Meng Zhao

The relationship between endogenous testosterone and lipid profile in middle-aged and elderly Chinese men

OBJECTIVE To evaluate the relationship between serum total testosterone (TT) level and lipid profile after adjusting for some traditional confounding factors, free thyroid hormones and TSH in Chinese men. METHODS This was a retrospective study based on an epidemiological investigation including 11 000 subjects. Bivariate and partial correlation analysis, multiple linear regression analysis, and a general linear model were used to assess the influence of TT on the lipid profile. Additionally, the odds ratios (ORs) (95% CIs) for hypertriglyceridemia and low HDL-C in relation to TT categories were calculated using logistic regression analysis. RESULTS A total of 4114 subjects whose mean age was 56.04±8.75 years were finally analyzed. There was a significant linear trend toward lower total cholesterol (TC), lower triglycerides (TG), and higher HDL-C with increasing serum TT, which remained significant after adjusting for age, BMI, fasting blood glucose, systolic blood pressure, free triiodothyronine, free thyroxine, and TSH. Compared with the bottom quartile of TT, the adjusted OR (95% CI) for hypertriglyceridemia and low HDL-C was 0.082 (0.048-0.138, P=0.000) and 0.669 (0.503-0.891, P=0.006) respectively in the top quartile of TT. CONCLUSIONS TT was correlated negatively and linearly with TC, TG, and LDL-C and positively and linearly with HDL-C. Low TT might have adverse effects on the lipid profile and thus represent a risk factor for hypercholesterolemia, hypertriglyceridemia, high LDL-C, and low HDL-C, suggesting the importance of maintaining an appropriate TT level in men.

Even mildly elevated TSH is associated with an atherogenic lipid profile in postmenopausal women with subclinical hypothyroidism

Abstract Postmenopausal women, a population with increased risk of atherosclerosis, also have an appreciable risk of subclinical hypothyroidism (SCH). The current study sought an association between serum thyrotropin (TSH), the biomarker of SCH and atherosclerosis lipid profile changes. A total of 45 postmenopausal women with SCH and 27 healthy women matched by age and body mass index were enrolled in this observational study. Serum lipid profiles and thyroid function were assessed. Compared with healthy controls, the serum levels of TC, TG, LDL-c and oxidized LDL (oxLDL) in SCH were increased by ∼22.8%, 29.6%, 30.5% and 23.2%, respectively. TSH was positively correlated with TC, LDL-c and oxLDL in all of the study subjects after adjusting for age and BMI. In particular, the positive correlation remained significant after adjusting for serum FT3 and FT4. When further stratified by TSH levels, both the subgroup of mildly elevated TSH (4.78–9.99 mU/L) and overtly elevated TSH (>10.00 mU/L) exhibited significantly higher serum levels of TC, TG, LDL-c and oxLDL compared to the normal TSH subgroup. Path analysis revealed that the total effects of TSH on TC (total effectsTC,TSH = 0.4323) included a significant direct effect (direct effectTC,TSH = 0.4932) and an indirect effect via an intermediary variable (FT3, FT4). Furthermore, TC exhibited a direct effect on LDL-c, as did LDL-c on oxLDL. In conclusion, even with a mild elevation of serum TSH, SCH is associated with atherogenic lipid profiles in postmenopausal women independent of thyroid hormones.

Dietary high-fat lard intake induces thyroid dysfunction and abnormal morphology in rats

Aim:Excess dietary fat intake can induce lipotoxicity in non-adipose tissues. The aim of this study was to observe the effects of dietary high-fat lard intake on thyroid in rats.Methods:Male Sprague-Dawley rats were fed a high-fat lard diet for 24 weeks, and then the rats were fed a normal control diet (acute dietary modification) or the high-fat lard diet for another 6 weeks. The serum lipid profile, total thyroxine (TT4), free thyroxine (FT4) and thyrotropin (TSH) levels were determined at the 12, 18, 24 and 30 weeks. High-frequency ultrasound scanning of the thyroid glands was performed at the 24 or 30 weeks. After the rats were sacrificed, the thyroid glands were collected for histological and immunohistochemical analyses.Results:The high-fat lard diet significantly increased triglyceride levels in both the serum and thyroid, and decreased serum TT4 and FT4 levels in parallel with elevated serum TSH levels. Ultrasonic imaging revealed enlarged thyroid glands with lowered echotexture and relatively heterogeneous features in the high-fat lard fed rats. The thyroid glands from the high-fat lard fed rats exhibited enlarged follicle cavities and flattened follicular epithelial cells under light microscopy, and dilated endoplasmic reticulum cisternae, twisted nuclei, fewer microvilli and secretory vesicles under transmission electron microscopy. Furthermore, the thyroid glands from the high-fat lard fed rats showed markedly low levels of thyroid hormone synthesis-related proteins TTF-1 and NIS. Acute dietary modification by withdrawal of the high-fat lard diet for 6 weeks failed to ameliorate the high-fat lard diet-induced thyroid changes.Conclusion:Dietary high-fat lard intake induces significant thyroid dysfunction and abnormal morphology in rats, which can not be corrected by short-term dietary modification.

