Estrogen‐related receptor γ regulates hepatic triglyceride metabolism through phospholipase A2 G12B

Hypersecretion of hepatic very LDL (VLDL)–associated triglyceride (TG) is the hallmark of hypertriglyceridemia. The estrogen‐related receptor γ (ERRγ), an orphan nuclear receptor, plays crucial roles in the regulation of metabolic homeostasis, including TG formation in the liver. It remains unclear whether ERRγ regulates hepatic VLDL‐TG secretion. We demonstrated that knockdown of ERRγ impairs hepatic VLDL‐TG secretion in mice, whereas overexpression of ERRγ favors the secretion, indicating a novel role of ERRγ in hepatic TG metabolism. We found that ERRγ transcriptionally regulates the expression of PLA2G12B by binding to the promoter region of the Pla2g12b gene. In Pla2g12b ‐null mice, ERRγ fails to regulate hepatic VLDL‐TG secretion. There is an apparent accumulation of large lipid droplets in the liver of Pla2g12b ‐null mice. These data suggest that ERRγ is a novel regulator of hepatic VLDL‐TG secretion, which is mediated through the action on PLA2G12B.—Chen, L., Wu, M., Zhang, S., Tan, W., Guan, M., Feng, L., Chen, C., Tao, J., Chen, L., Qu, L. Estrogen‐related receptor γ regulates hepatic triglyceride metabolism through phospholipase A2 G12B. FASEB J. 33, 7942–7952 (2019). www.fasebj.org