptake of a low concentration of (14)C-BT (10 microM) was reduced by acetaldehyde, acetylsalicylic acid, indomethacin, caffeine and theophylline and increased by MDMA. Chronically, uptake was increased by caffeine and decreased by tetrahydrocannabinol and MDMA; reverse transcription quantitative real-time PCR analysis showed that these three compounds decreased the mRNA levels of MCT1. Acutely, acetaldehyde, indomethacin and MDMA reduced the uptake of a high concentration of (14)C-BT (20 mM), and acetylsalicylic acid increased it. Chronically, none of the compounds affected uptake. Acetaldehyde, indomethacin and propionate seem to be competitive inhibitors of (14)C-BT uptake. Acetylsalicylic acid simultaneously increased the K (m) and the V (max) of (14)C-BT uptake. In conclusion, MCT1-mediated transport of (14)C-BT in Caco-2 cells is modulated by either acute or chronic exposure to some pharmacological agents and drugs of abuse (acetaldehyde, acetylsalicylic acid, indomethacin, caffeine, theophylline and the drugs of abuse tetrahydrocannabinol and MDMA).
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Affiliation(s)
- Pedro Gonçalves
- Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal
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Abstract
1. The monocarboxylate transporter (MCT, SLC16) family comprises 14 members, of which to date only MCT1-4 have been shown to carry monocarboxylates, transporting important metabolic compounds such as lactate, pyruvate and ketone bodies in a proton-coupled manner. The transport of such compounds is fundamental for metabolism, and the tissue locations, properties and regulation of these isoforms is discussed. 2. Of the other members of the MCT family, MCT8 (a thyroid hormone transporter) and TAT1 (an aromatic amino acid transporter) have been characterized more recently, and their physiological roles are reviewed herein. The endogenous substrates and functions of the remaining members of the MCT family await elucidation. 3. The MCT proteins have the typical twelve transmembrane-spanning domain (TMD) topology of membrane transporter proteins, and their structure-function relationship is discussed, especially in relation to the future impact of the single nucleotide polymorphism (SNP) databases and, given their ability to transport pharmacologically relevant compounds, the potential impact for pharmacogenomics.
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Affiliation(s)
- D Meredith
- School of Life Sciences, Oxford Brookes University, Headington, Oxford, UK.
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18
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Schultz M, Lindström AL. Rationale for probiotic treatment strategies in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2008; 2:337-55. [PMID: 19072384 DOI: 10.1586/17474124.2.3.337] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chronic inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are recurrent and aggressive inflammatory disorders that are most likely the result of an overly aggressive immune response to ubiquitous intestinal antigens in a genetically susceptible host. Despite decades of intense research, our knowledge of factors causing IBD remains incomplete and, therefore, conventional therapy to induce and maintain remission works in a symptomatic fashion, merely suppressing the immune response. Probiotic bacteria have long been known to confer health benefits, especially with regard to intestinal disorders. Although there is mounting evidence from in vitro and animal experiments supporting the use of probiotics in IBD, clinical trials have not provided definite evidence for the therapeutic effect of probiotic therapy in IBD to date. This is with the notable exception of pouchitis and the maintenance of remission in ulcerative colitis, whereas Crohn's disease and active ulcerative colitis do not seem amenable to probiotic intervention. The next 5 years will see more trials targeting specific clinical settings using tailor-made probiotic combinations, taking into account our increasing knowledge of individual probiotic properties and the diversity of these microorganisms.
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Affiliation(s)
- Michael Schultz
- Department of Medical and Surgical Sciences, Medicine Section, University of Otago Medical School, PO Box 913, Dunedin, New Zealand.
