Srivastava Rai Ajit K, Jahagirdar Ravi, Azhar Salman, Sharma Somesh, Bisgaier Charles L
CloneGen Biotechnology, Ann Arbor, MI, USA.
Mol Cell Biochem. 2006 Apr;285(1-2):35-50. doi: 10.1007/s11010-005-9053-y. Epub 2006 Feb 14.
Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.
非诺贝特是一种选择性过氧化物酶体增殖物激活受体α（PPAR-α）激动剂，常用于治疗人类血脂异常。本研究旨在阐明非诺贝特降低肥胖、改善胰岛素敏感性、降低甘油三酯（TG）和游离脂肪酸（FFA）的机制，并探究这些有益变化是否与抑制主动脉脂质沉积有关。为验证这一假设，我们使用了雄性低密度脂蛋白受体（LDLr）缺陷小鼠，这些小鼠在喂食高脂肪高胆固醇（HF）饮食时会表现出代谢综合征X的临床特征。喂食HF饮食并同时接受非诺贝特（100 mg/kg体重）治疗的LDLr缺陷小鼠可预防肥胖的发生，降低血清甘油三酯和胆固醇水平，改善胰岛素敏感性，并防止主动脉脂质蓄积。循环脂质的降低是通过下调包括脂肪酸合酶、乙酰辅酶A羧化酶和二酰甘油酰基转移酶-2在内的脂肪生成基因实现的，同时肝脏TG和胆固醇水平以及TG输出率也随之降低。非诺贝特还可抑制肝脏载脂蛋白CIII（apoCIII）mRNA水平，并显著增加脂蛋白脂肪酶（LPL）mRNA水平，已知这可增强血清TG的分解代谢。此外，非诺贝特可使附睾脂肪和肠系膜脂肪量大幅减少至瘦小鼠的水平。体重的减轻与肝脏解偶联蛋白2（UCP2）mRNA水平升高、酮体生成增加以及与肿瘤坏死因子-α降低和磷酸烯醇丙酮酸羧激酶下调相关的胰岛素敏感性改善有关。这些结果表明，非诺贝特部分通过抑制TG生成，部分通过提高LPL和降低apoCIII来清除富含TG的载脂蛋白B颗粒，从而改善脂质异常情况。肥胖的预防是通过能量消耗实现的。非诺贝特介导的降血脂作用以及改善的胰岛素敏感性和脂肪减少，可能通过调节血管细胞黏附分子-1（VCAM-1）抑制动脉粥样硬化的早期阶段，从而减少主动脉脂质沉积。这些结果表明，强效PPAR-α激动剂可能对治疗X综合征有用。
