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Sileo F, Leone A, De Amicis R, Foppiani A, Vignati L, Menichetti F, Pozzi G, Bertoli S, Battezzati A. Thyroid Stimulating Hormone Levels Are Related to Fatty Liver Indices Independently of Free Thyroxine: A Cross-Sectional Study. J Clin Med 2025; 14:2401. [PMID: 40217851 PMCID: PMC11990015 DOI: 10.3390/jcm14072401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/24/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025] Open
Abstract
Introduction: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and thyroid hormones has been established, but the direct effects of TSH on the liver, potentially leading to steatosis, and insulin resistance remain unclear. Objective: To investigate the association of TSH levels with MASLD and insulin resistance. Methods: We conducted a cross-sectional study of 8825 euthyroid individuals. Subjects were volunteers or patients referred to the International Center for Nutritional Status Assessment (University of Milan, Italy) undergoing clinical examination and blood drawing for thyroid function tests and liver indices calculation. Liver outcomes were fatty liver index (FLI), hepatic steatosis index (HSI), and FIB-4. All associations were adjusted for fT4 and confounders. Results: We found a positive association of TSH levels with FLI (β = 2.76; p < 0.001) and HSI (β = 0.58, p < 0.001). This relationship remained significant when stratifying by sex and BMI category, except for HSI in normal weight individuals. No significant association was found between TSH and hepatic fibrosis or insulin resistance. Conclusions: We found a positive association between TSH levels and MASLD in euthyroid individuals independently of fT4, sex, and BMI. Insulin resistance and hepatic fibrosis appear unrelated to TSH, independent of fT4 and BMI. The specific role of TSH in MASLD warrants further investigation.
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Affiliation(s)
- Federica Sileo
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy
- IRCCS Istituto Auxologico Italiano, Clinical Nutrition Unit, Department of Endocrine and Metabolic Diseases, 20145 Milan, Italy
| | - Alessandro Leone
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy
- IRCCS Istituto Auxologico Italiano, Clinical Nutrition Unit, Department of Endocrine and Metabolic Diseases, 20145 Milan, Italy
| | - Ramona De Amicis
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy
- IRCCS Istituto Auxologico Italiano, Obesity Unit and Laboratory of Nutrition and Obesity Research, Department of Endocrine and Metabolic Diseases, 20145 Milan, Italy
| | - Andrea Foppiani
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy
- IRCCS Istituto Auxologico Italiano, Clinical Nutrition Unit, Department of Endocrine and Metabolic Diseases, 20145 Milan, Italy
| | - Laila Vignati
- IRCCS Istituto Auxologico Italiano, Clinical Nutrition Unit, Department of Endocrine and Metabolic Diseases, 20145 Milan, Italy
| | - Francesca Menichetti
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy
| | - Giorgia Pozzi
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy
| | - Simona Bertoli
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy
- IRCCS Istituto Auxologico Italiano, Obesity Unit and Laboratory of Nutrition and Obesity Research, Department of Endocrine and Metabolic Diseases, 20145 Milan, Italy
| | - Alberto Battezzati
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy
- IRCCS Istituto Auxologico Italiano, Clinical Nutrition Unit, Department of Endocrine and Metabolic Diseases, 20145 Milan, Italy
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Han Z, Dong Q, Lu X, Liu S, Yang Y, Shao F, Tian L. TSH upregulates CYP4B1 through the PI3K/AKT/CREB pathway to promote cardiac hypertrophy. J Endocrinol Invest 2025:10.1007/s40618-025-02554-z. [PMID: 40056338 DOI: 10.1007/s40618-025-02554-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 02/09/2025] [Indexed: 03/10/2025]
Abstract
BACKGROUND Subclinical hypothyroidism (SCH) is closely associated with heart failure and cardiac hypertrophy, yet the underlying mechanism remains unclear. METHODS Cardiomyocytes treated with thyroid-stimulating hormone (TSH) were used as an in vitro model. Cardiac-specific TSHR knockout mice (CKO) were treated with isoproterenol (ISO) to induce cardiac hypertrophy in vivo. Serum FT4, TSH levels, heart weight, body weight and tibial length of mice were evaluated. Heart function was analyzed by M-mode cardiac ultrasonography. The pathological changes in cardiac tissues were detected by immunohistochemistry, hematoxylin-eosin and WGA staining. mRNA levels of ANP, BNP, α-MHC and β-MHC were evaluated by RT-PCR. Western blot was used to detect pathway related proteins. Besides, the transcriptome sequencing analysis and dual-luciferase reporter assays were used to verify the relevant molecular mechanisms. RESULTS TSH significantly promotes cardiomyocyte hypertrophy in cardiomyocytes. Meanwhile, cardiac-specific TSHR knockout significantly reduced ISO-induced cardiac hypertrophy. This was demonstrated by reductions in cell sizes, decreased HW/BW and HW/TL ratios, along with improved expression of hypertrophic genes. Further transcriptome sequencing results showed that TSH can significantly promote the expression of CYP4B1 in vitro. And the knockdown of CYP4B1 repressed TSH-induced cardiomyocyte hypertrophy. Further mechanistic studies revealed that TSH regulated the expression of CYP4B1 hypertrophy through the PI3K/AKT/CREB signaling pathway. Subsequently, the dual-luciferase assays demonstrated that CREB promotes the transcription of CYP4B1 by binding to its promoter region. CONCLUSION Overall, our findings highlight the direct impact of TSH/TSHR on cardiomyocyte hypertrophy and proposed CYP4B1 as a promising target for mitigating cardiac hypertrophy in SCH patients.
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Affiliation(s)
- Ziqi Han
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Qianqian Dong
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Xiao Lu
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Shanshan Liu
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Yanlong Yang
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Feifei Shao
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Limin Tian
- Gansu University of Chinese Medicine, Lanzhou, 730000, China.
- Department of Endocrinology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China.
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Ma S, Wang Y, Fan S, Jiang W, Sun M, Jing M, Bi W, Zhou M, Wu D. TSH-stimulated hepatocyte exosomes modulate liver-adipose triglyceride accumulation via the TGF-β1/ATGL axis in mice. Lipids Health Dis 2025; 24:81. [PMID: 40050912 PMCID: PMC11884018 DOI: 10.1186/s12944-025-02509-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/28/2025] [Indexed: 03/10/2025] Open
Abstract
Subclinical hypothyroidism (SCH) contributes to obesity, with the liver acting as a crucial metabolic regulator. Thyroid-stimulating hormone (TSH) affects systemic lipid balance, potentially linking SCH to obesity. While the direct impact of TSH on hepatic lipid metabolism has been extensively documented, its role in modulating lipid dynamics in peripheral organs through liver-mediated pathways remains insufficiently understood. This study identifies TSH-stimulated hepatocyte-derived exosomes (exosomesTSH) as key mediators in liver-adipose communication, promoting triglyceride accumulation in adipocytes via the transforming growth factor-beta 1 (TGF-β1)/adipose triglyceride lipase (ATGL) axis. ExosomesTSH enhance lipid storage in adipocytes, significantly increasing triglyceride content and lipid droplet formation while reducing lipolysis, effects that are dependent on TSH receptor (TSHR) activation in hepatocytes. In vivo, exosomesTSH induce weight gain and adipose tissue expansion, impairing glucose metabolism in both chow- and high-fat diet-fed mice. Mechanistically, exosomesTSH upregulate TGF-β1 and downregulate ATGL in adipocytes, establishing the TGF-β1/ATGL pathway as essential for exosome-mediated lipid accumulation. Further, miR-139-5p is identified as a modulator of TGF-β1 expression within this pathway, with overexpression of miR-139-5p alleviating exosomesTSH-induced lipid accumulation in adipocytes. This study elucidates a novel miR-139-5p-dependent mechanism through which TSH modulates lipid metabolism via liver-derived exosomes, highlighting the pivotal role of miR-139-5p in linking SCH to adipose lipid accumulation through the TGF-β1/ATGL signaling axis.
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Affiliation(s)
- Shizhan Ma
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Yayun Wang
- Department of Neurology, Qingdao Traditional Chinese Medicine Hospital Affiliated of Qingdao University, Qingdao, Shandong, 266033, China
| | - Shuteng Fan
- Department of Nursing, Taishan Vocational College of Nursing, Taian, Shandong, 271000, China
| | - Wanli Jiang
- First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Mingliang Sun
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250014, China
| | - Mengzhe Jing
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Wenkai Bi
- Department of Nuclear Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
| | - Meng Zhou
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
| | - Dongming Wu
- Department of Geriatric Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250014, China.
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Wang J, Zhong MY, Liu YX, Yu JY, Wang YB, Zhang XJ, Sun HP. Branched-chain amino acids promote hepatic Cyp7a1 expression and bile acid synthesis via suppressing FGF21-ERK pathway. Acta Pharmacol Sin 2025; 46:662-671. [PMID: 39567750 PMCID: PMC11845675 DOI: 10.1038/s41401-024-01417-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 10/22/2024] [Indexed: 11/22/2024]
Abstract
Branched-chain amino acids (BCAAs) including leucine, isoleucine and valine have been linked with metabolic and cardiovascular diseases. BCAAs homeostasis is tightly controlled by their catabolic pathway. BCKA dehydrogenase (BCKD) complex is the rate-limiting step for BCAA catabolism. Mitochondrial phosphatase 2C (PP2Cm) dephosphorylates the BCKD E1alpha subunit and activates BCKD complex. Deficiency of PP2Cm impairs BCAA catabolism, leading to higher plasma BCAA concentrations. Emerging evidence shows that bile acids are key regulators of glucose, lipid and energy metabolism. In this study, we investigated whether a direct link existed between BCAAs and bile acids metabolism. Wild-type mice were fed with normal-BCAA or high-BCAA diet, while PP2Cm deficiency mice were fed with normal chow for 14 weeks. The mice were fasted for 6 h before tissue harvest to exclude metabolic changes due to immediate food intake. We showed that the bile acids in tissues and feces were significantly elevated in wild-type mice fed with high-BCAA diet as well as in PP2Cm deficiency mice fed with normal chow. These mice displayed significantly increased expression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, and 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of CYP7A1 in plasma. BCAAs induced Cyp7a1 expression in cultured hepatocytes. In mouse liver and cultured hepatocytes, we demonstrated that elevated BCAAs inhibited fibroblast growth factor 21 (FGF21) expression and ERK signaling pathway. Direct inhibition of ERK by U0126 (800 nM) markedly induced Cyp7a1 expression in cultured hepatocytes. Moreover, the induced Cyp7a1 expression and inhibitory effects of BCAAs on ERK signaling pathway were abolished by treatment with recombinant FGF21 protein in mouse liver and cultured hepatocytes. Collectively, this study demonstrates a direct link between BCAAs and bile acid synthesis. BCAAs promotes Cyp7a1 expression and bile acid synthesis in liver via inhibiting FGF21-ERK signaling pathway. BCAAs-regulated bile acid synthesis and homeostasis may contribute to developing novel therapeutic strategies for the treatment of metabolic disorders.