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Borthakur A, Saksena S, Gill RK, Alrefai WA, Ramaswamy K, Dudeja PK. Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: involvement of NF-kappaB pathway. J Cell Biochem 2008; 103:1452-63. [PMID: 17786924 PMCID: PMC2673490 DOI: 10.1002/jcb.21532] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Butyrate, a short chain fatty acid (SCFA) produced by bacterial fermentation of undigested carbohydrates in the colon, constitutes the major fuel for colonocytes. We have earlier shown the role of apically localized monocarboxylate transporter isoform 1 (MCT1) in transport of butyrate into human colonic Caco-2 cells. In an effort to study the regulation of MCT1 gene, we and others have cloned the promoter region of the MCT1 gene and identified cis elements for key transcription factors. A previous study has shown up-regulation of MCT1 expression, and activity by butyrate in AA/C1 human colonic epithelial cells, however, the detailed mechanisms of this up-regulation are not known. In this study, we demonstrate that butyrate, a substrate for MCT1, stimulates MCT1 promoter activity in Caco-2 cells. This effect was dose dependent and specific to butyrate as other predominant SCFAs, acetate, and propionate, were ineffective. Utilizing progressive deletion constructs of the MCT1 promoter, we showed that the putative butyrate responsive elements are in the -229/+91 region of the promoter. Butyrate stimulation of the MCT1 promoter was found to be independent of PKC, PKA, and tyrosine kinases. However, specific inhibitors of the NF-kappaB pathway, lactacystein (LC), and caffeic acid phenyl ester (CAPE) significantly reduced the MCT1 promoter stimulation by butyrate. Also, butyrate directly stimulated NF-kappaB-dependent luciferase reporter activity. Histone deacetylase (HDAC) inhibitor trichostatin A (TSA) also stimulated MCT1 promoter activity, however, unlike butyrate, this stimulation was unaltered by the NF-kappaB inhibitors. Further, the combined effect of butyrate, and TSA on MCT1 promoter activity was additive, indicating that their mechanisms of action were independent. Our results demonstrate the involvement of NF-kappaB pathway in the regulation of MCT1 promoter activity by butyrate.
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Affiliation(s)
- Alip Borthakur
- Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois 60612
| | - Seema Saksena
- Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois 60612
| | - Ravinder K. Gill
- Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois 60612
| | - Waddah A. Alrefai
- Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois 60612
| | - Krishnamurthy Ramaswamy
- Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois 60612
| | - Pradeep K. Dudeja
- Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois 60612
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Young VB, Schmidt TM. Overview of the gastrointestinal microbiota. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2008; 635:29-40. [PMID: 18841701 PMCID: PMC4460826 DOI: 10.1007/978-0-387-09550-9_3] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The community of microbes that inhabits the mammalian intestinal tract exists in a symbiosis with their host. The structure of this community represents the combined effects of selection pressure on the part of the host and on the part of the microbes themselves. Through recent advances in the field of microbial ecology we are beginning to understand the forces that shape this complex community. We will review what is known about the interaction between the host and the indigenous microbial community. Following this discussion we will introduce methods that have been used to study the structure, function and dynamics of this community.
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Affiliation(s)
- Vincent B Young
- Department of Medicine, Division of Infectious Diseases, The University of Michigan, Ann Arbor, Michigan 48109, USA.
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Manolakopoulos S, Bethanis S, Liapi C, Stripeli F, Sklavos P, Margeli A, Christidou A, Katsanika A, Vogiatzakis E, Tzourmakliotis D, Theocharis S. An assessment of serum leptin levels in patients with chronic viral hepatitis: a prospective study. BMC Gastroenterol 2007; 7:17. [PMID: 17540037 PMCID: PMC1894974 DOI: 10.1186/1471-230x-7-17] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2007] [Accepted: 05/31/2007] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The role of leptin in the course of liver disease due to chronic viral hepatitis (CVH) remains controversial. Our aims were to investigate the relationship between serum leptin concentrations and the severity of liver disease in a cohort of subjects with HBeAg negative chronic hepatitis B (CHB) and C (CHC) and to analyze the effect of body composition, the leptin system and insulin resistance together with viral factors on virologic response to antiviral treatment. METHODS We studied 50 (36 men) consecutive patients suffering from biopsy-proven CVH due to HBV (n = 25) or HCV (n = 25) infection. Thirty-two (17 men) healthy volunteers served as controls. Levels of serum leptin and insulin were determined by immunoassays at baseline and at the end of the treatment. RESULTS A significant association between serum leptin levels and the stage of hepatic fibrosis was noted; patients with cirrhosis presented higher serum leptin levels compared to those with lower fibrosis stage [CHB patients (17436 pg/ml vs 6028.5 pg/ml, p = 0.03), CHC patients (18014 pg/ml vs 4385 pg/ml, p = 0.05]. An inverse correlation between lower leptin levels and response to lamivudine monotherapy was noted in patients with CHB; those with a virologic response presented lower serum leptin levels (5334 vs 13111.5 pg/ml; p-value = 0.003) than non-responders. In genotype 1 CHC patients, insulin resistance played a significant role in the response to antiviral therapy. CONCLUSION Our data clearly suggest that cirrhosis due to CHB or CHC is associated with higher leptin levels. Increased serum leptin levels represent a negative prognostic factor for response to lamivudine monotherapy in patients with CHB. In CHC patients insulin resistance strongly influences the response to antiviral treatment in patients infected with genotype 1.