Lipotoxicity, a Potential Risk Factor for the Increasing Prevalence of Subclinical Hypothyroidism?

CONTEXT Subclinical hypothyroidism (SCH) is an important public health problem worldwide for its increasing prevalence and potential deleterious effects, whereas its etiology has not been fully elucidated. Lipotoxicity exerts extensive and serious impact on human health, but so far, the potential effect of lipotoxicity on thyroid is unclear. OBJECTIVE The objective of the study was to assess the association between serum triglyceride levels and the risk for SCH. DESIGN, PARTICIPANTS, AND METHODS We conducted a population-based case-control study. A total of 24 100 subjects with similar and stable iodine nutrition status were recruited from China. Cases of 5033 SCH patients were identified and equal controls were matched by age, gender, and region. Conditional logistic regression was used to analyze the association between serum triglyceride levels and risk for SCH. RESULTS Hypertriglyceridemia was associated with an approximately 35% increased risk for SCH in both men (odds ratio 1.325; 95% confidence interval 1.002-1.753) and women (odds ratio 1.397; 95% confidence interval 1.217-1.604), even after adjustment for potential confounders. Notably, the risk for SCH increased progressively following the elevation of serum triglyceride levels. Compared with individuals with serum triglyceride levels less than 0.97 mmol/L, the risk for SCH increased approximately 1.9-fold in men and 1.4-fold in women, respectively, when triglyceride levels were greater than 1.99 mmol/L. CONCLUSION Our findings suggested that hypertriglyceridemia was positively associated with the risk for SCH.

Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients

Objectives. To evaluate the effect of levothyroxine (LT4) replacement therapy on nonalcoholic fatty liver disease (NAFLD) in subclinical hypothyroidism (SCH) patients. Methods. This study was a post hoc analysis of a randomized controlled trial and involved 33 significant and 330 mild SCH patients. All of the significant SCH patients received LT4 supplement. The mild SCH patients were grouped as LT4 treated or not. After 15 months of follow-up, prevalence of NAFLD in each group was reevaluated. Subgroup analysis was conducted in mild SCH patients with dyslipidemia. Results. After treatment with LT4, the prevalence of NAFLD in significant SCH patients reduced from 48.5% to 24.2% (p = 0.041). In mild SCH patients, prevalence of NAFLD and serum alanine aminotransferase (ALT) was not significantly affected by LT4 supplementation. Nonetheless, mild SCH patients with dyslipidemia who received LT4 treatment experienced decreases in the prevalence of NAFLD and serum ALT levels (p < 0.05 for both). In contrast, these parameters remained comparably stable in patients who were not treated. Conclusion. LT4 supplementation has benefits on NAFLD in significant SCH patients or mild SCH patients with dyslipidemia. For NAFLD patients with SCH, appropriate supplementation of LT4 may be an effective means of controlling NAFLD. The original trial was registered with ClinicalTrials.gov (NCT01848171).

A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP‐2

Cholesterol synthesis is regulated by the transcription factor sterol regulatory element binding protein 2 (SREBP‐2) and its target gene 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR), which is the rate‐limiting enzyme in cholesterol synthesis. Cyclic adenosine monophosphate–responsive element (CRE) binding protein–regulated transcription coactivator (CRTC) 2 is the master regulator of glucose metabolism. However, the effect of CRTC2 on cholesterol and its potential molecular mechanism remain unclear. Here, we demonstrated that CRTC2 expression and liver cholesterol content were increased in patients with high serum cholesterol levels who underwent resection of liver hemangiomas, as well as in mice fed a 4% cholesterol diet. Mice with adenovirus‐mediated CRTC2 overexpression also showed elevated lipid levels in both serum and liver tissues. Intriguingly, hepatic de novo cholesterol synthesis was markedly increased under these conditions. In contrast, CRTC2 ablation in mice fed a 4% cholesterol diet (18 weeks) showed decreased lipid levels in serum and liver tissues compared with those in littermate wild‐type mice. The expression of lipogenic genes (SREBP‐2 and HMGCR) was consistent with hepatic CRTC2 levels. In vivo imaging showed enhanced adenovirus‐mediated HMGCR‐luciferase activity in adenovirus‐mediated CRTC2 mouse livers; however, the activity was attenuated after mutation of CRE or sterol regulatory element sequences in the HMGCR reporter construct. The effect of CRTC2 on HMGCR in mouse livers was alleviated upon SREBP‐2 knockdown. CRTC2 modulated SREBP‐2 transcription by CRE binding protein, which recognizes the half‐site CRE sequence in the SREBP‐2 promoter. CRTC2 reduced the nuclear protein expression of forkhead box O1 and subsequently increased SREBP‐2 transcription by binding insulin response element 1, rather than insulin response element 2, in the SREBP‐2 promoter. Conclusion: CRTC2 regulates the transcription of SREBP‐2 by interfering with the recognition of insulin response element 1 in the SREBP‐2 promoter by forkhead box O1, thus inducing SREBP‐2/HMGCR signaling and subsequently facilitating hepatic cholesterol synthesis. (Hepatology 2017;66:481–497).

