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

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The variation in normal TSH levels is partially related to the lipid components and hypercholesterolemia in euthyroid subjects and includes both TH-dependent and TH-independent effects. Our study suggests the importance of controlling TSH in hypothyroid subjects.

Ad-siRNA(NF-kappaBp65) can suppress the progression of the early experimental OA which suggests that Ad-siRNA(NF-kappaBp65) has potential to be a useful preventive and therapeutic agent for OA.

Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in premenopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

Gene therapy olTers a radically different approach to the treatment of arthritis. We demonstrated that cDNA coding for human interleukin-1 receptor-antagonist protein (IL-1Ra) and cDNA coding for human interleukin-I0 (IL-10) can be delivered. by ex vivo techniques, to the synovial lining of joints, intra-articular expression of gene significantly reduced cartilage matrix degradation and cartilage breakdown. To achieve this, lapine synoviocytes were first transduced in culture by retroviral infection. The genetically modified synoviocytes were then transplanted by intra-articular injection into the knee joints of OA rabbits, assay of joint lavages confirmed that the gene expression was not lost 14 days after transfer. Knees receiving the IL-IRa gene had significantly reduced cartilage breakdown. Delivery of the IL-I0 gene was less effective, having only a moderate effect on cartilage breakdown. When both genes were injected together, there was a greater inhibition of cartilage breakdown, suggesting that simultaneous gene delivery may be necessary to treat OA by targeting the activities of multiple inflammatory effectors.

The aim of this paper was to study the effect of long-term supervised exercise-induced weight maintenance on metabolic risk factors and physical fitness in obese children in early puberty. A total of 49 obese children aged 12-14 years were divided into control and exercise groups. The children in the exercise group accepted exercise intervention supervised by a professional sports teacher for 9 of the 12 months. All participants in both groups received health education once every 3 months. Anthropometry and fasting serum lipids, glucose, insulin and homeostatic model assessment for insulin resistance (HOMA-IR) were measured at months 0, 3, 9, 12 of the intervention. Physical fitness was determined before and after intervention. After the intervention (i) BMI was reduced by 0.6 (P < 0.05) in the exercise group, but increased by 0.5 (P < 0.05) in the control group, compared with the pre-intervention level at the end of 9-month intervention; (ii) Triglyceride levels in the exercise group significantly decreased by 23.1% by 3 months (P < 0.05), and by 30.2% after 9 months (P < 0.05), but increased by 50% (P < 0.05) in the control group; high density lipoprotein-cholesterol (HDL-C) decreased more by 35% (P < 0.05) in the controls than in the exercise group (P < 0.05); (iii) Fasting serum glucose, insulin level and HOMA-IR decreased, respectively, by 23.1%, 36.6% and 48.5% in the exercise group at 9 months (P < 0.05), whereas glucose levels increased by 10.9% (P < 0.05) in the control group; (iv) Exercise performance, such as upper- and lower-limb strength, flexibility and endurance, were enhanced by 17.9%, 12.3%, 22.3% and 20.4% (P < 0.01), respectively and (v) At 12 months, i.e. 3 months after terminating the supervised exercise, serum triglycerides, glucose, insulin and HOMA-IR level all returned to the pre-intervention level. Supervised decrement exercise can effectively slow the progress of obesity, improve insulin sensitivity and metabolic risk factors, but once the supervised exercise is stopped, the health benefits weaken or vanish. The key to helping these obese children is for them to cultivate good exercise habits which are sustained throughout their lives.