A novel role for thyroid-stimulating hormone: up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein pathway.
Elevated thyroid-stimulating hormone (TSH) and hypercholesterolemia commonly coexist, as typically seen in hypothyroidism, but there is no known mechanism directly linking the two. Here, we demonstrated that in liver cells, TSH promoted the expression of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis, by acting on the TSH receptor in hepatocyte membranes and stimulating the cyclic adenosine monophosphate / protein kinase A / cyclic adenosine monophosphate-responsive element binding protein (cAMP/PKA/CREB) signaling system. In thyroidectomized rats, the production of endogenous thyroid hormone was eliminated and endogenous TSH was suppressed through pituitary suppression with constant administration of exogenous thyroid hormone, and hepatic HMGCR expression was increased by administration of exogenous TSH. These results suggested that TSH could up-regulate hepatic HMGCR expression, which indicated a potential mechanism for hypercholesterolemia involving direct action of TSH on the liver.
Tian
Limin
L
Endocrinology, Provincial Hospital affiliated to Shandong University, Jinan, China.
Song
Yongfeng
Y
Xing
Mingzhao
M
Zhang
Wei
W
Ning
Guang
G
Li
Xiaoying
X
Yu
Chunxiao
C
Qin
Chengkong
C
Liu
Jun
J
Tian
Xingsong
X
Sun
Xianglan
X
Fu
Rui
R
Zhang
Lin
L
Zhang
Xiujuan
X
Lu
Yan
Y
Zou
Jianwen
J
Wang
Laicheng
L
Guan
Qingbo
Q
Gao
Ling
L
Zhao
Jiajun
J
D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000096:biosynthesis; D011989:Receptors, Thyrotropin / Q000378:metabolism; D013972:Thyrotropin; D015854:Up-Regulation
D017362:Cyclic AMP Response Element-Binding Protein; D011973:Receptors, LDL; D011989:Receptors, Thyrotropin; D013972:Thyrotropin; D000242:Cyclic AMP; D006903:Hydroxymethylglutaryl CoA Reductases; D017868:Cyclic AMP-Dependent Protein Kinases