黄芪多糖对非酒精性脂肪性肝炎大鼠ACE2-[Ang-(1-7)]-Mas轴及胰岛素抵抗的影响
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摘要
目的探讨黄芪多糖对非酒精性脂肪性肝炎大鼠ACE2-[Ang-(1-7)]-Mas轴及胰岛素抵抗的影响。方法 40只大鼠随机分为正常组、模型组、黄芪多糖组(400 mg/kg)、吡格列酮组(20 mg/kg),每组10只,高脂饲料建立非酒精性脂肪性肝炎大鼠模型。给药4周后,测定体质量、肝湿重、血脂、肝功能、血清Ang(1-7)水平,观察肝脏组织病理学变化,RT-PCR、Western blot检测肝组织ACE2、Mas、IRS-1水平。结果与模型组比较,黄芪多糖组肝指数及ALT、AST、TG、TC、MDA水平显著降低(P<0.01),Ang-(1-7)、SOD水平,Mas、ACE2、IRS-1 mRNA及蛋白表达显著升高(P<0.05,P<0.01),肝脂肪变性、炎症反应明显减轻。结论黄芪多糖可有效缓解非酒精性脂肪性肝炎大鼠胰岛素抵抗,其机制可能与上调ACE2-[Ang-(1-7)]-Mas轴基因表达、改善胰岛素敏感性有关。
AIM To explore the effects of Astragali Radix polysaccharides on ACE2-[Ang-(1-7)]-Mas axis and insulin resistance in non-alcoholic steatohepatitis rats.METHODS Forty rats were randomly divided into normal group, model group, Astragali Radix polysaccharides group(400 mg/kg) and pioglitazone group(20 mg/kg), 10 rats in each group. The rat model for non-alcoholic steatohepatitis was established by high-fat diet. After 4-week administration, body weight, liver wet weight, serum lipid, liver function and serum Ang(1-7) level were detected and liver histopathological changes were observed. ACE2, Mas and IRS-1 levels in liver tissue were detected by RT-PCR and Western blot. RESULTS Compared with the model group, the Astragali Radix polysaccharides group demonstrated significant decrease in liver index and ALT, AST, TG, TC, MDA levels(P<0.01), marked increase in Ang-(1-7), SOD levels and Mas, ACE2, IRS-1 mRNA, protein expressions(P<0.05, P<0.01), as well as obvious reduction in liver fatty degeneration and inflammatory reactions. CONCLUSION Astragali Radix polysaccharides can effectively alleviate insulin resistance in non-alcoholic steatohepatitis rats, whose mechanisms may contribute to the up-regulation of ACE2-[Ang-(1-7)]-Mas axis gene expression and improvement of insulin sensitivity.
AIM To explore the effects of Astragali Radix polysaccharides on ACE2-[Ang-(1-7)]-Mas axis and insulin resistance in non-alcoholic steatohepatitis rats.METHODS Forty rats were randomly divided into normal group, model group, Astragali Radix polysaccharides group(400 mg/kg) and pioglitazone group(20 mg/kg), 10 rats in each group. The rat model for non-alcoholic steatohepatitis was established by high-fat diet. After 4-week administration, body weight, liver wet weight, serum lipid, liver function and serum Ang(1-7) level were detected and liver histopathological changes were observed. ACE2, Mas and IRS-1 levels in liver tissue were detected by RT-PCR and Western blot. RESULTS Compared with the model group, the Astragali Radix polysaccharides group demonstrated significant decrease in liver index and ALT, AST, TG, TC, MDA levels(P<0.01), marked increase in Ang-(1-7), SOD levels and Mas, ACE2, IRS-1 mRNA, protein expressions(P<0.05, P<0.01), as well as obvious reduction in liver fatty degeneration and inflammatory reactions. CONCLUSION Astragali Radix polysaccharides can effectively alleviate insulin resistance in non-alcoholic steatohepatitis rats, whose mechanisms may contribute to the up-regulation of ACE2-[Ang-(1-7)]-Mas axis gene expression and improvement of insulin sensitivity.
引文
[1] Haga Y,Kanda T,Sasaki R,et al.Nonalcoholic fatty liver disease and hepatic cirrhosis:Comparison with viral hepatitis-associated steatosis[J].World J Gastroenterol,2015,21(46):12989-12995.
[2] de Alwis N M,Day C P.Non-alcoholic fatty liver disease:the mist gradually clears[J].J Hepatol,2008,48(Suppl 1):S104-S112.
[3] De Minicis S,Agostinelli L,Rychlicki C,et al.HCC development is associated to peripheral insulin resistance in a mouse model of NASH[J].PLoS One,2014,9(5):e97136.
[4] Kido Y,Nakae J,Accili D.Clinical review 125:The insulin receptor and its cellular targets[J].J Clin Endocrinol Metab,2001,86(3):972-979.