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Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: A study with relevance to inflammatory bowel disease. World J Gastroenterol 2007; 13:2826-32. [PMID: 17569118 PMCID: PMC4395634 DOI: 10.3748/wjg.v13.i20.2826] [Citation(s) in RCA: 614] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the anti-inflammatory properties of butyrate with two other SCFAs, namely acetate and propionate, which have less well-documented effects on inflammation.
METHODS: The effect of SCFAs on cytokine release from human neutrophils was studied with ELISA. SCFA-dependent modulation of NF-κB reporter activity was assessed in the human colon adenocarcinoma cell line, Colo320DM. Finally, the effect of SCFAs on gene expression and cytokine release, measured with RT-PCR and ELISA, respectively, was studied in mouse colon organ cultures established from colitic mice.
RESULTS: Acetate, propionate and butyrate at 30 mmol/L decreased LPS-stimulated TNFα release from neutrophils, without affecting IL-8 protein release. All SCFAs dose dependently inhibited NF-κB reporter activity in Colo320DM cells. Propionate dose-dependently suppressed IL-6 mRNA and protein release from colon organ cultures and comparative studies revealed that propionate and butyrate at 30 mmol/L caused a strong inhibition of immune-related gene expression, whereas acetate was less effective. A similar inhibition was achieved with the proteasome inhibitor MG-132, but not the p38 MAPK inhibitor SB203580. All SCFAs decreased IL-6 protein release from organ cultures.
CONCLUSION: In the present study propionate and butyrate were equipotent, whereas acetate was less effective, at suppressing NF-κB reporter activity, immune-related gene expression and cytokine release in vitro. Our findings suggest that propionate and acetate, in addition to butyrate, could be useful in the treatment of inflammatory disorders, including IBD.
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Affiliation(s)
- Sofia Tedelind
- Department of Molecular Pharmacology, AstraZeneca R&D Molndal, SE-431 83 Molndal, Sweden
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23
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Abstract
Apoptosis of keratinocytes is a key mechanism required for epidermal homeostasis and the renewal of damaged cells. Its dysregulation has been implicated in many skin diseases including cancer and hyperproliferative disorders. In the present study, the effect of sodium butyrate, a histone deacetylase inhibitor, on keratinocyte apoptosis was investigated using the HaCaT human keratinocyte cell line. Sodium butyrate induced morphological changes associated with apoptosis and nuclear fragmentation of HaCaTs. Annexin V staining demonstrated that sodium butyrate induced apoptosis in a dose and time-dependent manner with 50% of HaCaTs apoptotic after exposure to 0.8 mg/ml sodium butyrate for 24 h. Apoptosis was associated with upregulation of cell surface expression of the death receptor Fas and activation of the extrinsic caspase pathway, with induction of caspase 8 activity peaking after 8 h. Caspase 3 activity peaked after 24 h and was associated with cleavage of the caspase 3 substrate, poly (ADP-ribose) polymerase (PARP). The intrinsic caspase pathway was not activated as caspase 9 activity was not detected, and there was no change in the expression of terminal differentiation markers keratin 10 and involucrin following sodium butyrate treatment. Together these results indicate that sodium butyrate is a potent inducer of Fas associated apoptosis via caspase activation in HaCaT keratinocytes, an effect that is independent of the induction of terminal differentiation.