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Affiliation(s)
- Ji Wang
- Department of Clinical Laboratory, The Second People's Hospital of Hefei / Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, China
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Meng-Yu Zhong
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Yun-Xia Liu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- The Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Jia-Yu Yu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yi-Bin Wang
- The Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Xue-Jiao Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
| | - Hai-Peng Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Yang M, Wei Y, Wang Y, Liu J, Wang G. TSH is independently associated with remnant cholesterol in euthyroid adults: a cross-sectional study based on 29,708 individuals. Hormones (Athens) 2025; 24:231-239. [PMID: 39215946 DOI: 10.1007/s42000-024-00596-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
PURPOSE The study aims to investigate the relationship between thyroid-stimulating hormone (TSH) and remnant cholesterol (RC) in euthyroid adults. METHODS The adults who were recruited for the study had undergone physical examination at Beijing Chao-Yang Hospital. High RC levels were defined as the upper quartile of RC levels in males and females, respectively. The relationship between TSH and RC was assessed using the logistic and linear regression models. RESULTS A total of 29,708 adults (14,347 males and 15,361 females) were enrolled in this study. RC ≥ 0.77 mmol/L in males and RC ≥ 0.60 mmol/L in females were defined as high RC levels. With increasing serum TSH levels, the percentage of adults with high RC levels increased. The odds ratios (ORs (95% confidence intervals (CIs)) for high RC levels increased as TSH quartiles (Q) rose after full adjustments [males: Q2 1.11 (1.00-1.24), P < 0.05; Q3 1.03 (0.92-1.15), P > 0.05; Q4 1.25 (1.12-1.40), P < 0.001; and females: Q2 1.07 (0.96-1.20), P > 0.05; Q3 1.17 (1.05-1.31), P < 0.01, Q4 1.33 (1.20-1.48), P < 0.001, all P for trend < 0.001], using Q1 as the reference. CONCLUSION Higher TSH levels were independently associated with higher RC levels in euthyroid adults, this underscoring the significance of regulating TSH levels appropriately.
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Affiliation(s)
- Mengge Yang
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Ying Wei
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Ying Wang
- Physical Examination Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Jia Liu
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China.
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China.
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Huang X, Cheng H, Wang S, Deng L, Li J, Qin A, Chu C, Liu X. Associations between indicators of lipid and glucose metabolism and hypothyroidism. Lipids Health Dis 2025; 24:58. [PMID: 39966896 PMCID: PMC11837584 DOI: 10.1186/s12944-025-02457-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Hypothyroidism, a prevalent thyroid hormone abnormality identified by biochemical indicators, is prone to serious consequences because of its insidious clinical manifestations and easy underdiagnosis. This research aimed to elucidate the relationships between indicators of lipid and glucose metabolism and hypothyroidism and to assess the value of metabolic indicators for hypothyroidism. METHODS Prevalence surveys were conducted utilizing information from 3254 NHANES individuals who passed screening between 2007 and 2012. Comparisons of baseline characteristics, assessment of logistic regression and subgroup analyses, visualization of restricted cubic splines curves, and validation of causal mediation analyses were performed to obtain a comprehensive view of the relationships between indicators of lipid and glucose metabolism and hypothyroidism. RESULTS Lipid and glucose metabolism indicators, especially the unconventional parameters triglyceride‒glucose index (TyG) and remnant cholesterol (RC) and the conventional parameter triglyceride (TG), exhibited robust positive relationships with hypothyroidism and served as crucial mediators in the pathways by which hypothyroidism affects health outcomes. Indicators were varying suggestive for hypothyroidism in distinct populations, with TyG being relatively more valuable. CONCLUSIONS Indicators of lipid and glucose metabolism (TyG, TG, and RC) were intimately associated with hypothyroidism, with potential applications in the assessment and management of hypothyroidism.
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Affiliation(s)
- Xinyi Huang
- Department of General Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Hengzheng Cheng
- Department of General Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Shuting Wang
- Department of General Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Laifu Deng
- Department of General Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Jiaxiu Li
- Department of General Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - An Qin
- Department of Thyroid and Breast Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Chunqiang Chu
- Department of Thyroid and Breast Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Xiao Liu
- Department of Thyroid and Breast Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
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Lin Q, Zhang J, Qi J, Tong J, Chen S, Zhang S, Liu X, Lou H, Lv J, Lin R, Xie J, Jin Y, Wang Y, Ying L, Wu J, Niu J. Hepatocyte-Derived FGF1 Alleviates Isoniazid and Rifampicin-Induced Liver Injury by Regulating HNF4α-Mediated Bile Acids Synthesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408688. [PMID: 39731358 PMCID: PMC11831436 DOI: 10.1002/advs.202408688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 12/09/2024] [Indexed: 12/29/2024]
Abstract
Isoniazid and rifampicin co-therapy are the main causes of anti-tuberculosis drug-induced liver injury (ATB-DILI) and acute liver failure, seriously threatening human health. However, its pathophysiology is not fully elucidated. Growing evidences have shown that fibroblast growth factors (FGFs) play a critical role in diverse aspects of liver pathophysiology. The aim of this study is to investigate the role of FGFs in the pathogenesis of isoniazid (INH) and rifampicin (RIF)-induced liver injury. Through systematic screening, this study finds that hepatic FGF1 expression is significantly downregulated in both mouse model and human patients challenged with INH and RIF. Hepatocyte-specific Fgf1 deficiency exacerbates INH and RIF-induced liver injury resulted from elevated bile acids (BAs) synthases and aberrant BAs accumulation. Conversely, pharmacological administration of the non-mitogenic FGF1 analog - FGF1ΔHBS significantly alleviated INH and RIF-induced liver injury via restoring BAs homeostasis. Mechanically, FGF1 repressed hepatocyte nuclear factor 4α (Hnf4α) transcription via activating FGF receptor 4 (FGFR4)-ERK1/2 signaling pathway, thus reducing BAs synthase. The findings demonstrate hepatic FGF1 functions as a negative regulator of BAs biosynthesis to protect against INH and RIF-induced liver injury via normalizing hepatic BAs homeostasis, providing novel mechanistic insights into the pathogenesis of ATB-DILI and potential therapeutic strategies for treatment of ATB-DILI.
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Affiliation(s)
- Qian Lin
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jiaren Zhang
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jie Qi
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jialin Tong
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Shenghuan Chen
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Sudan Zhang
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Xingru Liu
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Huatong Lou
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jiaxuan Lv
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Ruoyu Lin
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Junjun Xie
- Department of PharmacySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310016China
| | - Yi Jin
- Department of PathologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325035China
| | - Yang Wang
- School of Basic Medical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Lei Ying
- School of Basic Medical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jiamin Wu
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jianlou Niu
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
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Huang Y, Cai H, Han Y, Yang P. Mechanisms of Heat Stress on Neuroendocrine and Organ Damage and Nutritional Measures of Prevention and Treatment in Poultry. BIOLOGY 2024; 13:926. [PMID: 39596881 PMCID: PMC11591812 DOI: 10.3390/biology13110926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024]
Abstract
Heat stress (HS) due to high temperatures has adverse effects on poultry, including decreased feed intake, lower feed efficiency, decreased body weight, and higher mortality. There are complex mechanisms behind heat stress in poultry involving the neuroendocrine system, organ damage, and other physiological systems. HS activates endocrine glands, such as the pituitary, adrenal, thyroid, and gonadal, by the action of the hypothalamus and sympathetic nerves, ultimately causing changes in hormone levels: HS leads to increased corticosterone levels, changes in triiodothyronine and thyroxine levels, decreased gonadotropin levels, reduced ovarian function, and the promotion of catecholamine release, which ultimately affects the normal productive performance of poultry. Meanwhile, heat stress also causes damage to the liver, lungs, intestines, and various immune organs, severely impairing organ function in poultry. Nutrient additives to feed are important measures of prevention and treatment, including natural plants and extracts, probiotics, amino acids, and other nutrients, which are effective in alleviating heat stress in poultry. Future studies need to explore the specific mechanisms through which heat stress impacts the neuroendocrine system in poultry and the interrelationships between the axes and organ damage so as to provide an effective theoretical basis for the development of preventive and treatment measures.
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Affiliation(s)
| | | | | | - Peilong Yang
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (Y.H.); (H.C.); (Y.H.)
