Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA 95343, USA.
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Int J Mol Sci. 2022 Sep 17;23(18):10897. doi: 10.3390/ijms231810897.
Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world's population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): untreated, lean Long Evans Tokushima Otsuka (LETO), untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan/kg/d × 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1β) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development.
非酒精性脂肪性肝病（NAFLD）影响了全球多达 20%的人口。血管紧张素受体 1 型（AT1）的过度激活导致代谢功能障碍和氧化产物增加，这与 NAFLD 和肝脂质代谢受损有关。核因子红细胞 2 相关因子 2（Nrf2）通过与抗氧化反应元件（ARE）结合来调节抗氧化剂 II 相基因的表达；然而，AT1 在 NAFLD 进展过程中通过该途径的机制仍未解决。为了研究肝 Nrf2 对高血糖挑战的反应，我们研究了三组大鼠（雄性，10 周龄）：未治疗的瘦长野津富山糖尿病（LETO）、未治疗的肥胖大耳白家兔富山糖尿病（OLETF）和 OLETF +血管紧张素受体阻滞剂（OLETF + ARB；10 mg 奥美沙坦/ kg/ d × 6 周）。在隔夜禁食后（T0；基线）和口服葡萄糖负荷后 1 小时和 2 小时采集肝脏。在基线时，慢性 AT1 阻断增加了核 Nrf2 含量，降低了谷氨酸半胱氨酸连接酶催化亚基（GCLC）亚单位、谷胱甘肽过氧化物酶 1（GPx1）和超氧化物歧化酶 2（SOD2）、线粒体过氧化氢酶活性和肝 4-羟基-2-壬烯醛（4-HNE）含量的表达。与肝纤维化相关的肝白细胞介素-1β（IL-1β）和胶原 IV 的表达随着 AT1 阻断而减少。葡萄糖增加了 OLETF 中的 Nrf2 易位，但在 ARB 中减少，表明葡萄糖诱导了对抗氧化防御的需求，而 ARB 改善了这种需求。这些结果表明，AT1 的过度激活通过抑制 Nrf2 促进氧化损伤，并导致与 NAFLD 发展相关的肝纤维化。
