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胆汁酸受体TGR5介导的糖脂代谢在非酒精性脂肪性肝病中的作用

荀小霞 周铖 赵文霞

引用本文:
Citation:

胆汁酸受体TGR5介导的糖脂代谢在非酒精性脂肪性肝病中的作用

DOI: 10.3969/j.issn.1001-5256.2023.01.025
基金项目: 

国家自然科学基金面上项目 (81473651)

河南省中医药科学研究专项课题 (2018JDZX005)

河南省中医药科学研究专项课题 (2019JDZX2051)

河南省科技攻关计划项目 (202102310495)

河南省特色骨干学科中医学学科建设项目 (STG-ZYXKY-2020024)

利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:荀小霞负责撰写论文;周铖负责修改论文;赵文霞负责指导撰写文章、修改论文并最后定稿。
详细信息
    通信作者:

    赵文霞, zhao-wenxia@163.com (ORCID: 0000-0001-9070-4703)

Role of glucose and lipid metabolism mediated by the bile acid receptor Takeda G protein-coupled receptor 5 in nonalcoholic fatty liver disease

Research funding: 

National Natural Science Foundation of China (81473651);

Traditional Chinese Medicine Science Research Project of Henan Province (2018JDZX005);

Traditional Chinese Medicine Science Research Project of Henan Province (2019JDZX2051);

Key Science and Technology Project of Henan Province (202102310495);

TCM Discipline Construction Project of Characteristic Backbone Disciplines of Henan Province (STG-ZYXKY-2020024)

More Information
  • 摘要: 非酒精性脂肪性肝病(NAFLD)逐渐成为影响人类肝脏健康的主要原因,其发生发展与代谢功能障碍相关,糖脂代谢紊乱是其中的关键环节。武田G蛋白偶联受体5(TGR5)是胆汁酸的主要受体之一,在体内广泛表达,其介导的糖脂代谢在人体发挥重要作用。本文总结了TGR5在糖脂代谢中的作用和机制,以及基于TGR5治疗NAFLD的研究成果,以期对基础和临床研究提供参考。

     

  • 图  1  TGR5调节肠道L细胞分泌GLP-1的机制

    Figure  1.  Mechanism of TGR5 regulating GLP-1 secretion by intestinal L cells

    图  2  TGR5调节胰腺β细胞分泌胰岛素的机制

    Figure  2.  Mechanism of TGR5 regulating insulin secretion by pancreatic β cells

    图  3  骨骼肌内TGR5参与调节血糖代谢的机制

    Figure  3.  Mechanism of TGR5 in skeletal muscle involved in regulating blood glucose metabolism

    图  4  脂肪组织内TGR5参与调节脂质调节的机制

    Figure  4.  Mechanism of TGR5 involved in lipid regulation in adipose tissue

  • [1] RAZA S, RAJAK S, UPADHYAY A, et al. Current treatment paradigms and emerging therapies for NAFLD/NASH[J]. Front Biosci (Landmark Ed), 2021, 26(2): 206-237. DOI: 10.2741/4892.
    [2] LOOMBA R, SANYAL AJ. The global NAFLD epidemic[J]. Nat Rev Gastroenterol Hepatol, 2013, 10(11): 686-690. DOI: 10.1038/nrgastro.2013.171.
    [3] YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64(1): 73-84. DOI: 10.1002/hep.28431.
    [4] ESLAM M, SANYAL AJ, GEORGE J, et al. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology, 2020, 158(7): 1999-2014. e1. DOI: 10.1053/j.gastro.2019.11.312.
    [5] BECHMANN LP, KOCABAYOGLU P, SOWA JP, et al. Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis[J]. Hepatology, 2013, 57(4): 1394-1406. DOI: 10.1002/hep.26225.
    [6] ZHANG Y, LI JX, WANG YL. Role of bile acid metabolism and related receptors in the development and progression of non -alcoholic fatty liver disease[J]. J Clin Hepatol, 2020, 36(6): 1374-1377. DOI: 10.3969/j.issn.1001-5256.2020.06.040.

    张阳, 李军祥, 王允亮. 胆汁酸代谢及其受体在非酒精性脂肪性肝病发生发展中的作用[J]. 临床肝胆病杂志, 2020, 36(6): 1374-1377. DOI: 10.3969/j.issn.1001-5256.2020.06.040.
    [7] ZHAO HD, YANG F, ZHAN L. Research progress on pathogenesis of non-alcoholic fatty liver disease[J]. Acad J Chinese PLA Postgrad Med Sch, 2022, 43(3): 366-371. DOI: 10.3969/j.issn.2095-5227.2022.03.022.

