Just a little something to think about while cooking or eating turkey. Or nut roast. Or whatever else.
J Hepatol. 2014 Dec 19. pii: S0168-8278(14)00924-6. doi: 10.1016/j.jhep.2014.12.006. [Epub ahead of print]
Thyroid-stimulating hormone (TSH) regulates hepatic bile acid homeostasis via SREBP-2/HNF-4α/CYP7A1 axis.
Song Y1, Xu C1, Shao S1, Liu J2, Xing W1, Xu J1, Qin C3, Li C2, Hu B1, Yi S4, Xia X5, Zhang H1, Zhang X1, Wang T1, Pan W1, Yu C1, Wang Q6, Lin X6, Wang L7, Gao L8, Zhao J9.
BACKGROUND & AIMS:
Bile acids (BAs) play a crucial role in dietary fat digestion and in the regulation of lipid, glucose, and energy metabolism. Thyroid-stimulating hormone (TSH) is a hormone produced by the anterior pituitary gland that has been shown to directly regulate several metabolic pathways. However, the impact of TSH on BA homeostasis remains largely unknown.
We analyzed serum BA and TSH levels in healthy volunteers under strict control of caloric intake. Thyroidectomized rats were administered thyroxine and injected with different doses of TSH. Tshr (-/-) mice were supplemented with thyroxine, and C57BL/6 mice were injected with Tshr-siRNA via the tail vein. The serum BA levels, BA pool size, and fecal BA excretion rate were measured. The regulation of SREBP-2, HNF-4α, and CYP7A1 by TSH were analyzed using luciferase reporter, RNAi, EMSA, and CHIP assays.
A negative correlation was observed between the serum levels of TSH and the serum BA levels in healthy volunteers. TSH administration led to a decrease in BA content and CYP7A1 activity in thyroidectomized rats supplemented with thyroxine. When Tshr was silenced in mice, the BA pool size, fecal BA excretion rate, and serum BA levels all increased. Additionally, we found that HNF-4α acts as a critical molecule through which TSH represses CYP7A1 activity. We further confirmed that the accumulation of mature SREBP-2 protein can impair the capacity of nuclear HNF-4α to bind to the CYP7A1 promoter, a mechanism that appears to mediate the effects of TSH.
TSH represses hepatic BA synthesis via a SREBP-2/HNF-4α/CYP7A1 signaling pathway. This finding strongly supports the notion that TSH is an important pathophysiological regulator of liver BA homeostasis independent of thyroid hormones.
Copyright © 2014. Published by Elsevier B.V.
Bile acids; CYP7A1; HNF-4α; SREBP-2; Thyroid-stimulating hormone