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Chen M, Wu Y, Yang H, Liu T, Han T, Dai W, Cen J, Ouyang F, Chen J, Liu J, Zhou L, Hu X. Effects of fermented Arctium lappa L. root by Lactobacillus casei on hyperlipidemic mice. Front Pharmacol 2024; 15:1447077. [PMID: 39529876 PMCID: PMC11551023 DOI: 10.3389/fphar.2024.1447077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction This study aimed to establish a fermentation system based on Lactobacillus casei (LC) and Arctium lappa L. root (AR) to investigate its effects. The objectives included comparing metabolite profiles pre- and post-fermentation using untargeted metabolomics and evaluating the impact of LC-AR in high-fat diet-induced hyperlipidemic mice. Methods Untargeted metabolomics was used to analyze differences in metabolites before and after fermentation. In vitro antioxidant activity, liver injury, lipid levels, pro-inflammatory cytokine levels, and cholesterol-related mRNA expression were assessed. 16S rRNA sequencing was conducted to evaluate changes in gut microbiota composition. Results LC-AR exhibited stronger antioxidant activity and higher metabolite levels than AR. It also improved liver injury as well as better regulation of lipid levels, pro-inflammatory cytokine levels, and cholesterol-related mRNA. 16S rRNA analysis revealed that LC-AR decreased the Firmicutes/Bacteroidetes ratio, which correlated negatively with triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. Discussion These findings suggest that LC-AR may serve as a promising functional food and drug raw material for improving hyperlipidemia, particularly through its beneficial effects on gut microbiota and lipid regulation.
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Affiliation(s)
- MingJu Chen
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Yuxiao Wu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Hongxuan Yang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Tianfeng Liu
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Tongkun Han
- Shenzhen Bao’an District Songgang People’s Hospital, Shenzhen, Guangdong, China
| | - Wangqiang Dai
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Junyue Cen
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Fan Ouyang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Jingjing Chen
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Jianxin Liu
- School of Pharmaceutical Sciences, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, Hunan University of Medicine, Huaihua, Hunan, China
| | - Lin Zhou
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Xuguang Hu
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
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10
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Wang X, Wu Z, Liu Y, Wu C, Jiang J, Hashimoto K, Zhou X. The role of thyroid-stimulating hormone in regulating lipid metabolism: Implications for body-brain communication. Neurobiol Dis 2024; 201:106658. [PMID: 39236910 DOI: 10.1016/j.nbd.2024.106658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 08/09/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024] Open
Abstract
Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the thyroid gland to produce and release thyroid hormones, primarily thyroxine and triiodothyronine. These hormones are key players in body-brain communication, influencing various physiological processes, including the regulation of metabolism (both peripheral and central effects), feedback mechanisms, and lipid metabolism. Recently, the increasing incidence of abnormal lipid metabolism has highlighted the link between thyroid function and lipid metabolism. Evidence suggests that TSH can affect all bodily systems through body-brain communication, playing a crucial role in growth, development, and the regulation of various physiological systems. Lipids serve dual purposes: they are involved in energy storage and metabolism, and they act as vital signaling molecules in numerous cellular activities, maintaining overall human health or contributing to various diseases. This article reviews the role of TSH in regulating lipid metabolism via body-brain crosstalk, focusing on its implications for common lipid metabolism disorders such as obesity, atherosclerosis, nonalcoholic fatty liver disease, neuropsychiatric disorders (including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and depression), and cerebrovascular disorders such as stroke.
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Affiliation(s)
- Xueqin Wang
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Zhen Wu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuting Liu
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Chengxi Wu
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Jun Jiang
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Kenji Hashimoto
- Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Xiangyu Zhou
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.
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11
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Yang Y, Xiao J, Qiu W, Jiang L. Cross-Talk Between Thyroid Disorders and Nonalcoholic Fatty Liver Disease: From Pathophysiology to Therapeutics. Horm Metab Res 2024; 56:697-705. [PMID: 38408595 DOI: 10.1055/a-2276-7973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
The medical community acknowledges the presence of thyroid disorders and nonalcoholic fatty liver disease (NAFLD). Nevertheless, the interconnection between these two circumstances is complex. Thyroid hormones (THs), including triiodothyronine (T3) and thyroxine (T4), and thyroid-stimulating hormone (TSH), are essential for maintaining metabolic balance and controlling the metabolism of lipids and carbohydrates. The therapeutic potential of THs, especially those that target the TRβ receptor isoform, is generating increasing interest. The review explores the pathophysiology of these disorders, specifically examining the impact of THs on the metabolism of lipids in the liver. The purpose of this review is to offer a thorough analysis of the correlation between thyroid disorders and NAFLD, as well as suggest potential therapeutic approaches for the future.
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Affiliation(s)
- Yan Yang
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, China
| | - Jiyuan Xiao
- Department of Pharmacology, Lanzhou University Second Hospital, Lanzhou, China
| | - Wen Qiu
- Department of Pharmacology, Lanzhou University Second Hospital, Lanzhou, China
| | - Luxia Jiang
- Department of Cardiac Surgery ICU, Lanzhou University Second Hospital, Lanzhou, China
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12
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Li Y, Chai Y, Liu X, Wang X, Meng X, Tang M, Zhang L, Zhang H. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is associated with thyroid hormones and thyroid hormone sensitivity indices: a cross-sectional study. Lipids Health Dis 2024; 23:310. [PMID: 39334150 PMCID: PMC11428414 DOI: 10.1186/s12944-024-02292-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Lipids and thyroid hormones (TH) are closely interrelated. However, previous studies have not mentioned the linkage encompassing the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) alongside TH level, as well as sensitivity indices. METHODS This cross-sectional study leverages expansive datasets from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2012. Weighted multivariate linear regression, smoothed curve fitting and sensitivity analyses were used to investigate the associations of the NHHR with the thyroid. Subgroup analyses and interaction tests were conducted to determine the robustness of the findings across diverse segments of the population, ensuring the consistency and generalizability of the observed associations. RESULTS The NHHR was significantly positively correlated with free triiodothyronine (FT3) levels, thyroid-stimulating hormone (TSH) levels, the FT3 to FT4 ratio (FT3/FT4), and the quantile-based thyroid feedback index for FT3 (TFQIFT3) and negatively correlated with free thyroxin (FT4) levels [0.17(0.07-0.27), P = 0.001; 0.60 (0.03-1.17), P = 0.040; 0.06 (0.04-0.08), P < 0.0001; 0.23 (0.16-0.30), P < 0.0001; and -0.65 (-1.05--0.24), P = 0.002]. Smoothed curve fitting revealed nonlinear correlations of the NHHR with thyroid function and thyroid hormone sensitivity indices. In subgroup analyses, interaction tests, and smoothed curve fitting analyses, different populations presented largely consistent statistical differences. CONCLUSION Among American adults, the NHHR was significantly positively correlated with FT3 levels, TSH levels, the FT3/FT4 and the TFQIFT3. Conversely, a negative association was noted between the NHHR and FT4 levels.
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Affiliation(s)
- Yuchen Li
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, No. 324, Five-Jing Road, Jinan, Shandong, 250021, China
| | - Yuwei Chai
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, No. 324, Five-Jing Road, Jinan, Shandong, 250021, China
| | - Xue Liu
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, No. 324, Five-Jing Road, Jinan, Shandong, 250021, China
| | - Xinhui Wang
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, No. 324, Five-Jing Road, Jinan, Shandong, 250021, China
| | - Xue Meng
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Mulin Tang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Li Zhang
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Haiqing Zhang
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, No. 324, Five-Jing Road, Jinan, Shandong, 250021, China.
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
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Untalan M, A Crimmins N, Yates KP, A Mencin A, A Xanthakos S, Thaker VV. Prevalence of subclinical hypothyroidism and longitudinal thyroid-stimulating hormone changes in youth with metabolic dysfunction-associated steatotic liver disease: An observational study. Hepatology 2024:01515467-990000000-01029. [PMID: 39292865 PMCID: PMC11955797 DOI: 10.1097/hep.0000000000001095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 08/23/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND Studies on adults have shown an association between overt or subclinical hypothyroidism and metabolic dysfunction-associated steatotic liver disease (MASLD). The goal of this study was to assess the relationship between thyroid-stimulating hormone (TSH) levels and the histological characteristics of MASLD in youth. METHODS This observational study used prospectively collected liver biopsy and clinical data from youth enrolled in 2 pediatric clinical trials in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Thyroid assays were compared between youth with MASLD and population-based controls aged ≤18 years from the National Health and Nutrition Examination Survey. Individuals with overt hypothyroidism, abnormal antithyroid antibodies, or thyroid-related medications were excluded. Subclinical hypothyroidism was defined as TSH between 4.5 and 10.0 uIU/L. Multinomial logistic regression was used to test the association between TSH and MASLD histological changes at baseline, adjusting for age, sex, race/ethnicity, and body mass index. Mixed-effect models, including treatment and time, were used for the longitudinal analysis. RESULTS Mean TSH, total thyroxine (T4), total triiodothyronine (T3), and free T4 levels were higher ( p < 0.001) in the NASH CRN cohort (n = 218; 421 observations) than in the National Health and Nutrition Examination Survey cohort (n = 2198). TSH levels were positively associated with increased steatosis over time ( p = 0.03). Subclinical hypothyroidism was associated with borderline or definite metabolic-associated steatohepatitis on histology at baseline ( p = 0.03) and with changes in fibrosis over time ( p = 0.01). CONCLUSIONS The association between TSH and steatosis severity in individuals with normal thyroid hormone concentrations suggests an independent role of TSH in MASLD.
