Improved lipogenesis gene expression in liver is associated with elevated plasma angiotensin 1-7 after AT1 receptor blockade in insulin-resistant OLETF rats
Improved lipogenesis gene expression in liver is associated with elevated plasma angiotensin 1-7 after AT1 receptor blockade in insulin-resistant OLETF rats
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DOI：
10.1016/j.mce.2022.111729
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发表时间：
2022-09-15
影响因子：
4.1
通讯作者：
Ortiz, Rudy M.
中科院分区：
文献类型：
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作者：
Godoy-Lugo, Jose A.;Mendez, Dora A.;Ortiz, Rudy M.
血管紧张素II（Ang II）信号传导增加有助于胰岛素抵抗和肝脏脂肪变性。除了改善高血压外，血管紧张素受体阻滞剂（ARB）还可改善代谢综合征（MetS）受损的脂质代谢和肝脏脂肪变性。慢性阻断血管紧张素II 1型受体（AT 1）可增加血浆血管紧张素1-7（Ang 1-7），其介导AT 1信号的反调节机制。血浆Ang 1-7升高与血浆三酰甘油（TAG）、胆固醇、葡萄糖和胰岛素降低相关;然而，RAS调节预防非酒精性脂肪性肝病（NAFLD）的益处尚未得到充分研究。为了更好地阐明长期ARB治疗、血浆Ang 1-7和肝脏脂肪变性之间的关系，研究了三组10周龄大鼠：（1）未治疗的瘦型Long Evans德岛大冢（LETO），（2）未治疗的大冢Long Evans德岛脂肪（OLETF），和（3）OLETF + ARB（ARB; 10 mg奥美沙坦/kg/d x 6周）。禁食过夜后，大鼠接受急性葡萄糖负荷，以更好地了解肝脏脂肪变性和早期MetS期间的动态代谢反应。在基线（负荷前; T0）和葡萄糖负荷后1小时和2小时收集组织。AT 1阻断可增加血浆Ang 1-7和降低肝脏脂质，这与脂肪酸转运蛋白5（FATP 5）和脂肪酸合成酶（FATP 5）表达降低有关。AT 1阻断降低肝脏葡萄糖和增加葡萄糖激酶（GCK）的表达。这些结果表明，在代谢综合征，过度激活的AT 1促进肝脏脂质沉积，刺激了急性葡萄糖负荷和脂肪生成基因，这表明慢性高血糖症与代谢综合征有助于脂肪肝病理通过AT 1介导的机制。
Increased angiotensin II (Ang II) signaling contributes to insulin resistance and liver steatosis. In addition to ameliorating hypertension, angiotensin receptor blockers (ARBs) improve lipid metabolism and hepatic steatosis, which are impaired with metabolic syndrome (MetS). Chronic blockade of the Ang II receptor type 1 (AT1) increases plasma angiotensin 1-7 (Ang 1-7), which mediates mechanisms counterregulatory to AT1 signaling. Elevated plasma Ang 1-7 is associated with decreased plasma triacylglycerol (TAG), cholesterol, glucose, and insulin; however, the benefits of RAS modulation to prevent non-alcoholic fatty liver disease (NAFLD) are not fully investigated. To better address the relationships among chronic ARB treatment, plasma Ang 1-7, and he-patic steatosis, three groups of 10-week-old-rats were studied: (1) untreated lean Long Evans Tokushima Otsuka (LETO), (2) untreated Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/d x 6 weeks). Following overnight fasting, rats underwent an acute glucose load to better un-derstand the dynamic metabolic responses during hepatic steatosis and early MetS. Tissues were collected at baseline (pre-load; T0) and 1 and 2 h post-glucose load. AT1 blockade increased plasma Ang 1-7 and decreased liver lipids, which was associated with decreased fatty acid transporter 5 (FATP5) and fatty acid synthase (FASN) expression. AT1 blockade decreased liver glucose and increased glucokinase (GCK) expression. These results demonstrate that during MetS, overactivation of AT1 promotes hepatic lipid deposition that is stimulated by an acute glucose load and lipogenesis genes, suggesting that the chronic hyperglycemia associated with MetS contributes to fatty liver pathologies via an AT1-mediated mechanism.