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 protei

Abstract

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. (HEPATOLOGY 2010;52:1401-1409 H ypothyroidism is well known to be associated with elevated serum TC, which can result in hypercholesterolemia. 1,2 The underlying mechanism is widely thought to be TH deficiency.However, elevation of serum TC has also been observed in patients with subclinical hypothyroidism (SCH), in which TSH is elevated but TH stays within its normal range. 1,3,4 Thus, the development of

Natural history of mild subclinical hypothyroidism in a middle-aged and elderly Chinese population: a prospective study

“…Furthermore, lipid disorders including elevated cholesterol were observed even in SCH patients [21]. Previous studies in our laboratory suggested that the independent effect of TSH on hepatic cholesterol metabolism might be the mechanism involved [22][23][24]. On the other hand, lipid profile can somehow influence the prevalence of SCH.…”

Subclinical Hypothyroidism is Associated with Atherogenic Lipid Profile in Postmenopausal Women

“…The exact pathophysiological mechanism accounting for the effects of TSH on lipid profile has not been fully established. Tian et al (27) proposed that TSH upregulates the expression of hepatic 3-hydroxy-3-methyl-glutaryl co-enzyme A reductase (an enzyme that limits cholesterol synthesis) by acting on the TSH receptor on liver cells. Gagnon et al (28) showed that TSH stimulates lipolysis in cultured adipocytes and elevates serum-free fatty acid levels.…”

Kardiyovasküler risk faktörü olarak fibrinojen, yüksek duyarlılıklı C-reaktif protein ve lipid parametrelerinin subklinik hipotiroidili hastalardaki düzeyi

“…Nitekim TSH reseptörlerinin tiroid follikül hücreleri dışında lenfositler, testis, böbrek, beyin, adipoz doku ve fibroblastlar gibi diğer birçok ekstra tiroidal dokuda bulunduğu biliniyor. İnvitro olarak TSH nın, kolesterol sentezinin hız sınırlayıcı enzimi olan 3-hidroksi-3-metil glutaril koenzim A redüktazın transkripsiyonel aktivitesini CAMP/PKA/ CREB yolağı (cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein) aracılığıyla indüklediği [23], aynı zamanda cerrahi olarak tiroid bezi çıkarılan ratlara TSH verilmesinin serum TK düzeylerini artırdığı invivo olarak gösterilmiştir [23].…”