This event requires that CREB becomes phosphorylated by PKA at Ser133 and acts at the major CRE within the HMGCR promoter region. Even though there was no further research for other regulatory proteins in the present study, our results also demostrated that activation of CREB by TSH in hepatocytes was found to contribute to increased gene expression of HMGCR. A unique experimental approach

in the present study was the use of surgically thyroidectomized rats that completely lost the ability to produce endogenous thyroid hormones and were subsequently treated with exogenous T4 to correct hypothyroidism and maintained a constant serum level of thyroid hormone as well as stably suppressed endogenous TSH through feedback find more from the pituitary gland. With this approach, we were able to alter the TSH levels in the body of the animal by administering exogenous TSH without

altering the thyroid hormone levels which would otherwise have occurred through stimulation of the normal thyroid gland by exogenous TSH. Consequently, under these controlled conditions, we were able to test a sole role of TSH in cholesterol metabolism. As a result, we were not only able to demonstrate a role of TSH in up-regulating hepatic HMGCR expression RG7204 cell line in vivo but also a corresponding increase in serum TC. In this study, thyroidectomy with resulting hypothyroidism

itself caused elevated hepatic expression of HMGCR in rats. This is somewhat inconsistent with the results of Ness and Gertz, which showed lower expression of hepatic HMGCR in Tx rats.27 The explanation for this discrepancy might lie in differences in some of the experimental conditions, such as the duration of hypothyroidism and the types of foods (e.g., cholesterol contents) used to feed the animals. It is notable that in the studies of Ness and Gertz, the Tx animals were commercially obtained and likely had long-term hypothyroidism. Relatively long-term hypercholesterolemia that likely had occurred through other mechanisms, such as the TH deficiency-promoted down-regulation of LDLR in hepatocytes in such chronic hypothyroid conditions, could itself down-regulate selleck products HMGCR through a negative feedback mechanism. It is well known that a high level of serum cholesterol, such as that seen after intake of foods rich in cholesterol, can dramatically decrease HMGCR expression in liver.28 In contrast, the elevated hepatic HMGCR expression seen in our Tx animals occurred in a relative acute phase of hypothyroidism in which the positive effect of elevated TSH was probably quick and strong so that it overwhelmed the negative effect of the early and therefore still relatively mild hypercholesterolemia on the expression of hepatic HMGCR.