Patel Vishal, Joharapurkar Amit, Kshirsagar Samadhan, Sutariya Brijesh, Patel Maulik, Pandey Dheerendra, Patel Hiren, Ranvir Ramchandra, Kadam Shekhar, Patel Dipam, Bahekar Rajesh, Jain Mukul
Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India.
Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India.
Chem Biol Interact. 2018 Feb 25;282:13-21. doi: 10.1016/j.cbi.2018.01.004. Epub 2018 Jan 8.
Dyslipidemia enhances progression of atherosclerosis. Coagonist of GLP-1 and glucagon are under clinical investigation for the treatment of obesity and diabetes. Earlier, we have observed that coagonist reduced circulating and hepatic lipids, independent of its anorexic effects. Here, we investigated the role of coagonist of GLP-1 and glucagon receptors in complications of diet-induced dyslipidemia in hamsters and humanized double transgenic mice. Hamsters fed on high fat high cholesterol diet were treated for 8 weeks with coagonist of GLP-1 and glucagon receptors (75 and 150 μg/kg). Pair-fed control was maintained. Cholesterol fed transgenic mice overexpressing hApoB100 and hCETP with coagonist (300 μg/kg) for 4 weeks. After the completion of treatment, biochemical estimations were done. Coagonist treatment reduced triglycerides in plasma, liver and aorta, plasma cholesterol and hepatic triglyceride secretion rate. Expressions of HMG-CoA reductase and SBREBP-1C were reduced and expressions of LDLR, CYP7A1, ABCA1 and ABCB11 were increased in liver, due to coagonist treatment. Coagonist treatment increased bile flow rate and biliary cholesterol excretion. IL-6 and TNF-α were reduced in plasma and expression of TNF-α, MCP-1, MMP-9 and TIMP-1 decreased in liver. Treatment with coagonist reduced oxidative stress in liver and aorta. Energy expenditure was increased and respiratory quotient was reduced by coagonist treatment. These changes were correlated with reduced hepatic inflammation and lipids in liver and aorta in coagonist treated hamsters. Coagonist treatment also reduced lipids in cholesterol-fed transgenic mice. These changes were independent of glycaemia and anorexia observed after coagonist treatment. Long term treatment with coagonist of GLP-1 and glucagon receptor ameliorated diet-induced dyslipidemia and atherosclerosis by regulating bile homeostasis, liver inflammation and energy expenditure.
血脂异常会加速动脉粥样硬化的进展。胰高血糖素样肽-1（GLP-1）和胰高血糖素的协同激动剂正在进行治疗肥胖症和糖尿病的临床研究。此前，我们观察到协同激动剂可降低循环脂质和肝脏脂质，且与其厌食作用无关。在此，我们研究了GLP-1和胰高血糖素受体的协同激动剂在仓鼠和人源化双转基因小鼠饮食诱导的血脂异常并发症中的作用。以高脂高胆固醇饮食喂养的仓鼠用GLP-1和胰高血糖素受体的协同激动剂（75和150μg/kg）治疗8周。维持配对喂养对照。用协同激动剂（300μg/kg）处理过表达人载脂蛋白B100（hApoB100）和人胆固醇酯转运蛋白（hCETP）的胆固醇喂养转基因小鼠4周。治疗结束后，进行生化测定。协同激动剂治疗降低了血浆、肝脏和主动脉中的甘油三酯、血浆胆固醇和肝脏甘油三酯分泌率。由于协同激动剂治疗，肝脏中3-羟基-3-甲基戊二酰辅酶A还原酶（HMG-CoA reductase）和固醇调节元件结合蛋白-1C（SBREBP-1C）的表达降低，低密度脂蛋白受体（LDLR）、细胞色素P450 7A1（CYP7A1）、三磷酸腺苷结合盒转运体A1（ABCA1）和三磷酸腺苷结合盒转运体B11（ABCB11）的表达增加。协同激动剂治疗增加了胆汁流速和胆汁胆固醇排泄。血浆中的白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）降低，肝脏中TNF-α、单核细胞趋化蛋白-1（MCP-1）、基质金属蛋白酶-9（MMP-9）和金属蛋白酶组织抑制因子-1（TIMP-1）的表达减少。协同激动剂治疗降低了肝脏和主动脉中的氧化应激。协同激动剂治疗增加了能量消耗并降低了呼吸商。这些变化与协同激动剂处理的仓鼠肝脏和主动脉中肝脏炎症和脂质的减少相关。协同激动剂治疗也降低了胆固醇喂养的转基因小鼠中的脂质。这些变化与协同激动剂治疗后观察到的血糖和厌食无关。长期用GLP-1和胰高血糖素受体的协同激动剂治疗可通过调节胆汁稳态、肝脏炎症和能量消耗改善饮食诱导的血脂异常和动脉粥样硬化。