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Affiliation(s)
- Ilse S Daehn
- Child Health Research Institute, Women's and Children's Hospital, North Adelaide, SA, Australia
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Iwanaga T, Takebe K, Kato I, Karaki SI, Kuwahara A. Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8. Biomed Res 2007; 27:243-54. [PMID: 17099289 DOI: 10.2220/biomedres.27.243] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Short-chain fatty acids (SCFA) are monocarboxylates produced by bacterial fermentation that play a crucial role in maintaining homeostasis in the large intestine. Two major transporters for SCFA, monocarboxylate transporter (MCT) and slc5a8 (or SMCT), exist in the digestive tract. The present histochemical study using in situ hybridization and immunohistochemistry revealed the distribution and subcellular localization of the MCT family in the digestive tract of mice, rats, and humans, comparing these with that of slc5a8. The expression of mucosal MCT1 in the mouse and rat was most intense in the cecum, followed by the colon, but low in the stomach and small intestine. Among other MCT subtypes, only MCT2 was detected in the parietal cell region of the gastric mucosa. Slc5a8 had predominant expression sites in the distal half of the large bowel and in the most terminal ileum. The mucosal MCT1 was localized in the basolateral membrane of enterocytes, while slc5a8 was restricted to the apical cell membrane, suggesting the involvement of slc5a8 in the uptake of luminal SCFA, and of MCT1 in the efflux of SCFA and monocarboxylate metabolites towards blood circulation. The large intestine expressed both types of the transporter, but their distribution patterns differed along the longitudinal axis of the intestine and along the perpendicular axis of the mucosa.
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Affiliation(s)
- Toshihiko Iwanaga
- Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
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Zeissig S, Fromm A, Mankertz J, Weiske J, Zeitz M, Fromm M, Schulzke JD. Butyrate induces intestinal sodium absorption via Sp3-mediated transcriptional up-regulation of epithelial sodium channels. Gastroenterology 2007; 132:236-48. [PMID: 17241874 DOI: 10.1053/j.gastro.2006.10.033] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2006] [Accepted: 10/05/2006] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS The epithelial sodium channel (ENaC) is the rate-limiting factor for colonic electrogenic sodium absorption. This study aimed to investigate ENaC regulation by butyrate, a short-chain fatty acid (SCFA) produced by intestinal bacteria. METHODS ENaC was examined in HT-29/B6 cells and glucocorticoid receptor(GR)-transfected HT-29/B6 cells (HT-29/B6-GR) by reverse-transcription polymerase chain reaction, real-time polymerase chain reaction, and confocal microscopy. ENaC promoters were investigated by deletion/mutation analysis, electrophoretic mobility shift assays, and quantitative chromatin immunoprecipitation. Sodium transport of HT-29/B6-GR cells and rat distal colon was quantified in Ussing chambers. RESULTS Butyrate up-regulated beta- and gamma-ENaC mRNA expression in HT-29/B6 cells and induced transcription from beta- and gamma-ENaC promoter constructs. The gamma-ENaC promoter could also be induced by the SCFA propionate but not by acetate. Deletion/mutation assays revealed that activation of the gamma-ENaC promoter depended on 2 GC boxes, which were shown to bind Sp1 and Sp3 in vitro. Although both transcription factors increased butyrate-mediated gamma-ENaC transcription upon overexpression, chromatin immunoprecipitation revealed that only Sp3 binds to the gamma-ENaC promoter in vivo and that Sp3 binding is enhanced by butyrate. Transcriptional ENaC induction by butyrate led to synthesis of gamma-ENaC subunits, but correct targeting of ENaC channels to the apical cell membrane was dependent on corticosteroid hormones. Finally, butyrate substantially increased electrogenic sodium absorption via ENaC in the presence of corticosteroid hormones in HT-29/B6-GR cells and in rat distal colon. CONCLUSIONS Concerted action of SCFA and corticosteroid hormones is required for induction of ENaC and maintenance of intestinal electrogenic sodium absorption.