[5] 寻英,秦映芬,徐梦婕,等.ACE2-Ang- (1-7)-Mas轴对糖代谢作用的研究进展[J].广东医学,2015,36(1):150-153.
[6] Henriksen E J.Improvement of insulin sensitivity by antagonism of the renin-angiotensin system[J].Am J Physiol Regul Integr Comp Physiol,2007,293(3):R974-R980.
[7] Perkins J M,Davis S N.The renin-angiotensin-aldosterone system:a pivotal role in insulin sensitivity and glycemic control[J].Curr Opin Endocrinol Diabetes Obes,2008,15(2):147-152.
[8] Santos S H,Giani J F,Burghi V,et al.Oral administration of angiotensin-(1-7) ameliorates type 2 diabetes in rats[J].J Mol Med(Berl),2014,92(3):255-265.
[9] Santos S H,Fernandes L R,Mario E G,et al.Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism[J].Diabetes,2008,57(2):340-347.
[10] 唐纪兰,文新年,韦凌云,等.吡格列酮对非酒精性脂肪性肝病患者胰岛素抵抗及内皮功能的影响[J].中华实用诊断与治疗杂志,2015,29(3):303-304,307.
[11] 唐姣玉,刘兆辉,杨海,等.黄芪多糖对非酒精性脂肪肝大鼠血脂的影响[J].黑龙江畜牧兽医,2016(9下):171-172.
[12] 计莉强,姚晓霖,许广艳.黄芪多糖对2型糖尿病ZDF大鼠血糖及肝脏脂代谢影响[J].中国现代医生,2017,55(27):30-34,169.
[13] Kanwar P,Kowdley K V.The metabolic syndrome and its influence on nonalcoholic steatohepatitis[J].Clin Liver Dis,2016,20(2):225-243.
[14] Nandipati K C,Subramanian S,Agrawal D K.Protein kinases:mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance[J].Mol Cell Biochem,2017,426(1-2):27-45.
[15] 唐辰义,周后德.胰岛素受体底物家族成员的结构和组织特异性与功能的关系[J].临床与病理杂志,2016,36(3):295-302.
[16] Donoghue M,Hsieh F,Baronas E,et al.A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensinⅠto angiotensin 1-9[J].Circu Res,2000,87:e1-e9.
[17] Tipnis S R,Hooper N M,Hyde R,et al.A human homolog of angiotensin-converting enzyme.Cloning and functional expression as a captopril-insensitive carboxypeptidase[J].J Biol Chem,2000,275(43):33238-33243.
[18] Paizis G,Tikellis C,Cooper M E,et al.Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2[J].Gut,2005,54(12):1790-1796.
[19] Yoshiji H,Noguchi R,Ikenaka Y,et al.Losartan,an angiotensin-Ⅱ type 1 receptor blocker,attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat[J].BMC Res Notes,2009,2:70.
[20] Shimamoto K,Miura T.Metabolic syndrome[J].Nihon Rinsho,2009,67(4):771-776.
[21] Giani J F,Mayer M A,Muňoz M C,et al.Chronic infusion of angiotensin-(1-7) improves insulin resistance and hypertension induced by a high-fructose diet in rats[J].Am J Physiol Endocrinol Metab,2009,296(2):E262-E271.
[22] Giani J F,Gironacci M M,Muoz M C,et al.Angiotensin-(1-7) stimulates the phosphorylation of JAK2,IRS-1 and Akt in rat heart in vivo:role of the AT1 and Mas receptors[J].Am J Physiol Heart Circ Physiol,2007,293(2):H1154-H1163.
[23] Santos S H,Braga J F,Mario E G,et al.Improved lipid and glucose metabolism in transgenic rats with increased circulating angiotensin-(1-7)[J].Arterioscler Thromb Vasc Biol,2010,30(5):953-961.
[24] Abuissa H,Jones P G,Marso S P,et al.Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes:a meta-analysis of randomized clinical trials[J].J Am Coll Cardiol,2005,46(5):821-826.
[25] Bataller R,Sancho-Bru P,Ginès P,et al.Liver fibrogenesis:a new role for the renin-angiotensin system[J].Antioxid Redox Signal,2005,7(9-10):1346-1355.
[26] 刘月涛,贾璐,秦雪梅.多效黄芪物质基础的研究进展[J].中草药,2018,49(6):1476-1480.
[27] Mao X Q,Yu F,Wang N,et al.Hypoglycemic effect of polysaccharide enriched extract of Astragalus membranaceus in diet induced insulin resistant C57BL/6J mice and its potential mechanism[J].Phytomedicine,2009,16(5):416-425.
[2] de Alwis N M,Day C P.Non-alcoholic fatty liver disease:the mist gradually clears[J].J Hepatol,2008,48(Suppl 1):S104-S112.
[3] De Minicis S,Agostinelli L,Rychlicki C,et al.HCC development is associated to peripheral insulin resistance in a mouse model of NASH[J].PLoS One,2014,9(5):e97136.
