Up-regulation of hepatic CD36 by increased corticosterone/cortisol levels via GR leads to lipid accumulation in liver and hypertriglyceridaemia during pregnancy.

Abstract

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. 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. 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. 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.