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Affiliation(s)
- Sebastian Zeissig
- Department of Gastroenterology, Infectious Diseases, and Rheumatology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
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Blachier F, Mariotti F, Huneau JF, Tomé D. Effects of amino acid-derived luminal metabolites on the colonic epithelium and physiopathological consequences. Amino Acids 2006; 33:547-62. [PMID: 17146590 DOI: 10.1007/s00726-006-0477-9] [Citation(s) in RCA: 320] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2006] [Accepted: 11/09/2006] [Indexed: 02/07/2023]
Abstract
Depending on the amount of alimentary proteins, between 6 and 18 g nitrogenous material per day enter the large intestine lumen through the ileocaecal junction. This material is used as substrates by the flora resulting eventually in the presence of a complex mixture of metabolites including ammonia, hydrogen sulfide, short and branched-chain fatty acids, amines; phenolic, indolic and N-nitroso compounds. The beneficial versus deleterious effects of these compounds on the colonic epithelium depend on parameters such as their luminal concentrations, the duration of the colonic stasis, the detoxication capacity of epithelial cells in response to increase of metabolite concentrations, the cellular metabolic utilization of these metabolites as well as their effects on colonocyte intermediary and oxidative metabolism. Furthermore, the effects of metabolites on electrolyte movements through the colonic epithelium must as well be taken into consideration for such an evaluation. The situation is further complicated by the fact that other non-nitrogenous compounds are believed to interfere with these various phenomenons. Finally, the pathological consequences of the presence of excessive concentrations of these compounds are related to the short- and, most important, long-term effects of these compounds on the rapid colonic epithelium renewing and homeostasis.
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Affiliation(s)
- F Blachier
- Unité Mixte de Recherche de Physiologie de la Nutrition et du Comportement Alimentaire, Institut National de la Recherche Agronomique - Institut National Agronomique Paris-Grignon, Paris, France.
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Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci 2006; 78:2419-25. [PMID: 16375929 DOI: 10.1016/j.lfs.2005.10.028] [Citation(s) in RCA: 146] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2005] [Accepted: 10/06/2005] [Indexed: 12/23/2022]
Abstract
The identification of SLC5A8 as a tumor suppressor gene in colorectal cancer marks, for the first time, the association of a plasma membrane transporter with tumor suppressive properties. The subsequent establishment of the functional identity of SLC5A8 as a Na+-coupled transporter for short-chain monocarboxylates provides a mechanism for the tumor suppressive function of the transporter. Butyrate, a substrate for the transporter, is a histone deacetylase inhibitor and protective against colorectal cancer. This fatty acid is produced in the colonic lumen by bacterial fermentation of dietary fiber. SLC5A8 mediates the concentrative entry of butyrate from the lumen into colonocytes. Consequently, the transport function of SLC5A8 has the ability to influence the acetylation status of histones and hence gene expression in colonocytes. The ability of SLC5A8 to deliver butyrate into colonic epithelial cells most likely underlies the tumor suppressive role of this transporter.
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Affiliation(s)
- Naren Gupta
- Department of Biochemistry, Medical College of Georgia, Augusta, GA 30912, USA
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Zhou J, Hegsted M, McCutcheon KL, Keenan MJ, Xi X, Raggio AM, Martin RJ. Peptide YY and proglucagon mRNA expression patterns and regulation in the gut. Obesity (Silver Spring) 2006; 14:683-9. [PMID: 16741270 DOI: 10.1038/oby.2006.77] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Peptide YY (PYY) and glucagon-like peptide-1 are important in the control of energy homeostasis and are both secreted from the gut in response to ingested nutrients. However, more studies are needed on nutrient regulation of their gene expression patterns in specific areas of the gut. This study detailed PYY and proglucagon (the gene that encodes glucagon-like peptide-1) gene expression patterns and regulation in the gut. We further examined the regulation of PYY and proglucagon mRNA by a diet containing fermentation-resistant starch (in vivo) and butyrate (in vitro). RESEARCH METHODS AND PROCEDURES Quantitative real time reverse transcriptase-polymerase chain reaction was used to measure PYY and proglucagon gene expression in epithelial cells collected from the duodenum, jejunum, cecum, and colon in normal Sprague-Dawley rats and in rats fed a resistant starch diet for 4 weeks. The same measurements were also performed in primary epithelial cells collected from the cecum and colon of normal rats after the cells were incubated with butyrate for 3 hours. RESULTS The gene expression patterns for PYY and proglucagon are similar to their peptide distribution patterns in the gut. Also, PYY and proglucagon mRNA expression were up-regulated in the cecum and colon in resistant-starch-fed rats. Butyrate increased PYY and proglucagon gene expression in a dose-dependent manner in vitro. DISCUSSION Our data provide evidence that the distal part of the gut has the ability to sense nutrients such as butyrate, resulting in the up-regulation of PYY and proglucagon gene expression.
