雌激素及其受体在非酒精性脂肪性肝病发生发展中的作用机制

彭娟; 李良平

doi:10.3969/j.issn.1001-5256.2021.02.046

雌激素及其受体在非酒精性脂肪性肝病发生发展中的作用机制

DOI: 10.3969/j.issn.1001-5256.2021.02.046

彭娟¹,
李良平^2, ,

1.
川北医学院消化内科，四川南充 637000
2.
四川省医学科学院·四川省人民医院消化内科，成都 610072

基金项目:

四川省卫计委重点课题 (16ZD024)

作者贡献声明：彭娟负责收集、阅读、筛选文献，撰写论文；李良平负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
彭娟(1995—)，女，主要从事非酒精性脂肪性肝病研究

通信作者:
李良平，18981838872@163.com

中图分类号: R575.5
计量
- 文章访问数: 734
- HTML全文浏览量: 195
- PDF下载量: 46
- 被引次数: 0
出版历程
- 收稿日期: 2020-07-08
- 录用日期: 2020-08-18
- 出版日期: 2021-02-20

Mechanism of action of estrogen and its receptor in the development and progression of nonalcoholic fatty liver disease

Juan PENG¹,
Liangping LI^{2
, ,}

1.
Department of Gastroenterology, Chuanbei Medical College, Nanchong, Sichuan 637000, China
2.
Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China

摘要

摘要: 非酒精性脂肪性肝病(NAFLD)的发病率剧增，目前仍然缺乏有效的药物治疗。虽然对NAFLD发病相关机制研究取得了巨大进展，但对NAFLD的性别差异的理解依然不够。雌激素作为重要的性激素，通过调节情绪及能量稳态、脂肪组织功能及分布、炎症反应、胰岛素抵抗、肝脂蓄积、肝脏免疫等影响NAFLD的发生及发展。充分认识雌激素及雌激素受体在NAFLD中的作用机制，为NAFLD的治疗提供新思路。
- 非酒精性脂肪性肝病 /
- 雌激素类 /
- 受体, 雌激素
Abstract: The incidence rate of nonalcoholic fatty liver disease (NAFLD) has increased sharply, and there is still a lack of effective pharmacotherapy at present. Although great achievements have been made in the research on the pathogenesis of NAFLD, we still do not know enough about the gender differences of NAFLD. As an important sex hormone, estrogen affects the development and progression of NAFLD by regulating mood and energy homeostasis, adipose tissue function and distribution, inflammatory response, insulin resistance, liver fat accumulation, and liver immunity. An adequate understanding of the mechanism of action of estrogen and its receptor in NAFLD may provide new ideas for the treatment of NAFLD.
- Non-alcoholic Fatty Liver Disease /
- Estrogens /
- Receptors, Estrogen

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参考文献(45)