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Affiliation(s)
- Matthew Untalan
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
| | - Nancy A Crimmins
- Division of Gastroenterology, Department of Pediatrics, Hepatology and Nutrition, Cincinnati Children's Hospital and Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Katherine P Yates
- Department of Epidemiology, Bloomberg School of Public Health at Johns Hopkins University, Baltimore, Maryland, USA
| | - Ali A Mencin
- Divisions of Molecular Genetics and Pediatric Endocrinology, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
| | - Stavra A Xanthakos
- Division of Gastroenterology, Department of Pediatrics, Hepatology and Nutrition, Cincinnati Children's Hospital and Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Vidhu V Thaker
- Divisions of Molecular Genetics and Pediatric Endocrinology, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
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14
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Menotti S, Mura C, Raia S, Bergianti L, De Carolis S, Romeo DM, Rota CA, Pontecorvi A. Overt hypothyroidism in pregnancy and language development in offspring: is there an association? J Endocrinol Invest 2024; 47:2201-2212. [PMID: 38498228 PMCID: PMC11369058 DOI: 10.1007/s40618-024-02317-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 01/17/2024] [Indexed: 03/20/2024]
Abstract
PURPOSE Overt hypothyroidism during pregnancy is linked to various obstetric complications, such as premature birth and fetal death. While some studies have shown that maternal hypothyroidism can impact a child's Intelligence Quotient (IQ) and language development, findings are controversial. The aim of this study was to explore the connection between treated maternal hypothyroidism during pregnancy and offspring neurodevelopment, focusing on learning and language and examining related maternal obstetric complications. METHODS Group 1 included 31 hypothyroid women with elevated thyroid stimulating hormone (TSH) (> 10 mU/L, > 10 µIU/mL) during pregnancy, and Group 2 had 21 euthyroid women with normal TSH levels (0.5-2.5 mU/L, 0.5-2.5 µIU/mL). Children underwent neuropsycological assessments using the Griffiths-II scale. RESULTS Pregnancy outcome showed an average gestational age at delivery of 38.2 weeks for hypothyroid women, compared to 40 weeks for controls, and average birth weight of 2855.6 g versus 3285 g for controls, with hypothyroid women having children with higher intrauterine growth restriction (IUGR) prevalence and more caesarean sections. The 1-min APGAR score was lower for the hypothyroid group's children, at 8.85 versus 9.52. Neuropsychological outcomes showed children of hypothyroid mothers scored lower in neurocognitive development, particularly in the learning and language subscale (subscale C), with a notable correlation between higher maternal TSH levels and lower subscale scores. CONCLUSION Fetuses born to hypothyroid mothers appeared to be at higher risk of IUGR and reduced APGAR score at birth. Neurocognitive development seemed to affect language performance more than the developmental quotient. This alteration appeared to correlate with the severity of hypothyroidism and its duration.
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Affiliation(s)
- S Menotti
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.
- Department of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
| | - C Mura
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - S Raia
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - L Bergianti
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - S De Carolis
- Department of Woman and Child Health, Woman Health Area Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - D M Romeo
- Pediatric Neurology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Largo A. Gemelli, 00168, Rome, Italy
- Pediatric Neurology Unit, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
| | - C A Rota
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - A Pontecorvi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
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15
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Santos MTAN, Villela-Nogueira CA, Leite NC, Teixeira PDFDS, de Souza MVL. Use of transient elastography for hepatic steatosis and fibrosis evaluation in patients with subclinical hypothyroidism. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e230477. [PMID: 39420912 PMCID: PMC11460959 DOI: 10.20945/2359-4292-2023-0477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/24/2024] [Indexed: 10/19/2024]
Abstract
OBJECTIVE To evaluate the association between subclinical hypothyroidism and hepatic steatosis and fibrosis using the noninvasive diagnostic methods transient hepatic elastography (TE) and controlled attenuation parameter (CAP) in patients with subclinical hypothyroidism. SUBJECTS AND METHODS This was a cross-sectional study including women with confirmed spontaneous subclinical hypothyroidism and an age- and body mass index (BMI)-matched control group without thyroid disease or circulating antithyroperoxidase (anti-TPO) antibodies. Exclusion criteria were age > 65 years, thyroid-stimulating hormone (TSH) > 10.0 mIUI/L, BMI ≥ 35 kg/m2, diabetes, or other chronic liver diseases. Liver stiffness was classified according to TE values (in kPa) and ranged from absence of fibrosis (F0) to advanced fibrosis (F3). Hepatic steatosis was classified according to CAP values (in dB/m) and ranged from low-grade (S1) to advanced (S3) steatosis. RESULTS Of 68 women enrolled, 27 were included in the subclinical hypothyroidism group and 41 in the control group. Advanced steatosis (S3) was more frequent in the subclinical hypothyroidism group (25.9% versus 7.3%, respectively, p = 0.034). Circulating anti-TPO was an independent factor associated with advanced steatosis (odds ratio 9.5, 95% confidence interval 1.3-68.3). In multiple linear regression analysis, TE values (which evaluated fibrosis) correlated negatively with free thyroxine levels. CONCLUSION The results of this study strengthen the hypothesis that hepatic steatosis is associated with autoimmune (positive anti-TPO) subclinical hypothyroidism, independently from BMI. However, subclinical hypothyroidism alone does not appear to be associated with a significantly increased risk of hepatic fibrosis.
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Affiliation(s)
- Milena Tauil Auad Noronha Santos
- Universidade Federal do Rio de JaneiroHospital Universitário Clementino Fraga FilhoDivisão de EndocrinologiaRio de JaneiroRJBrasilDivisão de Endocrinologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - Cristiane Alves Villela-Nogueira
- Universidade Federal do Rio de JaneiroHospital Universitário Clementino Fraga FilhoDivisão de HepatologiaRio de JaneiroRJBrasilDivisão de Hepatologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - Nathalie Carvalho Leite
- Universidade Federal do Rio de JaneiroHospital Universitário Clementino Fraga FilhoDivisão de HepatologiaRio de JaneiroRJBrasilDivisão de Hepatologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - Patrícia de Fátima dos Santos Teixeira
- Universidade Federal do Rio de JaneiroHospital Universitário Clementino Fraga FilhoDivisão de EndocrinologiaRio de JaneiroRJBrasilDivisão de Endocrinologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - Marcus Vinicius Leitão de Souza
- Universidade Federal do Rio de JaneiroHospital Universitário Clementino Fraga FilhoDivisão de EndocrinologiaRio de JaneiroRJBrasilDivisão de Endocrinologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
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16
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Qin Y, Wu Y, Zang H, Cong X, Shen Q, Chen L, Chen X. Lipid Metabolism in Pregnancy Women with Hypothyroidism and Potential Influence on Pregnancy Outcome. J Lipids 2024; 2024:5589492. [PMID: 39015803 PMCID: PMC11251789 DOI: 10.1155/2024/5589492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 06/07/2024] [Accepted: 06/17/2024] [Indexed: 07/18/2024] Open
Abstract
Thyroid hormone (TH) is essential for maintaining normal physiological processes during pregnancy, including the metabolism of energy materials in both the mother and fetus and the growth and development of fetal bone and nervous system. TH can act on the liver, fat, and other tissues and organs to participate in lipid synthesis and breakdown through multiple pathways. Consequently, abnormal thyroid function is often accompanied by lipid metabolism disorders. Both clinical and subclinical hypothyroidism, as well as dyslipidemia during pregnancy, have been shown to be associated with an increased risk of multiple adverse pregnancy outcomes. Recently, there has been an increased interest in studying the alteration of lipidomic and hypothyroidism (both clinical and subclinical hypothyroidism) during pregnancy. Studies have suggested that altered lipid molecules might be used as potential biomarker and associated with adverse maternal and neonatal outcome. Thus, we summarized the associations between lipid metabolism and clinical or subclinical hypothyroidism during pregnancy in this review. Then, we discussed the underlying mechanisms of thyroid dysfunction and lipid metabolism. In addition, we reviewed the possible effect of dyslipidemia on pregnancy and neonatal outcome. However, the relationship between hypothyroidism during pregnancy and changes in the lipid profile and how to intervene in the occurrence and development of adverse pregnancy outcomes require further study.
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Affiliation(s)
- Yuxin Qin
- Department of EndocrinologyThe Affiliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Road, Suzhou 215000, China
| | - Ying Wu
- Department of EndocrinologyThe Affiliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Road, Suzhou 215000, China
| | - Huanhuan Zang
- Department of EndocrinologyThe Affiliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Road, Suzhou 215000, China
| | - Xiangguo Cong
- Department of EndocrinologyThe Affiliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Road, Suzhou 215000, China
| | - Qiong Shen
- Department of EndocrinologyThe Affiliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Road, Suzhou 215000, China
| | - Lei Chen
- Department of EndocrinologyThe Affiliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Road, Suzhou 215000, China
| | - Xinxin Chen
- Department of EndocrinologyThe Affiliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Road, Suzhou 215000, China
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17
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Alomair BM, Al-Kuraishy HM, Al-Gareeb AI, Alshammari MA, Alexiou A, Papadakis M, Saad HM, Batiha GES. Increased thyroid stimulating hormone (TSH) as a possible risk factor for atherosclerosis in subclinical hypothyroidism. Thyroid Res 2024; 17:13. [PMID: 38880884 PMCID: PMC11181570 DOI: 10.1186/s13044-024-00199-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 05/08/2024] [Indexed: 06/18/2024] Open
Abstract
Primary hypothyroidism (PHT) is associated with an increased risk for the development of atherosclerosis (AS) and other cardiovascular disorders. PHT induces atherosclerosis (AS) through the induction of endothelial dysfunction, and insulin resistance (IR). PHT promotes vasoconstriction and the development of hypertension. However, patients with subclinical PHT with normal thyroid hormones (THs) are also at risk for cardiovascular complications. In subclinical PHT, increasing thyroid stimulating hormone (TSH) levels could be one of the causative factors intricate in the progression of cardiovascular complications including AS. Nevertheless, the mechanistic role of PHT in AS has not been fully clarified in relation to increased TSH. Therefore, in this review, we discuss the association between increased TSH and AS, and how increased TSH may be involved in the pathogenesis of AS. In addition, we also discuss how L-thyroxine treatment affects the development of AS.