[4] Kido Y,Nakae J,Accili D.Clinical review 125:The insulin receptor and its cellular targets[J].J Clin Endocrinol Metab,2001,86(3):972-979.
[5] 寻英,秦映芬,徐梦婕,等.ACE2-Ang- (1-7)-Mas轴对糖代谢作用的研究进展[J].广东医学,2015,36(1):150-153.
[6] Henriksen E J.Improvement of insulin sensitivity by antagonism of the renin-angiotensin system[J].Am J Physiol Regul Integr Comp Physiol,2007,293(3):R974-R980.
[7] Perkins J M,Davis S N.The renin-angiotensin-aldosterone system:a pivotal role in insulin sensitivity and glycemic control[J].Curr Opin Endocrinol Diabetes Obes,2008,15(2):147-152.
[8] Santos S H,Giani J F,Burghi V,et al.Oral administration of angiotensin-(1-7) ameliorates type 2 diabetes in rats[J].J Mol Med(Berl),2014,92(3):255-265.
[9] Santos S H,Fernandes L R,Mario E G,et al.Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism[J].Diabetes,2008,57(2):340-347.
[10] 唐纪兰,文新年,韦凌云,等.吡格列酮对非酒精性脂肪性肝病患者胰岛素抵抗及内皮功能的影响[J].中华实用诊断与治疗杂志,2015,29(3):303-304,307.
[11] 唐姣玉,刘兆辉,杨海,等.黄芪多糖对非酒精性脂肪肝大鼠血脂的影响[J].黑龙江畜牧兽医,2016(9下):171-172.
[12] 计莉强,姚晓霖,许广艳.黄芪多糖对2型糖尿病ZDF大鼠血糖及肝脏脂代谢影响[J].中国现代医生,2017,55(27):30-34,169.
[13] Kanwar P,Kowdley K V.The metabolic syndrome and its influence on nonalcoholic steatohepatitis[J].Clin Liver Dis,2016,20(2):225-243.
[14] Nandipati K C,Subramanian S,Agrawal D K.Protein kinases:mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance[J].Mol Cell Biochem,2017,426(1-2):27-45.
[15] 唐辰义,周后德.胰岛素受体底物家族成员的结构和组织特异性与功能的关系[J].临床与病理杂志,2016,36(3):295-302.
[16] Donoghue M,Hsieh F,Baronas E,et al.A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensinⅠto angiotensin 1-9[J].Circu Res,2000,87:e1-e9.
[17] Tipnis S R,Hooper N M,Hyde R,et al.A human homolog of angiotensin-converting enzyme.Cloning and functional expression as a captopril-insensitive carboxypeptidase[J].J Biol Chem,2000,275(43):33238-33243.
[18] Paizis G,Tikellis C,Cooper M E,et al.Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2[J].Gut,2005,54(12):1790-1796.
[19] Yoshiji H,Noguchi R,Ikenaka Y,et al.Losartan,an angiotensin-Ⅱ type 1 receptor blocker,attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat[J].BMC Res Notes,2009,2:70.
[20] Shimamoto K,Miura T.Metabolic syndrome[J].Nihon Rinsho,2009,67(4):771-776.
[21] Giani J F,Mayer M A,Muňoz M C,et al.Chronic infusion of angiotensin-(1-7) improves insulin resistance and hypertension induced by a high-fructose diet in rats[J].Am J Physiol Endocrinol Metab,2009,296(2):E262-E271.
[22] Giani J F,Gironacci M M,Muoz M C,et al.Angiotensin-(1-7) stimulates the phosphorylation of JAK2,IRS-1 and Akt in rat heart in vivo:role of the AT1 and Mas receptors[J].Am J Physiol Heart Circ Physiol,2007,293(2):H1154-H1163.
[23] Santos S H,Braga J F,Mario E G,et al.Improved lipid and glucose metabolism in transgenic rats with increased circulating angiotensin-(1-7)[J].Arterioscler Thromb Vasc Biol,2010,30(5):953-961.
[24] Abuissa H,Jones P G,Marso S P,et al.Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes:a meta-analysis of randomized clinical trials[J].J Am Coll Cardiol,2005,46(5):821-826.
[25] Bataller R,Sancho-Bru P,Ginès P,et al.Liver fibrogenesis:a new role for the renin-angiotensin system[J].Antioxid Redox Signal,2005,7(9-10):1346-1355.
[26] 刘月涛,贾璐,秦雪梅.多效黄芪物质基础的研究进展[J].中草药,2018,49(6):1476-1480.
[27] Mao X Q,Yu F,Wang N,et al.Hypoglycemic effect of polysaccharide enriched extract of Astragalus membranaceus in diet induced insulin resistant C57BL/6J mice and its potential mechanism[J].Phytomedicine,2009,16(5):416-425.