    赵瀚东, 杨帆, 詹丽. 非酒精性脂肪性肝病发病机制研究进展[J]. 解放军医学院学报, 2022, 43(3): 366-371. DOI: 10.3969/j.issn.2095-5227.2022.03.022.
    [8] MARUYAMA T, MIYAMOTO Y, NAKAMURA T, et al. Identification of membrane-type receptor for bile acids (M-BAR)[J]. Biochem Biophys Res Commun, 2002, 298(5): 714-719. DOI: 10.1016/s0006-291x(02)02550-0.
    [9] HOLTER MM, CHIRIKJIAN MK, GOVANI VN, et al. TGR5 signaling in hepatic metabolic health[J]. Nutrients, 2020, 12(9): 2598. DOI: 10.3390/nu12092598.
    [10] POLS TW, NORIEGA LG, NOMURA M, et al. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation[J]. J Hepatol, 2011, 54(6): 1263-1272. DOI: 10.1016/j.jhep.2010.12.004.
    [11] KUMAR DP, RAJAGOPAL S, MAHAVADI S, et al. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells[J]. Biochem Biophys Res Commun, 2012, 427(3): 600-605. DOI: 10.1016/j.bbrc.2012.09.104.
    [12] HOLTER MM, CHIRIKJIAN MK, BRIERE DA, et al. Compound 18 improves glucose tolerance in a hepatocyte TGR5-dependent manner in mice[J]. Nutrients, 2020, 12(7): 2124. DOI: 10.3390/nu12072124.
    [13] SATO H, MACCHIARULO A, THOMAS C, et al. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies[J]. J Med Chem, 2008, 51(6): 1831-1841. DOI: 10.1021/jm7015864.
    [14] NAKHI A, WONG HL, WELDY M, et al. Structural modifications that increase gut restriction of bile acid derivatives[J]. RSC Med Chem, 2021, 12(3): 394-405. DOI: 10.1039/d0md00425a.
    [15] THOMAS C, GIOIELLO A, NORIEGA L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis[J]. Cell Metab, 2009, 10(3): 167-177. DOI: 10.1016/j.cmet.2009.08.001.
    [16] CHAUDHARI SN, HARRIS DA, ALIAKBARIAN H, et al. Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects[J]. Nat Chem Biol, 2021, 17(1): 20-29. DOI: 10.1038/s41589-020-0604-z.
    [17] DRUCKER DJ. The biology of incretin hormones[J]. Cell Metab, 2006, 3(3): 153-165. DOI: 10.1016/j.cmet.2006.01.004.
    [18] PARKER HE, WALLIS K, LE ROUX CW, et al. Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion[J]. Br J Pharmacol, 2012, 165(2): 414-423. DOI: 10.1111/j.1476-5381.2011.01561.x.
    [19] BRIGHTON CA, RIEVAJ J, KUHRE RE, et al. Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors[J]. Endocrinology, 2015, 156(11): 3961-3970. DOI: 10.1210/en.2015-1321.
    [20] GOLDSPINK DA, LU VB, BILLING LJ, et al. Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells[J]. Mol Metab, 2018, 7: 90-101. DOI: 10.1016/j.molmet.2017.11.005.
    [21] VETTORAZZI JF, RIBEIRO RA, BORCK PC, et al. The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells[J]. Metabolism, 2016, 65(3): 54-63. DOI: 10.1016/j.metabol.2015.10.021.
    [22] MACZEWSKY J, KAISER J, GRESCH A, et al. TGR5 activation promotes stimulus-secretion coupling of pancreatic β-cells via a PKA-dependent pathway[J]. Diabetes, 2019, 68(2): 324-336. DOI: 10.2337/db18-0315.
    [23] SRIKANTHAN P, KARLAMANGLA AS. Relative muscle mass is inversely associated with insulin resistance and prediabetes. Findings from the third National Health and Nutrition Examination Survey[J]. J Clin Endocrinol Metab, 2011, 96(9): 2898-2903. DOI: 10.1210/jc.2011-0435.
    [24] HAN TS, AL-GINDAN YY, GOVAN L, et al. Associations of BMI, waist circumference, body fat, and skeletal muscle with type 2 diabetes in adults[J]. Acta Diabetol, 2019, 56(8): 947-954. DOI: 10.1007/s00592-019-01328-3.
    [25] SASAKI T, KUBOYAMA A, MITA M, et al. The exercise-inducible bile acid receptor Tgr5 improves skeletal muscle function in mice[J]. J Biol Chem, 2018, 293(26): 10322-10332. DOI: 10.1074/jbc.RA118.002733.
    [26] HUANG S, MA S, NING M, et al. TGR5 agonist ameliorates insulin resistance in the skeletal muscles and improves glucose homeostasis in diabetic mice[J]. Metabolism, 2019, 99: 45-56. DOI: 10.1016/j.metabol.2019.07.003.
    [27] SASAKI T, WATANABE Y, KUBOYAMA A, et al. Muscle-specific TGR5 overexpression improves glucose clearance in glucose-intolerant mice[J]. J Biol Chem, 2021, 296: 100131. DOI: 10.1074/jbc.RA120.016203.
    [28] VASSILEVA G, HU W, HOOS L, et al. Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice[J]. J Endocrinol, 2010, 205(3): 225-232. DOI: 10.1677/JOE-10-0009.
    [29] FINN PD, RODRIGUEZ D, KOHLER J, et al. Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice[J]. Am J Physiol Gastrointest Liver Physiol, 2019, 316(3): G412-G424. DOI: 10.1152/ajpgi.00300.2018.
    [30] CARINO A, CIPRIANI S, MARCHIANÒ S, et al. Gpbar1 agonism promotes a Pgc-1α-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice[J]. Sci Rep, 2017, 7(1): 13689. DOI: 10.1038/s41598-017-13102-y.
    [31] CARINO A, MARCHIANÒ S, BIAGIOLI M, et al. Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis[J]. FASEB J, 2019, 33(2): 2809-2822. DOI: 10.1096/fj.201801373RR.
    [32] BERTHOLET AM, KAZAK L, CHOUCHANI ET, et al. Mitochondrial patch clamp of beige adipocytes reveals UCP1-positive and UCP1-negative cells both exhibiting futile creatine cycling[J]. Cell Metab, 2017, 25(4): 811-822. e4. DOI: 10.1016/j.cmet.2017.03.002.
    [33] DONEPUDI AC, BOEHME S, LI F, et al. G-protein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice[J]. Hepatology, 2017, 65(3): 813-827. DOI: 10.1002/hep.28707.
    [34] PELLICCIARI R, GIOIELLO A, MACCHIARULO A, et al. Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity[J]. J Med Chem, 2009, 52(24): 7958-7961. DOI: 10.1021/jm901390p.
    [35] GENET C, STREHLE A, SCHMIDT C, et al. Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes[J]. J Med Chem, 2010, 53(1): 178-190. DOI: 10.1021/jm900872z.
    [36] HE B, JIANG J, SHI Z, et al. Pure total flavonoids from citrus attenuate non-alcoholic steatohepatitis via regulating the gut microbiota and bile acid metabolism in mice[J]. Biomed Pharmacother, 2021, 135: 111183. DOI: 10.1016/j.biopha.2020.111183.
    [37] XUE YN. Mechanism of scutellariae rhizoma coptidis on improving nonalcoholic fatty liver disease based on FXR/CYP7A1 pathway[D]. Yichang: China Three Gorges University, 2021.