THYROID-STIMULATING HORMONE LEVELS ARE INVERSELY ASSOCIATED WITH SERUM TOTAL BILE ACID LEVELS: A CROSS-SECTIONAL STUDY.

OBJECTIVE Bile acids (BAs) synthesized from cholesterol play a critical role in eliminating excess cholesterol to maintain cholesterol homeostasis. BAs are also signaling molecules that are involved in the regulation of lipid, glucose, and energy metabolism. Thyroid-stimulating hormone (TSH) has been found to decrease liver BA synthesis via a sterol regulatory element-binding protein 2/hepatocyte nuclear factor 4 alpha/cholesterol 7α-hydroxylase (SREBP-2/HNF-4α/CYP7A1) pathway in vivo and in vitro. However, the relationship between serum TSH and total BA levels in humans is still unclear. METHODS This was a single-center cross-sectional study of 339 subclinical hypothyroidism (SCH) patients and an equal number of controls matched by age and sex from 11,000 subjects. RESULTS Serum total BA levels significantly decreased (3.11 ± 2.05 vs. 5.87 ± 2.39, P<.01), while total cholesterol (TC) levels increased (5.02 ± 0.65 vs. 4.88 ± 0.63, P<.01) in subclinical hypothyroidism (SCH) patients compared to control subjects. Serum TSH and BA levels were significantly and negatively correlated in subclinical hypothyroid patients who were also hypercholesterolemic (rs = -0.189, P = .004). Each 1 μIU/mL increase in TSH level was associated with a decrease in log-transformed values of total BAs (logTBAs) by 0.182 after controlling for confounding factors relevant to BA metabolism. The relationship between TSH and serum total BAs was more significant in subjects younger than 65 years. CONCLUSION Our results suggested that TSH is correlated with the total BA level in SCH patients independent of thyroid hormone, which suggests a potential physiological role of TSH and the importance of maintaining normal range TSH in SCH patients.

First Principle Study on Origin of Ferroelectricity of PbFe0.5Nb0.5O3

The crystal structure and electronic structure properties of PbFe0.5Nb0.5O3 (PFN) are studied by full potential linearized augmented plane wave (FLAPW) method. The optimized crystal structure, density of states and band structure have been obtained to understand the ferroelectric behavior of PFN. From the density of states analysis, it is shown that there is hybridization of Fe d − O p and Nb d − O p in ferroelectric PFN. This is consistent with the calculation of electronic band structure. This hybridization is responsible for the tendency to the ferroelectricity.

Non-high-density lipoprotein cholesterol is more informative than traditional cholesterol indices in predicting diabetes risk for women with normal glucose tolerance

Limited data are available regarding the performance of non‐high‐density lipoprotein cholesterol (non‐HDL) in predicting incident diabetes. We aimed to analyze the association between non‐HDL and development of diabetes, and to estimate the cut‐off point of non‐HDL for discriminating incident diabetes in people with normal glucose tolerance.

Thyrotropin Alters T Cell Development in the Thymus in Subclinical Hypothyroidism Mouse Model

Subclinical hypothyroidism (SCH) is highly prevalent in the general population and is associated with potential deleterious effects. Although developing T cells express thyroid‐stimulating hormone receptor (TSH‐R), the changes of T cell development in thymus in SCH have not been fully clarified. SCH mouse model, which is characterized by elevated serum TSH but similar thyroid hormone levels, was used to study the role of TSH in T cell development. Thymus weight of SCH mice increased 18% compared with controls. Importantly, the frequencies of CD4+ and CD8+ single‐positive (SP) thymocytes increased 38% and 44%, respectively. We demonstrated that TSH protected thymocytes from apoptosis as evidenced by a significant decrease of Annexin V‐positive thymocytes in SCH mice. Further analysis showed that extracellular‐regulated kinases (ERK) 1/2 in thymus were activated in SCH mice. With analysis of T cell receptor excision circles (TREC), we found that TSH increased recent thymic emigrants (RTE) in spleen tissue in SCH mice. Thus, these results suggest that TSH promoted T cell development and enhanced the thymic recent output in SCH mice, possibly by suppression of apoptosis of thymocytes, indicating that modification of the ERK signalling pathways.