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Affiliation(s)
- Basil Mohammed Alomair
- Assistant Professor, Internal Medicine and Endocrinology, Department of Medicine, College of Medicine, Jouf University, Sakakah, 04631, Kingdom of Saudi Arabia
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Majed Ayed Alshammari
- Department of Medicine, Prince Mohammed Bin Abdulaziz Medical City, Al Jouf-Sakkaka, 42421, Saudi Arabia
| | - Athanasios Alexiou
- University Centre for Research & Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India
- Department of Research & Development, Funogen, Athens, Greece
- Department of Research & Development, AFNP Med, Vienna, 1030, Austria
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, 2770, NSW, Australia
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, Wuppertal, 42283, Germany.
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, 51744, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt.
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18
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Peng L, Luan S, Shen X, Zhan H, Ge Y, Liang Y, Wang J, Xu Y, Wu S, Zhong X, Zhang H, Gao L, Zhao J, He Z. Thyroid hormone deprival and TSH/TSHR signaling deficiency lead to central hypothyroidism-associated intestinal dysplasia. Life Sci 2024; 345:122577. [PMID: 38521387 DOI: 10.1016/j.lfs.2024.122577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/22/2024] [Accepted: 03/15/2024] [Indexed: 03/25/2024]
Abstract
BACKGROUND Central hypothyroidism (CH) is characterized by low T4 levels and reduced levels or bioactivity of circulating TSH. However, there is a lack of studies on CH-related intestinal maldevelopment. In particular, the roles of TH and TSH/TSHR signaling in CH-related intestinal maldevelopment are poorly understood. Herein, we utilized Tshr-/- mice as a congenital hypothyroidism model with TH deprival and absence of TSHR signaling. METHODS The morphological characteristics of intestines were determined by HE staining, periodic acid-shiff staining, and immunohistochemical staining. T4 was administrated into the offspring of homozygous mice from the fourth postnatal day through weaning or administrated after weaning. RT-PCR was used to evaluate the expression of markers of goblet cells and intestinal digestive enzymes. Single-cell RNA-sequencing analysis was used to explore the cell types and gene profiles of metabolic alternations in early-T4-injected Tshr-/- mice. KEY FINDINGS Tshr deletion caused significant growth retardation and intestinal maldevelopment, manifested as smaller and more slender small intestines due to reduced numbers of stem cells and differentiated epithelial cells. Thyroxin supplementation from the fourth postnatal day, but not from weaning, significantly rescued the abnormal intestinal structure and restored the decreased number of proliferating intestinal cells in crypts of Tshr-/- mice. Tshr-/- mice with early-life T4 injections had more early goblet cells and impaired metabolism compared to Tshr+/+ mice. SIGNIFICANCE TH deprival leads to major defects of CH-associated intestinal dysplasia while TSH/TSHR signaling deficiency promotes the differentiation of goblet cells and impairs nutrition metabolism.
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Affiliation(s)
- Li Peng
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Sisi Luan
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Xin Shen
- Department of General Practice, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Huidong Zhan
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Yueping Ge
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Yixiao Liang
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Jing Wang
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Yang Xu
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Shanshan Wu
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Xia Zhong
- Department of General Practice, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Haiqing Zhang
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Ling Gao
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Zhao He
- Department of Endocrinology, Shandong Provincial Hospital, Medical Integration and Practice Center, Shandong University, Jinan, Shandong 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.
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Li Y, Zheng M, Limbara S, Zhang S, Yu Y, Yu L, Jiao J. Effects of the Pituitary-targeted Gland Axes on Hepatic Lipid Homeostasis in Endocrine-associated Fatty Liver Disease-A Concept Worth Revisiting. J Clin Transl Hepatol 2024; 12:416-427. [PMID: 38638376 PMCID: PMC11022059 DOI: 10.14218/jcth.2023.00421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 12/28/2023] [Accepted: 01/03/2024] [Indexed: 04/20/2024] Open
Abstract
Hepatic lipid homeostasis is not only essential for maintaining normal cellular and systemic metabolic function but is also closely related to the steatosis of the liver. The controversy over the nomenclature of non-alcoholic fatty liver disease (NAFLD) in the past three years has once again sparked in-depth discussions on the pathogenesis of this disease and its impact on systemic metabolism. Pituitary-targeted gland axes (PTGA), an important hormone-regulating system, are indispensable in lipid homeostasis. This review focuses on the roles of thyroid hormones, adrenal hormones, sex hormones, and their receptors in hepatic lipid homeostasis, and summarizes recent research on pituitary target gland axes-related drugs regulating hepatic lipid metabolism. It also calls on researchers and clinicians to recognize the concept of endocrine-associated fatty liver disease (EAFLD) and to re-examine human lipid metabolism from the macroscopic perspective of homeostatic balance.
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Affiliation(s)
- Yifang Li
- Department of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Meina Zheng
- Department of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Steven Limbara
- Department of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Shanshan Zhang
- Department of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Yutao Yu
- Department of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Le Yu
- Department of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Jian Jiao
- Department of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
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20
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Fang H, Li Q, Wang H, Ren Y, Zhang L, Yang L. Maternal nutrient metabolism in the liver during pregnancy. Front Endocrinol (Lausanne) 2024; 15:1295677. [PMID: 38572473 PMCID: PMC10987773 DOI: 10.3389/fendo.2024.1295677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 03/08/2024] [Indexed: 04/05/2024] Open
Abstract
The liver plays pivotal roles in nutrient metabolism, and correct hepatic adaptations are required in maternal nutrient metabolism during pregnancy. In this review, hepatic nutrient metabolism, including glucose metabolism, lipid and cholesterol metabolism, and protein and amino acid metabolism, is first addressed. In addition, recent progress on maternal hepatic adaptations in nutrient metabolism during pregnancy is discussed. Finally, the factors that regulate hepatic nutrient metabolism during pregnancy are highlighted, and the factors include follicle-stimulating hormone, estrogen, progesterone, insulin-like growth factor 1, prostaglandins fibroblast growth factor 21, serotonin, growth hormone, adrenocorticotropic hormone, prolactin, thyroid stimulating hormone, melatonin, adrenal hormone, leptin, glucagon-like peptide-1, insulin glucagon and thyroid hormone. Our vision is that more attention should be paid to liver nutrient metabolism during pregnancy, which will be helpful for utilizing nutrient appropriately and efficiently, and avoiding liver diseases during pregnancy.
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Affiliation(s)
- Hongxu Fang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan, China
| | - Qingyang Li
- College of Life Sciences, Hebei Normal University, Shijiazhuang, China
| | - Haichao Wang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan, China
| | - Ying Ren
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan, China
| | - Leying Zhang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan, China
| | - Ling Yang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan, China
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21
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Yorke E. Co-Morbid Hypothyroidism and Liver Dysfunction: A Review. Clin Med Insights Endocrinol Diabetes 2024; 17:11795514241231533. [PMID: 38348020 PMCID: PMC10860496 DOI: 10.1177/11795514241231533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/11/2024] [Indexed: 02/15/2024] Open
Abstract
The liver and thyroid hormones interact at multiple levels to maintain homoeostasis. The liver requires large adequate amounts of thyroid hormones to execute its metabolic functions optimally, and deficiency of thyroid hormones may lead to liver dysfunction. Hypothyroidism has been associated with abnormal lipid metabolism, non-alcoholic fatty liver disease (NAFLD), hypothyroidism-induced myopathy, hypothyroidism-associated gallstones and occasionally, interferon-induced thyroid dysfunction. NAFLD remain an important association with hypothyroidism and further studies are needed that specifically compare the natural course of NAFLD secondary to hypothyroidism and primary NAFLD. Hepatic dysfunction associated with hypothyroidism is usually reverted by normalizing thyroid status. Large scale studies geared towards finding new and effective therapies, especially for NAFLD are needed. The clinician must be aware that there exists overlapping symptomatology between liver dysfunction and severe hypothyroidism which may make delay the diagnosis and treatment of hypothyroidism; this requires a high index of suspicion.
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Affiliation(s)
- Ernest Yorke
- Department of Medicine & Therapeutics, University of Ghana Medical School, Accra, Ghana
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22
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Ramanathan R, Patwa SA, Ali AH, Ibdah JA. Thyroid Hormone and Mitochondrial Dysfunction: Therapeutic Implications for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Cells 2023; 12:2806. [PMID: 38132126 PMCID: PMC10741470 DOI: 10.3390/cells12242806] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/30/2023] [Accepted: 12/07/2023] [Indexed: 12/23/2023] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets, and preclinical and clinical studies suggest that TH, thyroid receptor β (TR-β) analogs, and synthetic analogs specific to the liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD.
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Affiliation(s)
- Raghu Ramanathan
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, University of Missouri, Columbia, MO 65212, USA
| | - Sohum A. Patwa
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
| | - Ahmad Hassan Ali
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, University of Missouri, Columbia, MO 65212, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, University of Missouri, Columbia, MO 65212, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
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23
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Heidarpour M, Rezvanian P, Sadri MA, Keshavarzrad P, Zakeri R, Vakilbashi O, Shafie D, Shekarchizadeh M, Zarfeshani S, Rabbanipour N, Najafian J, Vaseghi G, Sarrafzadegan N. The Association of Thyroid-Stimulating Hormone (TSH) Levels and Lipid Profile in Euthyroid Patients with Familial Hypercholesterolemia. BIOMED RESEARCH INTERNATIONAL 2023; 2023:4711275. [PMID: 37228643 PMCID: PMC10205407 DOI: 10.1155/2023/4711275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 03/13/2023] [Accepted: 05/03/2023] [Indexed: 05/27/2023]
Abstract
Previous studies reported a relationship between thyroid-stimulating hormone (TSH) and low-density lipoprotein cholesterol (LDL-C) levels. In this study, we aim to evaluate the impact of TSH levels on lipid profile in patients with familial hypercholesterolemia (FH) and euthyroid state. Patients were selected from the Isfahan FH registry. The Dutch Lipid Clinic Network (DLCN) criteria are used to detect FH. Patients were classified into no FH, possible FH, probable FH, and definite FH groups based on the DLCN scores. Patients with any cause of secondary hyperlipidemia, including hypothyroidism, were excluded from this study. The study group consisted of 103 patients with possible FH, 25 patients with definite FH, and 63 individuals with no FH. The mean TSH and LDL-C levels among participants were 2.10 ± 1.22 mU/l and 142.17 ± 62.56 mg/dl, respectively. No positive or negative correlation was found between serum TSH and total cholesterol (P value = 0.438), high-density lipoprotein cholesterol (P = 0.225), triglycerides (P value = 0.863), and LDL-C (P value = 0.203). We found no correlation between serum TSH levels and lipid profiles in euthyroid patients with FH.
