The Effects Of TSH On SREBP-2 In Human Hepatocytes

Background:Cholesterol is an important biologial lipids in vivo,which is one of the basic component of the biofilm. On the other hand,it is also the raw materials of bile acid,steroid hormones and other physiologically active substances. However,the cholesterol with high concentration can bind to low-density lipoprotein and thereby increase the risk of atherosclerosis and heart disease.Therefore, the concentration of cholesterol in the body must be strictly regulated to ensure that they can play their normal biological functions without affecting the body's health.Hypothyroidism is an important reason that can cause secondary hypercholesteremia. The mainly reason of hypothyroidism that cause hypercholes-teremia which is generally accepted is because of the decrease of thyroid hormone (TH).The mainly mechanism is that:thyroid hormone can regulate the LDL receptor activity. In the state of hypothyroidism, the LDL receptor content on hepatic cell surface decreased, the eliminate of LDL particle in serum is delayed, so the LDL-C level increases,and the serum cholesterol level also increases.Because of the decrease of thyroid hormone, the anti-oxidant function which is provided by thyroid hormone also decreases,the LDL is early peroxidized in circulation, while the peroxidized LDL can not be identified by LDL receptor and eliminated by the scavenger receptor of macrophage cell.So the intracellular cholesterol accumulate. The thyroid hormone can induce synthesis of hepatic HMG-CoA reductase, promote the synthesis of cholesterol,and can promote the cholesterol to be transformed into bile acid in liver.while the ability to promote cholesterol synthesis of thyroid hormone is greater than the ability to promote cholesterol degradation.so the total cholesterol increase when hypothyroidism occurred.Subclinical hypothyroidism is an endocrine metabolic disease with the characteristics that the serum thyroid stimulating hormone (TSH) increases, while serum free thyroxine (FT4), free 3,5,3'-triiodothyronine (FT3)in the normal range.In cases of sustained subclinical hypothyroidism,dysfunction of lipid metabolism may also occur although thyroid hormones are normal.These features of subclinical hypothyroidism can not be interpreted by the raditional theory.The role of TSH in lipid metabolism therefore causes peple's attention.Transcriptional regulation of cholesterol are closely related to the sterol regulator element binding proteins(SREBPs).SREBPs belong to the transcription factors family with classic structure of"Basic helix-loop-helix leucine zipper" (bHLH-Zip).They can bind to the promotor/enhancer of sterol regulatory elements and activate the expression of target genes.SREBP-2 is a member of this transcription factors family,which mainly regulate the enzymes involved in cholesterol synthesis, including the rate-limiting enzyme of cholesterol synthesis,3-hydroxy-3-methyl glutaric acid malonyl CoA (HMG-CoA) reductase.Recently studies find a phenomenon that:the TSH receptor also expresses in a lot of tissues such as lymphocytes, adipose cells, retroocular fibroblasts, erythrocytes, osteocytes, neurons and astrocytes et al besides the thyroid tissue. And TSH can take part in the function modulation of this tissues through binding with the TSH receptor. And our recently studies also find:the TSH receptor also expresses in normal human liver tissue, the human normal liver cell line L02,and the normal Wistar and SD rat liver tissue, and the TSH can dose-dependently increase the cAMP content in L02 cells, this indicates that the TSHR in liver cells is functional.This provides a theoretical basis for our study about effects of TSH on hepatocytes.In a previous study, we have confirmed that treatment with different concentrations of bTSH on L-02 cells and with different time,levels of SREBP m RNA increased.Objective:According to the previous results,to discuss the probable regulatory function of TSH on the liver cholesterol synthesis,we design two experiments as follows:1.Observe the changes of SREBP-2 mRNA content in L-02 cells treated with bTSH of different concentrations.2.Observe the changes of SREBP-2 mRNA content in L-02 cells treated with 4μMbTSH for different time.Results:1.The SREBP-2 mRNA content increases in the L-02 cells after treated by bTSH, and the increases are dose-dependent.2.In a certain time frame TSH increases SREBP-2 mRNA levels,while SREBP-2 mRNA decreases due to the feedback inhibition of high cholesterol in a extend treatment.Conclusions:1.TSH can dose-dependently increase the SREBP-2 mRNA Content in the L-02 cells through binding to TSH receptor.2.The long-term effecs of bTSH on SREBP-2 mRNA can be inhibited by high cholesterol.