绿原酸抑制JNK信号通路对非酒精性脂肪性肝病的防治作用

延华; 张颖; 王欢; 高艳琼; 刘贵生; 雷建园

doi:10.3969/j.issn.1001-5256.2018.02.028

绿原酸抑制JNK信号通路对非酒精性脂肪性肝病的防治作用

DOI: 10.3969/j.issn.1001-5256.2018.02.028

1. 陕西省人民医院西院一病区
2. 陕西省人民医院超声室
3. 陕西省人民医院功能检查科
4. 陕西省人民医院消化内科
5. 陕西省人民医院病理科

基金项目:

陕西省自然科学基金(2016JM8142)；

详细信息

中图分类号: R575.5
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出版历程
- 收稿日期: 2017-08-31
- 出版日期: 2018-02-20

Chlorogenic acid exerts preventive and therapeutic effects on nonalcoholic fatty liver disease by inhibiting the JNK signaling pathway

First Disease Area, West Branch of Shaanxi Provincial People's Hospital

Research funding:

摘要

摘要:
目的非酒精性脂肪性肝病（NAFLD）与胰岛素抵抗密切相关。绿原酸（CG）能调节糖脂代谢、改善胰岛素抵抗。探讨CG在NAFLD中的作用及其可能的分子基础。方法选取30只SD大鼠,随机分为正常饮食组（NG组）、高脂饮食组（HG组）和绿原酸干预组（CG组）。所有大鼠第1周采用普通饲料适应性喂养,第2周开始NG组喂饲普通饲料,HG组和CG组喂饲高脂饮食。第4周起NG组、HG组给予每周3次生理盐水灌胃,CG组给予每周3次灌胃CG。采用全自动生化仪和放射免疫法检测血清生化指标,采用全波长分光光度计测定超氧化物歧化酶（SOD）、丙二醛（MDA）和游离脂肪酸（FFA）。正常血糖高胰岛素钳夹试验技术测定胰岛素抵抗。Western Blot检测自噬及C-Jun氨基末端激酶（JNK）蛋白。计量资料多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验。相关分析采用Pearson相关性分析。结果与NG组相比,HG组体质量、肝指数、肝湿重、ALT、AST、TG、TC、TNFα及肝匀浆MDA、FFA均明显升高,而SOD明显低于NG组（P值均<0.05）。HG组与NG组相比,p-JNK1和JNK1的蛋...
- 非酒精性脂肪性肝病 /
- 绿原酸 /
- JNK丝裂原活化蛋白激酶类 /
- 大鼠,Sprague-Dawley
Abstract:
Objective To investigate the role of chlorogenic acid (CG) in nonalcoholic fatty liver disease (NAFLD) and possible molecular basis, since NAFLD is closely associated with insulin resistance and CG can regulate glucose and lipid metabolism and improve insulin resistance.Methods A total of 30 Sprague-Dawley rats were randomly divided into normal diet group (NG group) , high-fat diet group (HG group) , and chlorogenic acid group (CG group) .All rats were given normal diet in week 1 as adaptive feeding; in weeks 2 and 3, the rats in NG group were given normal diet, and those in HG and CG groups were given high-fat diet; since week 4, the rats in NG and HG groups were given normal saline by gavage three times a week, and those in CG group were given CG by gavage three times a week.An automatic biochemical analyzer and radioimmunoassay were used to measure serum biochemical parameters, and a full-wavelength spectrophotometer was used to measure superoxide dismutase (SOD) , malondialdehyde (MDA) , and free fatty acid (FFA) .A euglycemic-hyperinsulinemic clamp was used to measure insulin resistance.Western blot was used to measure autophagy-related proteins and c-Jun N-terminal kinase (JNK) proteins.A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups.A Pearson correlation analysis was used for correlation analysis.Results Compared with the NG group, the HG group had significantly higher body weight, liver index, liver wet weight, alanine aminotransferase (ALT) , aspartate aminotransferase (AST) , triglyceride (TG) , total cholesterol (TC) , tumor necrosis factor-α (TNF-α) , and levels of MDA and FFA in liver homogenate and a significantly lower level of SOD (all P < 0.05) .Compared with the NG group, the HG group had significant increases in the levels of p-JNK1 and JNK1 proteins and autophagy-related proteins LC3-Ⅰ, LC3-Ⅱ, Beclin-1, Atg3, and Atg5 (all P < 0.05) .The protein expression of JNK1 was positively correlated with insulin resistance.Compared with the HG group, the CG group had significantly lower body weight, liver wet weight, liver index, levels of ALT, AST, TG, TC, and TNF-α, and levels of MDA and FFA in liver homogenate, a significantly higher level of SOD, and significantly lower expression of LC3-Ⅰ, LC3-Ⅱ, Beclin-1, Atg3, and Atg5 (all P < 0.05) .Conclusion CG improves liver injury and insulin resistance by inhibiting autophagy via the inactivation of the JNK pathway.CG may be a potential method for the treatment of NAFLD.
- nonalcoholic fatty liver disease /
- chlorogenic acid /
- JNK mitogen-activated protein kinases /
- rats, Sprague-Dawley

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参考文献(22)

[1]AMATO A, CALDARA GF, NUZZO D, et al.NAFLD and atherosclerosis are prevented by a natural dietary supplement containing curcumin, silymarin, guggul, chlorogenic acid and inulin in mice fed a high-fat diet[J].Nutrients, 2017, 9 (5) :492.