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Affiliation(s)
- Jun Zhou
- Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
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Manderson K, Pinart M, Tuohy KM, Grace WE, Hotchkiss AT, Widmer W, Yadhav MP, Gibson GR, Rastall RA. In vitro determination of prebiotic properties of oligosaccharides derived from an orange juice manufacturing by-product stream. Appl Environ Microbiol 2006; 71:8383-9. [PMID: 16332825 PMCID: PMC1317361 DOI: 10.1128/aem.71.12.8383-8389.2005] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Fermentation properties of oligosaccharides derived from orange peel pectin were assessed in mixed fecal bacterial culture. The orange peel oligosaccharide fraction contained glucose in addition to rhamnogalacturonan and xylogalacturonan pectic oligosaccharides. Twenty-four-hour, temperature- and pH-controlled, stirred anaerobic fecal batch cultures were used to determine the effects that oligosaccharides derived from orange products had on the composition of the fecal microbiota. The effects were measured through fluorescent in situ hybridization to determine changes in bacterial populations, fermentation end products were analyzed by high-performance liquid chromatography to assess short-chain fatty acid concentrations, and subsequently, a prebiotic index (PI) was determined. Pectic oligosaccharides (POS) were able to increase the bifidobacterial and Eubacterium rectale numbers, albeit resulting in a lower prebiotic index than that from fructo-oligosaccharide metabolism. Orange albedo maintained the growth of most bacterial populations and gave a PI similar to that of soluble starch. Fermentation of POS resulted in an increase in the Eubacterium rectale numbers and concomitantly increased butyrate production. In conclusion, this study has shown that POS can have a beneficial effect on the fecal microflora; however, a classical prebiotic effect was not found. An increase in the Eubacterium rectale population was found, and butyrate levels increased, which is of potential benefit to the host.
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Affiliation(s)
- K Manderson
- School of Food Biosciences, The University of Reading, P.O. Box 226, Whiteknights, Reading RG6 6AP, United Kingdom.
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Hadjiagapiou C, Borthakur A, Dahdal RY, Gill RK, Malakooti J, Ramaswamy K, Dudeja PK. Role of USF1 and USF2 as potential repressor proteins for human intestinal monocarboxylate transporter 1 promoter. Am J Physiol Gastrointest Liver Physiol 2005; 288:G1118-26. [PMID: 15691871 DOI: 10.1152/ajpgi.00312.2004] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Butyrate, a short-chain fatty acid, is the major energy fuel for the colonocytes. We have previously reported that monocarboxylate transporter isoform 1 (MCT1) mediates uptake of butyrate by human colonic Caco-2 cells. To better understand the mechanisms of MCT1 expression and regulation in the human intestine, we examined the activity and regulation of MCT1 promoter in Caco-2 cells. The transcription initiation site in the MCT1 promoter was identified as a guanine nucleotide 281 bp upstream from the translation initiation site and is surrounded by a guanine-cytosine-rich area. The promoter was found to be highly active when transfected into Caco-2 cells, and its activity decreased with deletions at its 5'-end. Gel mobility shift experiments showed binding of the transcription factors upstream stimulatory factor (USF)1 and 2 to the site -114 to -119 of the MCT1 promoter. With the use of site-directed mutagenesis and promoter activity in Caco-2 cells, the USF proteins appeared to have a repressor role on the MCT1 promoter, which was further confirmed by cotransfecting expression vectors encoding USF1 and 2 in Caco-2 cells and determining endogenous MCT1 expression in USF2 overexpressed cells. The two potential SP1 binding sites found in the same region of the promoter were found not to be involved in its regulation.
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Affiliation(s)
- Christos Hadjiagapiou
- Univ. of Illinois at Chicago, Medical Research Service (600/151 Jesse Brown VA Medical Center, 820 South Damen Ave., Chicago, IL 60612, USA
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