[1]	SEEBACHER F, ZEIGERER A, KORY N, et al. Hepatic lipid droplet homeostasis and fatty liver disease[J]. Semin Cell Dev Biol, 2020. [Epub ahead of print]
[2]	TOBARI M, HASHIMOTO E. Characteristic features of nonalcoholic fatty liver disease in japan with a focus on the roles of age, sex and body mass index[J]. Gut Liver, 2020.[Epub ahead of print]
[3]	SAYINER M, YOUNOSSI ZM. Nonalcoholic steatohepatitis is becoming a top indication for liver transplantation worldwide[J]. Liver Transpl, 2019, 25(1): 10-11. DOI: 10.1002/lt.25387
[4]	YANG Z, FU BS. Research status of liver transplantation in the treatment of non-alcoholic fatty liver disease[J]. Ogran Transplantation, 2020, 11(3): 419-423. (in Chinese) DOI: 10.3969/j.issn.1674-7445.2020.03.017 杨洲, 傅斌生. 肝移植治疗非酒精性脂肪性肝病的研究现状[J]. 器官移植, 2020, 11(3): 419-423. DOI: 10.3969/j.issn.1674-7445.2020.03.017
[5]	JIANG YZ, NIE HM, WANG R. Research advances in the pathogenesis of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2019, 35(11): 2588-2591.(in Chinese) DOI: 10.3969/j.issn.1001-5256.2019.11.044 姜煜资, 聂红明, 汪蓉. 非酒精性脂肪性肝病的发病机制[J]. 临床肝胆病杂志, 2019, 35(11): 2588-2591. DOI: 10.3969/j.issn.1001-5256.2019.11.044
[6]	LONARDO A, NASCIMBENI F, BALLESTRI S, et al. Sex differences in nonalcoholic fatty liver disease: State of the art and identification of research gaps[J]. Hepatology, 2019, 70(4): 1457-1469. DOI: 10.1002/hep.30626
[7]	LEE, C, KIM J, JUNG Y. Potential therapeutic application of estrogen in gender disparity of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J]. Cells, 2019, 8(10): 1259. DOI: 10.3390/cells8101259
[8]	ESTRADA CM, GHISAYS V, NGUYEN ET, et al. Estrogen signaling in the medial amygdala decreases emotional stress responses and obesity in ovariectomized rats[J]. Horm Behav, 2018, 98: 33-44. DOI: 10.1016/j.yhbeh.2017.12.002
[9]	QIU S, VAZQUEZ JT, BOULGER E, et al. Hepatic estrogen receptor α is critical for regulation of gluconeogenesis and lipid metabolism in males[J]. Sci Rep, 2017, 7(1): 1661. DOI: 10.1038/s41598-017-01937-4
[10]	VANDEL J, DUBOIS-CHEVALIER J, GHEERAERT C, et al. Hepatic molecular signatures highlight the sexual dimorphism of Non-Alcoholic SteatoHepatitis (NASH)[J]. Hepatology, 2020.[Epub ahead of print]
[11]	GROSSMANN M, WIERMAN ME, ANGUS P, et al. Reproductive endocrinology of nonalcoholic fatty liver disease[J]. Endocr Rev, 2019, 40(2): 417-446. DOI: 10.1210/er.2018-00158
[12]	HART-UNGER S, ARAO Y, HAMILTON KJ, et al. Hormone signaling and fatty liver in females: Analysis of estrogen receptor α mutant mice[J]. Int J Obes (Lond), 2017, 41(6): 945-954. DOI: 10.1038/ijo.2017.50
[13]	ASCHA MS, HANOUNEH IA, LOPEZ R, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis[J]. Hepatology, 2010, 51(6): 1972-1978. DOI: 10.1002/hep.23527
[14]	PALMISANO BT, ZHU L, STAFFORD JM. Role of estrogens in the regulation of liver lipid metabolism[J]. Adv Exp Med Biol, 2017, 1043: 227-256. DOI: 10.1007%2F978-3-319-70178-3_12
[15]	WINN NC, JURRISSEN TJ, GRUNEWALD ZI, et al. Estrogen receptor-α signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver[J]. Am J Physiol Endocrinol Metab, 2019, 316(2): e156-e167. DOI: 10.1152/ajpendo.00259.2018
