Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Br J Pharmacol. 2010 Aug;160(7):1796-807. doi: 10.1111/j.1476-5381.2010.00835.x.
Hypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well-established angiotensin II type 1 receptor (AT(1)) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear.
Male obese Koletsky (fa(k)/fa(k)) rats, which exhibit spontaneous hypertension and metabolic abnormalities, received irbesartan (40 mg x kg(-1) x day(-1)) or vehicle by oral gavage over 7 weeks. Adipocyte-derived hormones in plasma were measured by ELISA. Gene expression in liver and other tissues was assessed by real-time PCR and Western immunoblotting.
In Koletsky (fa(k)/fa(k)) rats irbesartan lowered plasma concentrations of triglycerides and non-esterified fatty acids, and decreased plasma insulin concentrations and the homeostasis model assessment of insulin resistance index. However, this treatment did not affect food intake, body weight, epididymal white adipose tissue weight, adipocyte size and plasma leptin concentrations, although plasma adiponectin was decreased. Irbesartan up-regulated hepatic expression of mRNAs corresponding to peroxisome proliferator-activated receptor (PPAR)alpha and its target genes (carnitine palmitoyltransferase-1a, acyl-CoA oxidase and fatty acid translocase/CD36) that mediate hepatic fatty acid uptake and oxidation; the increase in hepatic PPARalpha expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARgamma and its downstream genes or hepatic genes that mediate fatty acid synthesis.
These findings demonstrate that irbesartan treatment up-regulates PPARalpha and several target genes in liver of obese spontaneously hypertensive Koletsky (fa(k)/fa(k)) rats and offers a novel insight into the lipid-lowering mechanism of irbesartan.
高甘油三酯血症与心血管疾病风险增加相关。血管紧张素 II 型 1 型受体（AT(1)）阻滞剂厄贝沙坦可改善啮齿动物和人类的高甘油三酯血症，但作用机制尚不清楚。
雄性肥胖 Koletsky（fa(k)/fa(k)）大鼠自发性高血压合并代谢异常，给予厄贝沙坦（40mg·kg(-1)·d(-1)）或载体经口灌胃 7 周。用 ELISA 法检测血浆中的脂肪细胞衍生激素。实时 PCR 和 Western 免疫印迹法检测肝和其他组织中的基因表达。
在 Koletsky（fa(k)/fa(k)）大鼠中，厄贝沙坦降低了血浆甘油三酯和非酯化脂肪酸浓度，降低了血浆胰岛素浓度和胰岛素抵抗评估的稳态模型评估指数。然而，这种治疗并未影响食物摄入量、体重、附睾白色脂肪组织重量、脂肪细胞大小和血浆瘦素浓度，尽管血浆脂联素降低。厄贝沙坦上调了肝脏中过氧化物酶体增殖物激活受体（PPAR）α及其靶基因（肉毒碱棕榈酰转移酶-1a、酰基辅酶 A 氧化酶和脂肪酸转运蛋白/CD36）的 mRNA 表达，这些基因介导肝脏脂肪酸摄取和氧化；在蛋白质水平上也证实了肝 PPARα表达增加。相反，厄贝沙坦不影响脂肪组织 PPARγ及其下游基因或介导脂肪酸合成的肝基因的表达。
这些发现表明，厄贝沙坦治疗可上调肥胖自发性高血压 Koletsky（fa(k)/fa(k)）大鼠肝脏中的 PPARα 和几个靶基因，为厄贝沙坦的降脂机制提供了新的见解。