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Affiliation(s)
- Maryam Heidarpour
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parastesh Rezvanian
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Amin Sadri
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parsa Keshavarzrad
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rezvan Zakeri
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Davood Shafie
- Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Masood Shekarchizadeh
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sonia Zarfeshani
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najmeh Rabbanipour
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jamshid Najafian
- Hypertension Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Golnaz Vaseghi
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nizal Sarrafzadegan
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
- School of Population & Public Health, University of British Columbia, Vancouver, BC, Canada
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24
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Wu J, Yang K, Fan H, Wei M, Xiong Q. Targeting the gut microbiota and its metabolites for type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2023; 14:1114424. [PMID: 37229456 PMCID: PMC10204722 DOI: 10.3389/fendo.2023.1114424] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 04/28/2023] [Indexed: 05/27/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance. The incidence of T2DM is increasing globally, and a growing body of evidence suggests that gut microbiota dysbiosis may contribute to the development of this disease. Gut microbiota-derived metabolites, including bile acids, lipopolysaccharide, trimethylamine-N-oxide, tryptophan and indole derivatives, and short-chain fatty acids, have been shown to be involved in the pathogenesis of T2DM, playing a key role in the host-microbe crosstalk. This review aims to summarize the molecular links between gut microbiota-derived metabolites and the pathogenesis of T2DM. Additionally, we review the potential therapy and treatments for T2DM using probiotics, prebiotics, fecal microbiota transplantation and other methods to modulate gut microbiota and its metabolites. Clinical trials investigating the role of gut microbiota and its metabolites have been critically discussed. This review highlights that targeting the gut microbiota and its metabolites could be a potential therapeutic strategy for the prevention and treatment of T2DM.
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Affiliation(s)
- Jiaqiang Wu
- The Second Clinical Medical College of Nanchang University, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kangping Yang
- The Second Clinical Medical College of Nanchang University, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hancheng Fan
- Department of Histology and Embryology, School of Basic Medicine, Nanchang University, Nanchang, China
| | - Meilin Wei
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qin Xiong
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, China
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25
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Hu J, Ji Y, Lang X, Zhang XY. Association of thyroid function with abnormal lipid metabolism in young patients with first-episode and drug naïve major depressive disorder. Front Psychiatry 2023; 14:1085105. [PMID: 36865071 PMCID: PMC9971224 DOI: 10.3389/fpsyt.2023.1085105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
INTRODUCTION Abnormal lipid metabolism in patients with major depressive disorder (MDD) has received increasing attention. The coexistence of MDD and abnormal thyroid function has been intensively studied. Moreover, thyroid function is closely related to lipid metabolism. The aim of this study was to investigate the relationship between thyroid function and abnormal lipid metabolism in young patients with first-episode and drug naïve (FEDN) MDD. METHODS A total of 1,251 outpatients aged 18-44 years with FEDN MDD were enrolled. Demographic data were collected, and lipid and thyroid function levels were measured, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free tetraiodothyronine (FT4), anti-thyroglobulin antibody (TG-Ab), and anti-thyroid peroxidase antibody (TPO-Ab). The Hamilton Rating Scale for Depression (HAMD), Hamilton Anxiety Rating Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS) positive subscale were also assessed for each patient. RESULTS Compared with young MDD patients without comorbid lipid metabolism abnormalities, patients with comorbid lipid metabolism abnormalities had higher body mass index (BMI) values, HAMD score, HAMA score, PANSS positive subscale score, TSH levels, TG-Ab levels, and TPO-Ab levels. Binary logistic regression analysis showed that TSH level, HAMD score and BMI were risk factors for abnormal lipid metabolism. TSH levels were an independent risk factor for abnormal lipid metabolism in young MDD patients. Stepwise multiple linear regression showed that both TC and LDL-C levels were positively correlated with TSH levels, HAMD and PANSS positive subscale scores, respectively. HDL-C levels were negatively correlated with TSH levels. TG levels were positively correlated with TSH and TG-Ab levels and HAMD score. DISCUSSION Our results show that thyroid function parameters, especially TSH levels, are implicated in abnormal lipid metabolism in young patients with FEDN MDD.
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Affiliation(s)
- Jieqiong Hu
- Department of Psychosomatic Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Yunxin Ji
- Department of Psychosomatic Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Xiaoe Lang
- Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiang-Yang Zhang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.,Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
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Shao F, Li R, Guo Q, Qin R, Su W, Yin H, Tian L. Plasma Metabolomics Reveals Systemic Metabolic Alterations of Subclinical and Clinical Hypothyroidism. J Clin Endocrinol Metab 2022; 108:13-25. [PMID: 36181451 PMCID: PMC9759175 DOI: 10.1210/clinem/dgac555] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 09/01/2022] [Indexed: 02/03/2023]
Abstract
CONTEXT Clinical hypothyroidism (CH) and subclinical hypothyroidism (SCH) have been linked to various metabolic comorbidities but the underlying metabolic alterations remain unclear. Metabolomics may provide metabolic insights into the pathophysiology of hypothyroidism. OBJECTIVE We explored metabolic alterations in SCH and CH and identify potential metabolite biomarkers for the discrimination of SCH and CH from euthyroid individuals. METHODS Plasma samples from a cohort of 126 human subjects, including 45 patients with CH, 41 patients with SCH, and 40 euthyroid controls, were analyzed by high-resolution mass spectrometry-based metabolomics. Data were processed by multivariate principal components analysis and orthogonal partial least squares discriminant analysis. Correlation analysis was performed by a Multivariate Linear Regression analysis. Unbiased Variable selection in R algorithm and 3 machine learning models were utilized to develop prediction models based on potential metabolite biomarkers. RESULTS The plasma metabolomic patterns in SCH and CH groups were significantly different from those of control groups, while metabolite alterations between SCH and CH groups were dramatically similar. Pathway enrichment analysis found that SCH and CH had a significant impact on primary bile acid biosynthesis, steroid hormone biosynthesis, lysine degradation, tryptophan metabolism, and purine metabolism. Significant associations for 65 metabolites were found with levels of thyrotropin, free thyroxine, thyroid peroxidase antibody, or thyroglobulin antibody. We successfully selected and validated 17 metabolic biomarkers to differentiate 3 groups. CONCLUSION SCH and CH have significantly altered metabolic patterns associated with hypothyroidism, and metabolomics coupled with machine learning algorithms can be used to develop diagnostic models based on selected metabolites.
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Affiliation(s)
| | | | - Qian Guo
- Department of Endocrinology (Cadre Ward 3), Gansu Provincial Hospital, Lanzhou, Gansu 730099, China
- Clinical Research Center for Metabolic Disease, Gansu Province. 204 Donggang West Road, Lanzhou, Gansu 730099, China
| | - Rui Qin
- Clinical Research Center for Metabolic Disease, Gansu Province. 204 Donggang West Road, Lanzhou, Gansu 730099, China
| | - Wenxiu Su
- Clinical Research Center for Metabolic Disease, Gansu Province. 204 Donggang West Road, Lanzhou, Gansu 730099, China
| | - Huiyong Yin
- Correspondence: Limin Tian, M.D., The First School of Clinical Medicine, Lanzhou University, Gansu Provincial Hospital, Donggang West Road, 730030, Lanzhou, Gansu, China. ; Huiyong Yin, Ph.D., Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, China 200031.
| | - Limin Tian
- Correspondence: Limin Tian, M.D., The First School of Clinical Medicine, Lanzhou University, Gansu Provincial Hospital, Donggang West Road, 730030, Lanzhou, Gansu, China. ; Huiyong Yin, Ph.D., Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, China 200031.
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Su X, Chen X, Wang B. Relationship between the development of hyperlipidemia in hypothyroidism patients. Mol Biol Rep 2022; 49:11025-11035. [PMID: 36097119 DOI: 10.1007/s11033-022-07423-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 03/17/2022] [Accepted: 03/24/2022] [Indexed: 11/24/2022]
Abstract
As shown in the previous studies, hypothyroidism (HT) is identified to be closely associated with the elevated plasma levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and with the decreased plasma levels of high density lipoprotein cholesterol (HDL-C). On the other hand, the thyroid hormone (TH), which has been considered as a vital hormone produced and released by the thyroid gland, are well-established to regulate the metabolism of plasma TC; whereas other evidence proposed that the thyroid-stimulating hormone (TSH) also regulated the plasma cholesterol metabolism independently of the TH, which further promotes the progression of hyperlipidemia. Nevertheless, the potential mechanism is still not illustrated. It is worth noting that several studies has found that the progression of HT-induced hyperlipidemia might be associated with the down-regulated plasma levels of TH and the up-regulated plasma levels of TSH, revealing that HT could promote hyperlipidemia and its related cardio-metabolic disorders. Otherwise, multiple novel identified plasma proteins, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein (ANGPTLs), and fibroblast growth factors (FGFs), have also been demonstrated to embrace a vital function in modulating the progression of hyperlipidemia induced by HT. In the present comprehensive review, the recent findings which elucidated the association of HT and the progression of hyperlipidemia were summarized. Furthermore, other results which illustrated the underlying mechanisms by which HT facilitates the progression of hyperlipidemia and its cardio-metabolic disorders are also listed in the current review.
