Up-regulation of hepatic CD36 by increased corticosterone/cortisol levels via GR leads to lipid accumulation in liver and hypertriglyceridaemia during pregnancy
Up-regulation of hepatic CD36 by increased corticosterone/cortisol levels via GR leads to lipid accumulation in liver and hypertriglyceridaemia during pregnancy
复制标题
DOI：
10.1111/bph.15863
复制
发表时间：
2022-05-28
影响因子：
7.3
通讯作者：
Jiang, Huidi
中科院分区：
文献类型：
--
作者：
Bai, Mengru;Chen, Mingyang;Jiang, Huidi
背景与目的血浆甘油三酯（TG）水平随着妊娠的进行而升高，TG的异常升高会增加妊娠并发症的风险。目前的研究探讨了妊娠期间高脂血症的机制。实验方法研究了非妊娠和妊娠小鼠的血脂谱和参与肝脏TG代谢的关键基因的表达水平。妊娠相关激素对关键基因的影响及其潜在机制在体外和体内被揭示。关键结果妊娠小鼠血浆和肝脏TG水平升高，而肝脏脂肪酸转位酶（FAT/CD 36）上调。皮质酮和皮质醇（妊娠期间升高的内源性糖皮质激素），但不是雌二醇或孕酮，显著上调肝细胞中的CD 36，并且在使用siRNA敲低糖皮质激素受体（GR）或在GR拮抗剂RU 486和AL 082 D 06存在下，这被消除。荧光素酶报告基因和染色质免疫沉淀分析进一步揭示，皮质酮/皮质醇促进GR的直接结合的CD 36启动子和上调其转录。慢性皮质酮暴露诱导小鼠肝脏脂质蓄积和血浆TG水平升高，RU 486通过抑制GR-CD 36途径减弱了这一作用。结论和影响增加皮质酮/皮质醇诱导肝脏脂质蓄积和高脂血症在怀孕期间通过加速脂肪酸摄取到肝细胞通过激活GR及其靶基因，CD 36。我们的研究结果可能有助于预防严重的高血脂症和相关的妊娠并发症。
Background and Purpose Plasma triglyceride (TG) levels increase as gestation proceeds, and abnormal elevation of TG increases the risk of pregnancy complications. The current study explored the mechanisms involved in hypertriglyceridaemia during pregnancy. Experimental Approach Lipid profile and expression levels of key genes involved in liver TG metabolism in non-pregnant and pregnant mice were studied. The effects of pregnancy-related hormones on key genes and the underlying mechanisms were uncovered in vitro and in vivo. Key Results Plasma and hepatic TG levels were elevated, while hepatic fatty acid translocase (FAT/CD36) was up-regulated in pregnant mice. Corticosterone and cortisol (endogenous glucocorticoids that are elevated during pregnancy), but not oestradiol or progesterone, significantly up-regulated CD36 in hepatocytes, and this was abolished after knockdown of the glucocorticoid receptor (GR) using a siRNA or in the presence of GR antagonists, RU486 and AL082D06. The luciferase reporter gene and chromatin immunoprecipitation assay further revealed that corticosterone/cortisol promoted the direct binding of GR to the CD36 promoter and up-regulated its transcription. Chronic corticosterone exposure induced liver lipid accumulation and increased plasma TG levels in mice, which were attenuated by RU486 via inhibition of the GR-CD36 pathway. Conclusions and Implications Increased corticosterone/cortisol induces liver lipid accumulation and hypertriglyceridaemia during pregnancy by accelerating fatty acid uptake into hepatocytes via activation of GR and its target gene, CD36. Our results may be useful for the prevention of severe hypertriglyceridaemia and associated pregnancy complications.