NR1H2 和 NR1H3 调节与脂合成相关的基因表达
中文名称
通路描述
肝脏 X 受体α (LXRα 或 NR1H3) 和 LXRβ (NR1H2) 是核受体，由已知的氧化胆固醇衍生物，即氧化固醇激活 (Janowski BA et al. 1999; Jakobsson T et al. 2012)。NR1H2 和 NR1H3 作为全身胆固醇传感器，其激活导致胆固醇从体内净消除，并通过动员外周胆固醇改善血浆脂蛋白谱 (Venkateswaran A et al. 2000; Repa JJ et al. 2000a; Ishibashi M et al. 2013)。NR1H3 (LXRα) 和 NR1H2 (LXRβ) 还通过将乙酰辅酶 A 单位从胆固醇从头合成转移到脂肪酸合成来降低全身胆固醇水平。NR1H2 或 3 诱导的 rodents 和人类中的肝脂合成由直接上调固醇调节元件结合蛋白 1 (SREBF1) 介导，SREBF1 是肝脂合成的主要调节者，控制参与脂肪酸合成的基因的转录 (Schultz JR et al. 2000)。NR1H2 或 3 可能通过结合促进脂生元件 (LXRE) 直接激活脂生基因转录，该元件位于几个基因，如脂肪酸合酶 (FAS 或 FASN) 和 1-脱氢 -2-甲基戊烯酸 -3- 脱氢酶 1 (SCD1) 的启动子区域中 (Repa JJ et al. 2000b; Yoshikawa T et al. 2001; Joseph SB et al. 2002; Chu K et al. 2006)。携带靶向破坏 NR1H3 (LXRα) 基因的啮齿动物在 FAS、SCD1、ACC 和 SREBF1 的表达中缺乏 (Peet DJ et al. 1998)。NR1H3 和 NR1H2 双缺失的啮齿动物显示出肝脏脂质代谢缺陷，降低脂合成 80%，并对肥胖具有抗性 (Repa JJ et al. 2000; Kalaany NY et al. 2005; Beaven SW et al. 2013)。此外，向啮齿动物施用合成的 NR1H2 或 NR1H3 配体触发脂生途径的诱导并升高血浆甘油三酯水平 (Schultz JR et al. 2000)。这些研究证明了 NR1H3 (LXRα) 和 NR1H2 (LXRβ) 在控制脂合成中的作用。
英文描述
NR1H2 & NR1H3 regulate gene expression linked to lipogenesis The liver X receptor α (LXRα or NR1H3) and LXRβ (NR1H2) are nuclear receptors that are activated by endogenous oxidized derivatives of cholesterol known as oxysterols (Janowski BA et al. 1999; Jakobsson T et al. 2012). NR1H2 and NR1H3 act as whole-body cholesterol sensors and their activation results in a net elimination of cholesterol from the body and amelioration of the plasma lipoprotein profile by mobilizing cholesterol from the periphery (Venkateswaran A et al. 2000; Repa JJ et al. 2000a; Ishibashi M et al. 2013). NR1H3 (LXRα) and NR1H2 (LXRβ) also contribute to lowering of whole-body cholesterol levels by shifting acetyl-CoA units from cholesterol de novo biosynthesis to fatty acid synthesis. NR1H2 or 3-induced hepatic lipogenesis in rodents and humans is mediated by direct upregulation of sterol regulatory element-binding protein 1 (SREBF1), the main regulator of hepatic lipogenesis that controls the transcription of genes involved in fatty acid biosynthesis (Schultz JR et al. 2000). NR1H2 & NR1H3 may activate lipogenic gene transcription directly by biding LXR responsive element (LXRE) found in the promoter regions of several genes, such as fatty acid synthase (FAS or FASN) and stearoyl-CoA desaturase 1 (SCD1) (Repa JJ et al. 2000b; Yoshikawa T et al. 2001; Joseph SB et al. 2002; Chu K et al. 2006). Mice carrying a targeted disruption in the NR1H3 (LXRα) gene were deficient in expression of FAS, SCD1, ACC, and SREBF1 (Peet DJ et al. 1998). Mice ablated of both NR1H3 and NR1H2 showed defective hepatic lipid metabolism decreasing lipogenesis by 80% and were resistant to obesity (Repa JJ et al. 2000; Kalaany NY et al. 2005; Beaven SW et al. 2013). Further, the administration of the synthetic NR1H2 or NR1H3 ligands to mice triggered induction of the lipogenic pathway and raised plasma triglyceride levels (Schultz JR et al. 2000). These studies demonstrate the role of NR1H3 (LXRα) and NR1H2 (LXRβ) in the control of lipogenesis.
所含基因
8 个基因