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Affiliation(s)
- Xin Su
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, No. 2999 Jinshan Road, 361000, Xiamen, Fujian, China
| | - Xiang Chen
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, No. 2999 Jinshan Road, 361000, Xiamen, Fujian, China.
| | - Bin Wang
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, No. 2999 Jinshan Road, 361000, Xiamen, Fujian, China.
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28
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Hatziagelaki E, Paschou SA, Schön M, Psaltopoulou T, Roden M. NAFLD and thyroid function: pathophysiological and therapeutic considerations. Trends Endocrinol Metab 2022; 33:755-768. [PMID: 36171155 DOI: 10.1016/j.tem.2022.08.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 01/21/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a worldwide rising challenge because of hepatic, but also extrahepatic, complications. Thyroid hormones are master regulators of energy and lipid homeostasis, and the presence of abnormal thyroid function in NAFLD suggests pathogenic relationships. Specifically, persons with hypothyroidism feature dyslipidemia and lower hepatic β-oxidation, which favors accumulation of triglycerides and lipotoxins, insulin resistance, and subsequently de novo lipogenesis. Recent studies indicate that liver-specific thyroid hormone receptor β agonists are effective for the treatment of NAFLD, likely due to improved lipid homeostasis and mitochondrial respiration, which, in turn, may contribute to a reduced risk of NAFLD progression. Taken together, the possible coexistence of thyroid disease and NAFLD calls for increased awareness and optimized strategies for mutual screening and management.
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Affiliation(s)
- Erifili Hatziagelaki
- Diabetes Center, Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula A Paschou
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Martin Schön
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany
| | - Theodora Psaltopoulou
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
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29
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Important Hormones Regulating Lipid Metabolism. Molecules 2022; 27:molecules27207052. [PMID: 36296646 PMCID: PMC9607181 DOI: 10.3390/molecules27207052] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/07/2022] [Accepted: 10/10/2022] [Indexed: 11/17/2022] Open
Abstract
There is a wide variety of kinds of lipids, and complex structures which determine the diversity and complexity of their functions. With the basic characteristic of water insolubility, lipid molecules are independent of the genetic information composed by genes to proteins, which determine the particularity of lipids in the human body, with water as the basic environment and genes to proteins as the genetic system. In this review, we have summarized the current landscape on hormone regulation of lipid metabolism. After the well-studied PI3K-AKT pathway, insulin affects fat synthesis by controlling the activity and production of various transcription factors. New mechanisms of thyroid hormone regulation are discussed, receptor α and β may mediate different procedures, the effect of thyroid hormone on mitochondria provides a new insight for hormones regulating lipid metabolism. Physiological concentration of adrenaline induces the expression of extrapituitary prolactin in adipose tissue macrophages, which promotes fat weight loss. Manipulation of hormonal action has the potential to offer a new therapeutic horizon for the global burden of obesity and its associated complications such as morbidity and mortality.
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30
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Zheng H, Zhao T, Xu YC, Zhang DG, Song YF, Tan XY. Dietary choline prevents high fat-induced disorder of hepatic cholesterol metabolism through SREBP-2/HNF-4α/CYP7A1 pathway in a freshwater teleost yellow catfish Pelteobagrus fulvidraco. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2022; 1865:194874. [PMID: 36122892 DOI: 10.1016/j.bbagrm.2022.194874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/03/2022] [Accepted: 09/07/2022] [Indexed: 06/15/2023]
Abstract
Lipid overload-induced hepatic cholesterol accumulation is a major public health problem worldwide, and choline has been reported to ameliorate cholesterol accumulation, but its mechanism remains unclear. Our study found that choline prevented high-fat diet (HFD)-induced cholesterol metabolism disorder and enhanced choline uptake and phosphatidylcholine synthesis in the liver tissues; choline incubation prevented fatty acid (FA)-induced cholesterol accumulation and FA-induced inhibition of bile acid synthesis. Moreover, compared to single FA incubation, choline incubation or FA + choline co-incubation increased the mRNA abundances and protein levels of HNF4α and up-regulated the degradation of cholesterol into bile acids. Mechanistically, choline prevented the FA-induced accumulation of SREBP2 protein and the interaction between SREBP2 and HNF4α, thereby enhancing the DNA binding capacity of the HNF4α to the CYP7A1 promoter, and promoting the degradation of cholesterol into bile acids. Our study elucidated the novel regulatory mechanisms of choline preventing HFD-induced cholesterol accumulation and increasing bile acid synthesis by SREBP-2/HNF-4α/CYP7A1 pathway.
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Affiliation(s)
- Hua Zheng
- Laboratory of Molecular Nutrition, Huazhong Agricultural University, Wuhan 430070, China
| | - Tao Zhao
- Laboratory of Molecular Nutrition, Huazhong Agricultural University, Wuhan 430070, China
| | - Yi-Chuang Xu
- Laboratory of Molecular Nutrition, Huazhong Agricultural University, Wuhan 430070, China
| | - Dian-Guang Zhang
- Laboratory of Molecular Nutrition, Huazhong Agricultural University, Wuhan 430070, China
| | - Yu-Feng Song
- Laboratory of Molecular Nutrition, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiao-Ying Tan
- Laboratory of Molecular Nutrition, Huazhong Agricultural University, Wuhan 430070, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
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Thyroid-Stimulating Hormone Predicts Total Cholesterol and Low-Density Lipoprotein Cholesterol Reduction during the Acute Phase of COVID-19. J Clin Med 2022; 11:jcm11123347. [PMID: 35743420 PMCID: PMC9225372 DOI: 10.3390/jcm11123347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/03/2022] [Accepted: 06/08/2022] [Indexed: 02/05/2023] Open
Abstract
A complex dysregulation of lipid metabolism occurs in COVID-19, leading to reduced total cholesterol (TC), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) levels, along with a derangement of thyroid function, leading to reduced thyroid-stimulating hormone (TSH) levels. This study aimed to explore the association between TSH levels during COVID-19 and the variation (Δ) of lipid profile parameters in the period preceding (from 1 month up to 1 year) hospital admission due to COVID-19. Clinical data of 324 patients (mean age 76 ± 15 years, 54% males) hospitalized due to COVID-19 between March 2020 and March 2022 were retrospectively analyzed. The association between TSH levels at hospital admission and either Δ-TC, Δ-LDL-C, or Δ-HDL-C over the selected time frame was assessed through univariable and multivariable analyses. TSH levels were below the lower reference limit of 0.340 μUI/mL in 14% of COVID-19 patients. A significant reduction of plasma TC, LDL-C, and HDL-C was recorded between the two time points (p < 0.001 for all the comparisons). TSH was directly associated with Δ-TC (rho = 0.193, p = 0.001), Δ-LDL-C (rho = 0.201, p = 0.001), and Δ-HDL-C (rho = 0.160, p = 0.008), and inversely associated with C-reactive protein (CRP) (rho = −0.175, p = 0.004). Moreover, TSH decreased with increasing COVID-19 severity (p < 0.001). CRP and COVID-19 severity were inversely associated with Δ-TC, Δ-LDL-C, and Δ-HDL-C (p < 0.05 for all associations). A significant independent association was found between TSH and either Δ-TC (β = 0.125, p = 0.044) or Δ-LDL-C (β = 0.131, p = 0.036) after adjusting for multiple confounders including CRP and COVID-19 severity. In conclusion, lower levels of TSH may contribute to explain TC and LDL-C reduction in the acute phase of COVID-19.
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32
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Sadik NA, Rashed LA, El-Sawy SS. The Relationship of Circulating Proprotein Convertase Subtilisin/Kexin Type 9 With TSH and Lipid Profile in Newly Diagnosed Patients With Subclinical and Overt Hypothyroidism. Clin Med Insights Endocrinol Diabetes 2022; 15:11795514221093317. [PMID: 35494422 PMCID: PMC9039449 DOI: 10.1177/11795514221093317] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 03/11/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction: Overt and subclinical hypothyroidism are mostly associated with dyslipidemia, an essential cardiovascular risk factor. Recently, thyroid stimulating hormone (TSH) was identified to have a direct role on lipid metabolism via increased expression of hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 plays a crucial role in lipid metabolism via regulating LDL-C levels. Thus, we aimed to evaluate circulating PCSK9 levels and to assess its relationship with serum TSH and lipids in newly diagnosed patients had overt and subclinical hypothyroidism. Methods: In our study, we enrolled 60 newly diagnosed untreated patients with overt and subclinical hypothyroidism and 30 euthyroid subjects served as the control group. Serum TSH, FT4, FT3, lipid profile and circulating PCSK9 levels using ELISA kits were measured in all subjects. Our data were summarized using mean ± SD or median and interquartile range. Correlations between PCSK9 expression levels and different variables were done using Spearman correlation coefficient. Results: Circulating PCSK9 median levels were significantly increased in patients had overt and subclinical hypothyroidism (12.45 ng/ml, 7.50 ng/ml respectively) compared to the control group (3.30 ng/ml) (P < .001). Circulating PCSK9 levels significantly correlated positively with TSH, total cholesterol, triglycerides, and BMI, and negatively correlated with FT4 and FT3 among all studied subjects. Using multivariate regression analysis TSH was the only significant independent predictor of circulating PCSK9 (P < .001). Conclusion: Our results supports the new implication of TSH in lipid metabolism via the significant association with PCSK9. Whether this relationship between TSH and PCSK9 is a cause or just an association needs further evaluation.