    薛亚楠. 基于FXR/CYP7A1通路探究黄芩黄连药对改善非酒精性脂肪性肝病的作用机制[D]. 宜昌: 三峡大学, 2021.
    [38] ZHOU TT. Correlation between intestinal flora-cholic acid-liver metabolic axis and NAFLD and intervention effect of green brick tea[D]. Nanchang: Jiangxi University of Traditional Chinese Medicine, 2021.

    周婷婷. 肠道菌群-胆汁酸-肝代谢轴与NAFLD的相关性及青砖茶干预作用研究[D]. 南昌: 江西中医药大学, 2021.
    [39] DING L, YANG Q, ZHANG E, et al. Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice[J]. Acta Pharm Sin B, 2021, 11(6): 1541-1554. DOI: 10.1016/j.apsb.2021.03.038.
    [40] LI M, ZHOU W, DANG Y, et al. Berberine compounds improves hyperglycemia via microbiome mediated colonic TGR5-GLP pathway in db/db mice[J]. Biomed Pharmacother, 2020, 132: 110953. DOI: 10.1016/j.biopha.2020.110953.
    [41] LI T, HOLMSTROM SR, KIR S, et al. The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling[J]. Mol Endocrinol, 2011, 25(6): 1066-1071. DOI: 10.1210/me.2010-0460.
    [42] MASYUK TV, MASYUK AI, LORENZO PISARELLO M, et al. TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling[J]. Hepatology, 2017, 66(4): 1197-1218. DOI: 10.1002/hep.29284.
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  • 收稿日期:  2022-05-15
  • 录用日期:  2022-06-30
  • 出版日期:  2023-01-20
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