[16]	WANG X, LU Y, WANG E, et al. Hepatic estrogen receptor α improves hepatosteatosis through upregulation of small heterodimer partner[J]. J Hepatol, 2015, 63(1): 183-190. DOI: 10.1016/j.jhep.2015.02.029
[17]	GUILLAUME M, RIANT E, FABRE A, et al. Selective liver estrogen receptor α modulation prevents steatosis, diabetes, and obesity through the anorectic growth differentiation factor 15 hepatokine in mice[J]. Hepatol Commun, 2019, 3(7): 908-924. DOI: 10.1002/hep4.1363
[18]	ZHANG B, ZHANG CG, JI LH, et al. Estrogen receptor β selective agonist ameliorates liver cirrhosis in rats by inhibiting the activation and proliferation of hepatic stellate cells[J]. J Gastroenterol Hepatol, 2018, 33(3): 747-755. DOI: 10.1111/jgh.13976
[19]	MAUVAIS-JARVIS F, ARNOLD AP, REUE K. A guide for the design of pre-clinical studies on sex differences in metabolism[J]. Cell Metab, 2017, 25(6): 1216-1230. DOI: 10.1016/j.cmet.2017.04.033
[20]	XU Y, NEDUNGADI TP, ZHU L, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction[J]. Cell Metab, 2011, 14(4): 453-465. DOI: 10.1016/j.cmet.2011.08.009
[21]	GONZÁIEZ-GARCÍA I, CONTRERAS C, ESTÉVEZ-SALGUERO Á, et al. Estradiol regulates energy balance by ameliorating hypothalamic ceramide-induced ER stress[J]. Cell Rep, 2018, 25(2): 413-423. e5. DOI: 10.1016/j.celrep.2018.09.038
[22]	BOLDARINE VT, PEDROSO AP, NETO N, et al. High-Fat diet intake induces depressive-like behavior in ovariectomized rats[J]. Sci Rep, 2019, 9(1): 10551. DOI: 10.1038/s41598-019-47152-1
[23]	ESTRADA CM, GHISAYS V, NGUYEN ET, et al. Estrogen signaling in the medial amygdala decreases emotional stress responses and obesity in ovariectomized rats[J]. Horm Behav, 2018, 98: 33-44. DOI: 10.1016/j.yhbeh.2017.12.002
[24]	GERDTS E, REGITZ-ZAGROSEK V. Sex differences in cardiometabolic disorders[J]. Nat Med, 2019, 25(11): 1657-1666. DOI: 10.1038/s41591-019-0643-8
[25]	FAULKNER JL, BELIN DE CHANTEMÈLE EJ. Sex hormones, aging and cardiometabolic syndrome[J]. Biol Sex Differ, 2019, 10(1): 30. DOI: 10.1186/s13293-019-0246-6
[26]	LINK JC, REUE K. Genetic basis for sex differences in obesity and lipid metabolism[J]. Annu Rev Nutr, 2017, 37: 225-245. DOI: 10.1146/annurev-nutr-071816-064827
[27]	KLEIN SL, MARRIOTT L, FISH EN. Sex-based differences in immune function and responses to vaccination[J]. Trans R Soc Trop Med Hyg, 2015, 109(1): 9-15. DOI: 10.1093/trstmh/tru167
[28]	KLEIN SL, MORGAN R. The impact of sex and gender on immunotherapy outcomes[J]. Biol Sex Differ, 2020, 11(1): 24. DOI: 10.1186/s13293-020-00301-y
[29]	MAUVAIS-JARVIS F, MANSON JE, STEVENSON JC, et al. Menopausal hormone therapy and type 2 diabetes prevention: Evidence, mechanisms, and clinical implications[J]. Endocr Rev, 2017, 38(3): 173-188. DOI: 10.1210/er.2016-1146
[30]	CHEN JQ, CAMMARATA PR, BAINES CP, et al. Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications[J]. Biochim Biophys Acta, 2009, 1793(10): 1540-1570. DOI: 10.1016/j.bbamcr.2009.06.001
[31]	GALMÉS-PASCUAL BM, MARTÍNEZ-CIGNONI MR, MORÁN-COSTOYA A, et al. 17β-estradiol ameliorates lipotoxicity-induced hepatic mitochondrial oxidative stress and insulin resistance[J]. Free Radic Biol Med, 2020, 150: 148-160. DOI: 10.1016/j.freeradbiomed.2020.02.016