[2]LIM S, OH TJ, KOH KK.Mechanistic link between nonalcoholic fatty liver disease and cardiometabolicdisorders[J].Int J Cardio, 2015, 201:408-414.

[3]POLYZOS SA, KOUNTOURAS J, ZAVOS C, et al.Nonalcoholic fatty liver disease:multimodal treatment options for a pathogenetically multiple-hit disease[J].J Clin Gastroenterol, 2012, 46 (4) :272-284.

[4]AZUMA K, IPPOUSHI K, NAKAYAMA M, et al.Absorption of chlorogenic acid and caffeic acid in rats after oral administration[J].J Agric Food Chem, 2000, 48 (11) :5496-5500.

[5]MA Y, GAO M, LIU D.Chlorogenic acid improves high fat dietinduced hepatic steatosis and insulin resistance in mice[J].Pharm Res, 2015, 32 (4) :1200-1209.

[6]SCHATTENBERG JM, SINGH R, WANG Y, et al.JNK1 but not JNK2 promotes the development of steatohepatitis in mice[J].Hepatology, 2006, 43:163-172.

[7]SOLINAS G, BECATTINI B.JNK at the crossroad of obesity, insulin resistance, and cell stress response[J].Mol Metab, 2017, 6 (2) :174-184.

[8]MAO Y, YU F, WANG J, et al.Autophagy:a new target for nonalcoholic fatty liver disease therapy[J].Hepat Med, 2016, 8:27-37.

[9]BUREN J, LIU HX, LAURITZ J, et al.High glucose and insulin in combination cause insulin receptor substrate-1 and-2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes:possible implications for insulin resistance in type 2 diabetes[J].Eur J Endocrinol, 2003, 148 (1) :157-167.

[10]LIU QS, DING B, DOU XB, et al.Activity of JNK pathway by cysteine contributes to the non-alcoholic steatohepatitis[J].Chin J Clin Pharmacol Ther, 2016, 21 (4) :366-371. (in Chinese) 刘庆生, 丁滨, 窦晓兵, 等.基于JNK信号通路探究半胱氨酸在非酒精性脂肪性肝炎发病机制中的作用[J].中国临床药理学与治疗学, 2016, 21 (4) :366-371.

[11]PAL M, FEBBRAIO MA, LANCASTER GI.The roles of c-Jun NH2-terminal kinases (JNKs) in obesity and insulin resistance[J].J Physiol, 2016, 594 (2) :267-279.

[12]KODAMA Y, BRENNER DA.c-Jun N-terminal kinase signaling in the pathogenesis of nonalcoholic fatty liver disease:Multiple roles in multiple steps[J].Hepatology, 2009, 49:6-8.

[13]WANG H, TENG T, WANG L, et al.Research advance in the pathogenesis of nonalcoholic fatty disease[J].J Clin Hepatol, 2017, 33 (4) :769-773. (in Chinese) 王虎, 腾田, 王莉, 等.非酒精性脂肪性肝病发病机制的研究进展[J].临床肝胆病杂志, 2017, 33 (4) :769-773.

[14]RAUTOU PE, MANSOURI A, LEBREC D, et al.Autophagy in liver diseases[J].J Hepatol, 2010, 53 (6) :1123-1134.

[15]GONZALEZ-RODRIGUEZ A, MAYORAL R, AGRA N, et al.Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD[J].Cell Death Dis, 2014, 5:1179.

[16]SINGH R, KAUSHIK S, WANG Y, et al.Autophagy regulates lipid metabolism[J].Nature, 2009, 458 (7242) :1131-1135.

[17]MA D, MOLUSKY MM, SONG J, et al.Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD[J].Mol Endocrinol, 2013, 27 (10) :1643-1654.

[18]KIM KH, JEONG YT, OH H, et al.Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine[J].Nat Med, 2013, 19 (1) :83-92.

[19]WANG H, SUN RQ, ZENG XY, et al.Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice[J].Endocrinology, 2015, 156 (1) :169-181.

[20]YAN H, GAOY, ZHANGY.Inhibition of JNK suppresses autophagy and attenuates insulin resistance in a rat model ofnonalcoholic fatty liver disease[J].Mol Med Rep, 2017, 15 (1) :180-186.

[21]Mc CARTY MF.A chlorogenic acid-induced increase in GLP-1production may mediate the impact of heavy coffee consumption on diabetes risk[J].Med Hypotheses, 2005, 64 (4) :848-853.

[22]GHADIEH HE, SMILEY ZN, KOPFMANMW, et al.Chlorogenic acid/chromium supplement rescues diet-induced insulin resistance and obesity in mice[J].Nutr Metab, 2015, 12:19.

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