NR1H2 和 NR1H3 调节与脂肪组织中甘油三酯脂解相关的基因表达
中文名称
通路描述
脂肪组织中的甘油三酯（TGs）代表人体的主要能量储备。在脂肪细胞脂解过程中，甘油三酯（TGs）由脂肪组织甘油三酯脂酶（ATGL，由 PNPLA2 编码）水解为游离脂肪酸（FFAs）和甘油，随后由激素敏感性脂肪酶（HSL）水解，该酶由胰高血糖素和肾上腺素（肾上腺素）激活，并由胰岛素抑制。两种形式的肝脏 X 受体，LXRα（NR1H3）和 LXRβ（NR1H2），在成熟小鼠和人类脂肪细胞中表达（Juvet LK 等，2003）。NR1H3 的表达在脂肪细胞分化过程中上调（Juvet LK 等，2003；Darimont C 等，2006）。LXR（NR1H2 或 NR1H3）配体激活可诱导脂肪细胞脂解和 FFAs 氧化（Stenson BM 等，2011；Ross SE 等，2002）。例如，在小鼠 3T3L1 脂肪细胞和人类原代脂肪细胞中，LXR 激活导致基础脂解增加，但并未导致激素刺激后的脂解增加（以甘油释放测量）（Ross SE 等，2002；Stenson BM 等，2011）。另一项研究表明，向小鼠施用 NR1H2/NR1H3 合成配体 T0901317 或 GW3965，导致脂肪细胞变小，血清游离脂肪酸和甘油浓度增加，表明脂肪细胞脂解增加（Commerford SR 等，2007）。此外，对 NR1H3 或 NR1H2 激活后的人类脂肪细胞进行微阵列分析，发现了几种脂解调节蛋白如 perilipin1（PLIN1）的基因表达发生改变，这一结果也得到了定量实时 PCR（Stenson BM 等，2011）的证实。选择性敲低 NR1H2 或 NR1H3 表明，NR1H3（LXRα）是介导 LXR 激动剂脂解相关作用的主要等位基因（Stenson BM 等，2011）。此外，NR1H3（LXRα）在鼠脂肪组织中的缺失导致通过降低白色脂肪组织的脂解和氧化能力而导致脂肪堆积增加（Dib L 等，2014）。
英文描述
NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose Adipose tissue triglycerides (TGs) represent the major energy store of the body. During adipocyte lipolysis triglycerides (TGs) are hydrolyzed into free fatty acids (FFAs) and glycerol by the action of adipose triglyceride lipase (ATGL, encoded by PNPLA2), then hormone-sensitive lipase (HSL), which is activated by glucagon and adrenaline (epinephrine) and inhibited by insulin. Both isoforms of liver X receptor, LXRα (NR1H3) and LXRβ (NR1H2), are expressed in mature mouse and human adipocytes (Juvet LK et al. 2003). Expression of NR1H3 is up-regulated during adipocyte differentiation (Juvet LK et al. 2003; Darimont C et al. 2006). Ligand activation of LXRs (NR1H2 or NR1H3) can induce adipocyte lipolysis and FFA oxidation (Stenson BM et al. 2011; Ross SE et al. 2002). For instance, in mouse 3T3L1 adipocytes and human primary adipocytes, LXR activation led to an increase in basal, but not hormone-stimulated, lipolysis as measured by glycerol release (Ross SE et al. 2002; Stenson BM et al. 2011). Another study showed that administration of synthetic ligands of NR1H2/ NR1H3, T0901317 or GW3965, to mice resulted in smaller adipocytes and increased serum free fatty acid and glycerol concentrations, suggesting increased adipocyte lipolysis (Commerford SR et al. 2007). Further, microarray analysis of human adipocytes following NR1H3 or NR1H2 activation revealed altered gene expression of several lipolysis-regulating proteins such as perilipin1 (PLIN1), which was also confirmed by quantitative real-time PCR (Stenson BM et al. 2011). Selective knockdown of either NR1H2 or NR1H3 showed that NR1H3 (LXRα) was the major isoform mediating the lipolysis-related effects of LXR agonists (Stenson BM et al. 2011). In addition, the absence of NR1H3 (LXRα) in mouse adipose tissue resulted in elevated adiposity through a decrease of both lipolytic and oxidative capacities in white adipose tissue (Dib L et al. 2014).
所含基因
5 个基因