[32]	LIU S, MAUVAIS-JARVIS F. Minireview: Estrogenic protection of beta-cell failure in metabolic diseases[J]. Endocrinology, 2010, 151(3): 859-864. DOI: 10.1210/en.2009-1107
[33]	de BANDT JP, JEGATHEESAN P, TENNOUNE-EI-HAFAIA N. Muscle loss in chronic liver diseases: The example of nonalcoholic liver disease[J]. Nutrients, 2018, 10(9): 1195. DOI: 10.3390/nu10091195
[34]	YU J, MARSH S, HU J, et al. The pathogenesis of nonalcoholic fatty liver disease: Interplay between diet, gut microbiota, and genetic background[J]. Gastroenterol Res Pract, 2016, 2016: 2862173. http://downloads.hindawi.com/journals/grp/2016/2862173.xml
[35]	CHOUDHARY NS, KUMAR N, DUSEJA A. Peroxisome proliferator-activated receptors and their agonists in nonalcoholic fatty liver disease[J]. J Clin Exp Hepatol, 2019, 9(6): 731-739. DOI: 10.1016/j.jceh.2019.06.004
[36]	VIDELA LA, PETTINELLI P. Misregulation of PPAR functioning and its pathogenic consequences associated with nonalcoholic fatty liver disease in human obesity[J]. PPAR Res, 2012, 2012: 107434. http://www.ncbi.nlm.nih.gov/pubmed/23304111
[37]	VACCA M, ALLISON M, GRIFFIN JL, et al. Fatty acid and glucose sensors in hepatic lipid metabolism: Implications in NAFLD[J]. Semin Liver Dis, 2015, 35(3): 250-261. DOI: 10.1055/s-0035-1562945
[38]	KLEINERT M, CLEMMENSEN C, HOFMANN SM, et al. Animal models of obesity and diabetes mellitus[J]. Nat Rev Endocrinol, 2018, 14(3): 140-162. DOI: 10.1038/nrendo.2017.161
[39]	LI FJ, WEI SN, WANG LY, et al. Estrogen reduces lipid deposition in liver cells by inhibiting Perilipin 2[J]. J Cardiovascular Pulmonary Dis, 2018, 37(7): 687-691. (in Chinese) DOI: 10.3969/j.issn.1007-5062.2018.07.022 李凤娟, 魏苏宁, 王绿娅, 等. 雌激素抑制脂滴包被蛋白Perilipin2减少肝细胞脂质沉积[J]. 心肺血管病杂志, 2018, 37(7): 687-691. DOI: 10.3969/j.issn.1007-5062.2018.07.022
[40]	BARB D, BRIL F, KALAVALAPALLI S, et al. Plasma fibroblast growth factor 21 is associated with severity of nonalcoholic steatohepatitis in patients with obesity and type 2 diabetes[J]. J Clin Endocrinol Metab, 2019, 104(8): 3327-3336. DOI: 10.1210/jc.2018-02414
[41]	ALISI A, CECCARELLI S, PANERA N, et al. Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease[J]. Plos One, 2013, 8(6): e67160. DOI: 10.1371/journal.pone.0067160
[42]	SANTOS-MARCOS JA, HARO C, VEGA-ROJAS A, et al. Sex differences in the gut microbiota as potential determinants of gender predisposition to disease[J]. Mol Nutr Food Res, 2019, 63(7): e1800870. DOI: 10.1002/mnfr.201800870
[43]	SANTOS-MARCOS JA, RANGEL-ZUÑIGA OA, JIMENEZ-LUCENA R, et al. Influence of gender and menopausal status on gut microbiota[J]. Maturitas, 2018, 116: 43-53. DOI: 10.1016/j.maturitas.2018.07.008
[44]	ACHARYA KD, GAO X, BLESS EP, et al. Estradiol and high fat diet associate with changes in gut microbiota in female ob/ob mice[J]. Sci Rep, 2019, 9(1): 20192. DOI: 10.1038/s41598-019-56723-1
[45]	GANZ M, CSAK T, SZABO G. High fat diet feeding results in gender specific steatohepatitis and inflammasome activation[J]. World J Gastroenterol, 2014, 20(26): 8525-8534. DOI: 10.3748/wjg.v20.i26.8525