TSH increases synthesis of hepatic ATP-binding cassette subfamily A member 1 in hypercholesterolemia
Introduction
Hypercholesterolemia, characterized by elevated plasma cholesterol, primarily contributes to increased morbidity and mortality in coronary heart disease [1], [2], [3]. Cholesterol plays an important role in maintaining the stability of cell function. Excessive cholesterol leads to formation of solid crystals, which disrupt the normal function of cell membrane [4]. In addition, excessive cholesterol deposits accumulate within the arterial wall contributing to atherosclerosis [5]. In this study, we identified a hormone potentially mediating hypercholesterolemia.
Thyroid-stimulating hormone (TSH) synthesized and secreted by adenohypophysis, is a glycoprotein directly involved in the regulation of thyroid function via thyroid-stimulating hormone receptor (TSHR) in thyroid cells and many non-thyroid tissues including adipocytes, lymphocytes and hepatocytes [6], [7]. Moderately elevated TSH increases the risk of metabolic syndrome [8]. Several epidemiological studies indicate that TSH is positively correlated with total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) [9], [10], [11], [12], [13]. Subclinical hypothyroidism (SCH), characterized by elevated TSH and normal free thyroxine (FT4) levels, is often accompanied by hypercholesterolemia and is associated with cardiovascular disease [14], [15]. Therefore, studies are increasingly focused on the relationship between TSH and hypercholesterolemia to explore novel approaches for prevention of cardiovascular disease.
Cholesterol is combined with plasma protein and transported in the form of lipoprotein. It is synthesized mainly within the body, and dietary intake contributes to no more than 10% of the plasma cholesterol level [16], [17]. Liver is the major organ involved in cholesterol metabolism, accounting for 70%–80% of cholesterol synthesis. HMGCR, a rate-limiting enzyme in cholesterol synthesis, transports redundant cholesterol from liver to plasma. Our previous studies demonstrated that TSH upregulated hepatic HMGCR expression, which indicated a potential mechanism underlying hypercholesterolemia directly mediated by TSH via liver [18]. However, the role of TSH in regulating cholesterol transport has not been completely clarified.
ATP binding cassette subfamily A member 1(ABCA1), a 254 kDa integral membrane protein, controls the rate of plasma HDL-cholesterol synthesis by transporting cholesterol and phospholipid to lipid-deficient apolipoproteins [19], [20], [21]. The ABCA1 protein is ubiquitously expressed in murine [22] and human [23] tissues. Mutations in ABCA1 lead to depletion of HDL-cholesterol and increased risk of atherosclerosis [24], [25]. In addition, ABCA1 plays a pivotal role in the regulation of intracellular cholesterol efflux in the liver [26]. In this study, our aim was to determine whether TSH regulated ABCA1 expression in the liver, resulting in increased plasma cholesterol levels. This study provides a comprehensive understanding of the pathophysiology of TSH in hypercholesterolemia and suggests a novel interpretation of the mechanism of SCH in patients diagnosed with hypercholesterolemia.
Section snippets
Animals and treatment
All the mice were housed in an SPF room under controlled light conditions (12 h on, 12 h off), with the temperature maintained at 23 °C.
TSH regulated cholesterol content in liver
Only elevated serum TSH is diagnostic of SCH. Therefore, we first established the SCH mouse model. The SCH mice exhibited normal serum FT4 levels and higher TSH levels compared with controls (Fig. 1A). Significantly, hepatic total and free cholesterol levels were increased in SCH mice compared with the controls (Fig. 1B).
TSH function is mediated via highly specific TSHR [29]. In a previous study, we demonstrated the presence of functional TSHRs in hepatocytes [6]. To determine the effect of TSH
Discussion
Our findings demonstrated a close relationship between subclinical hypothyroidism and hypercholesterolemia. TSH upregulated hepatic ABCA1 to promote cumulative intercellular cholesterol efflux, which resulted in increased plasma cholesterol level. The data obtained with Tshr−/− mice confirm that TSH acts via hepatic TSHR. The findings reveal a novel mechanism of TSH underlying cholesterol transport in liver and might partially explain the pathogenesis of hypercholesterolemia in SCH patients.
Financial support
This work was supported by the National Natural Science Foundation of China (Grant No. 81270970) and Promotive Research Fund for Excellent Young and Middle-aged Scientists of Shandong Province (Grant No. BS2011SW034).
Author contributions
The work presented here was carried out in collaboration between all authors. Tiantian Zhang performed the experiments and prepared the figures. Lingyan Zhou and Congcong Li prepared all the animals of the experiments. Lingyan Zhou and Tiantian Zhang wrote the main manuscript text. Lingyan Zhou, Tiantian Zhang, Hong Shi and Xinli Zhou designed the experiments. All authors reviewed the manuscript.
Additional information
Competing financial interests: The authors declare no competing financial interests.
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These authors contributed equally to this study.