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Affiliation(s)
- Noha Adly Sadik
- Internal Medicine Department, Diabetes and Endocrinology division, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Laila Ahmed Rashed
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Shereen Sadik El-Sawy
- Internal Medicine Department, Diabetes and Endocrinology division, Faculty of Medicine, Cairo University, Cairo, Egypt
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33
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Liu H, Peng D. Update on dyslipidemia in hypothyroidism: the mechanism of dyslipidemia in hypothyroidism. Endocr Connect 2022; 11:e210002. [PMID: 35015703 PMCID: PMC8859969 DOI: 10.1530/ec-21-0002] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/11/2022] [Indexed: 11/18/2022]
Abstract
Hypothyroidism is often associated with elevated serum levels of total cholesterol, LDL-C and triglycerides. Thyroid hormone (TH) affects the production, clearance and transformation of cholesterol, but current research shows that thyroid-stimulating hormone (TSH) also participates in lipid metabolism independently of TH. Therefore, the mechanism of hypothyroidism-related dyslipidemia is associated with the decrease of TH and the increase of TSH levels. Some newly identified regulatory factors, such as proprotein convertase subtilisin/kexin type 9, angiogenin-like proteins and fibroblast growth factors are the underlying causes of dyslipidemia in hypothyroidism. HDL serum concentration changes were not consistent, and its function was reportedly impaired. The current review focuses on the updated understanding of the mechanism of hypothyroidism-related dyslipidemia.
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Affiliation(s)
- Huixing Liu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Daoquan Peng
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Correspondence should be addressed to D Peng:
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34
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Yang X, Zhang C, Williamson C, Liu Y, Zhou Y, Liu C, Chen L, Zhang Y, Korevaar T, Wu W, Fan J. Association of Maternal Thyroid Function with Gestational Hypercholanemia. Thyroid 2022; 32:97-104. [PMID: 34941431 DOI: 10.1089/thy.2021.0242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Background: High bile acid concentration is associated with adverse perinatal outcomes (i.e., stillbirth and preterm birth) and experimental studies indicate that thyroid hormone regulates bile acid metabolism, but this has not yet been translated to clinical data in pregnant women. We aim to explore the association of thyroid function with bile acid concentrations and the risk of gestational hypercholanemia. Methods: This study comprised 68,016 singleton pregnancies without known thyroid or hepatobiliary diseases before pregnancy and thyroid medication based on a prospective cohort. Thyroid function and serum total bile acid (TBA) were routinely screened in both early (9-13 weeks) and late pregnancy (32-36 weeks). Hypercholanemia was defined as serum TBA concentration ≥10 μmol/L. Multiple linear regression models and multiple logistic regression models were performed. Results: A higher free thyroxine (fT4) during both early or late pregnancy was associated with a higher TBA concentration and a higher risk of hypercholanemia (all p < 0.01). A higher thyrotropin (TSH) in early pregnancy was associated with a higher TBA concentration in early pregnancy (p = 0.0155), but with a lower TBA concentration during later pregnancy (p < 0.0001), and there was no association of TSH with hypercholanemia. Overt hyperthyroidism in late pregnancy was associated with a 2.12-fold higher risk of hypercholanemia ([confidence interval; CI 1.12-4.03], p = 0.021) and subclinical hyperthyroidism during later pregnancy was associated with a 1.5-fold higher risk of hypercholanemia ([CI 1.14-1.97], p = 0.0034). Sensitivity analyses indicated that a high fT4 throughout pregnancy was associated with a higher risk of hypercholanemia rather than only in early or late pregnancy. Conclusions: A higher fT4 concentration during either early or late pregnancy, but not the TSH concentration, is associated with higher TBA and a higher risk of gestational hypercholanemia. Furthermore, hyperthyroidism during pregnancy could be a novel risk factor for hypercholanemia.
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Affiliation(s)
- Xi Yang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Chen Zhang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Catherine Williamson
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Yindi Liu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Yulai Zhou
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Chunxiao Liu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Lei Chen
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yong Zhang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Tim Korevaar
- Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Weibin Wu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Jianxia Fan
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- Shanghai Municipal Key Clinical Specialty, Shanghai, China
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35
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Hyperlipidemia and hypothyroidism. Clin Chim Acta 2022; 527:61-70. [DOI: 10.1016/j.cca.2022.01.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/09/2022] [Accepted: 01/10/2022] [Indexed: 12/16/2022]
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36
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Lin X, Xing Y, Zhang Y, Dong B, Zhao M, Wang J, Geng T, Gong D, Zheng Y, Liu L. Glucose participates in the formation of goose fatty liver by regulating the expression of miRNA-33/CROT. Anim Sci J 2021; 92:e13674. [PMID: 34935255 DOI: 10.1111/asj.13674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 11/27/2022]
Abstract
Glucose oversupply promotes formation of fatty liver, and fatty liver is usually accompanied with hyperglycemia. However, the mechanism by which glucose promotes formation of fatty liver is not very clear. In this study, fatty liver was successfully induced in Landes goose by 19 days of overfeeding with corn-based feed, the overfed geese had a significantly higher level of blood glucose than the normally fed geese (control group). In goose primary liver cells, high level of glucose promoted fat deposition and induced the expression of SREBF2(or SREBP2), a key regulator of lipid metabolism, and its intronic gene, miR-33. Moreover, overexpression of miRNA-33(miR-33) promotes lipid accumulation in goose primary liver cells. Consistently, miR-33 inhibitor suppressed glucose induced lipid accumulation in liver cells. Interestingly, the relative abundance of miR-33 in goose fatty liver was significantly higher than that in normal liver, while the relative mRNA and protein abundances of CROT, the target gene of miR-33, in goose fatty liver were significantly lower than those in goose normal liver. Taken together, these findings suggest that miR-33 mediates glucose promotion of lipid accumulation in goose primary liver cells, and that glucose participates in formation of goose fatty liver by regulating the expression of miR-33/CROT.
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Affiliation(s)
- Xiao Lin
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Ya Xing
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Yihui Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Biao Dong
- Department of Animal Science and Technology, Jiangsu Agri-Animal Husbandry Vocational College, Taizhou, China
| | - Minmeng Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Jian Wang
- Department of Animal Science and Technology, Jiangsu Agri-Animal Husbandry Vocational College, Taizhou, China
| | - Tuoyu Geng
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Daoqing Gong
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Yun Zheng
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Long Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
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Identification and expression analysis of thyroid-stimulating hormone β subunit, and effects of T3 on gonadal differentiation-related gene expression in rice field eel, Monopterus albus. Comp Biochem Physiol B Biochem Mol Biol 2021; 258:110681. [PMID: 34688906 DOI: 10.1016/j.cbpb.2021.110681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/08/2021] [Accepted: 10/18/2021] [Indexed: 01/12/2023]
Abstract
Thyroid-stimulating hormone (TSH) is an important glycoprotein in hypothalamic-pituitary-thyroid axis, which plays a crucial role in the synthesis and release of thyroid hormones in vertebrates. Rice field eel, Monopterus albus, a protogynous hermaphroditic fish, which undergoes sex reversal from a functional female to a male, is an ideal model to investigate the regulation of sex differentiation. In this study, we obtained the cDNA sequence of thyroid-stimulating hormone β subunit (tshβ) from rice field eel, which contained a complete open reading frame and encoded a putative protein of 151 amino acids. Multiple alignment of protein sequences showed that tshβ was highly conserved in teleost. The tissue distribution indicated that tshβ showed high expression in the pituitary, moderate expression in the brain region, gonad, intestine and liver, and low expression in other peripheral tissues. During natural sex reversal, the expression of tshβ had no significant difference in the pituitary. Compared to that in the ovary, the expression of tshβ increased significantly in the gonad at late intersexual and male stages. After treatment by different doses of triiodothyronine (T3) (1 μg/g, 10 μg/g and 100 μg/g body weight), serum T3 and free triiodothyronine (FT3) increased sharply, while the expression of tshβ were inhibited significantly in the pituitary. Although T3 had no significant effect on the levels of serum E2, it stimulated the release of serum 11-KT at high-dose group. We also detected the effects of T3 on the expression of gonadal differentiation-related genes in rice field eel. T3 treatment inhibited the expression of foxl2, cyp19a1a and dax1, while stimulated the expression of sox9a1. These results indicate that TSH may be involved in sex differentiation, and THs may play roles in the regulation of male development and sex reversal in rice field eel.
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Metabolic profile differences in ACTH-dependent and ACTH-independent Cushing syndrome. Chronic Dis Transl Med 2021; 8:36-40. [PMID: 35620164 PMCID: PMC9128563 DOI: 10.1016/j.cdtm.2021.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/18/2021] [Indexed: 11/21/2022] Open
Abstract
Background The most common etiologies of Cushing's syndrome (CS) are adrenocorticotropic hormone (ACTH)‐producing pituitary adenoma (pitCS) and primary adrenal gland disease (adrCS), both of which burden patients with metabolic disturbance. The aim of this study was to compare the metabolic features of pitCS and adrCS patients. Methods A retrospective review including 114 patients (64 adrCS and 50 pitCS) diagnosed with CS in 2009–2019 was performed. Metabolic factors were then compared between pitCS and adrCS groups. Results Regarding sex, females suffered both adrCs (92.2%) and pitCS (88.0%) more frequently than males. Regarding age, patients with pitCS were diagnosed at a younger age (35.40 ± 11.94 vs. 39.65 ± 11.37 years, p = 0.056) than those with adrCS, although the difference was not statistically significant. Moreover, pitCS patients had much higher ACTH levels and more serious occurrences of hypercortisolemia at all time points (8 AM, 4 PM, 12 AM) than that in adrCS patients. Conversely, indexes, including body weight, BMI, blood pressure, serum total cholesterol, low density lipoprotein cholesterol (LDL‐C), high density lipoprotein cholesterol (HDL‐C), triglycerides, fasting plasma glucose, and uric acid, showed no differences between adrCS and pitCS patients. Furthermore, diabetes prevalence was higher in pitCS patients than in adrCS patients; however, there were no significant differences in hypertension or dyslipidemia prevalence between the two. Conclusions Although adrCS and pitCS had different pathogenetic mechanisms, different severities of hypercortisolemia, and different diabetes prevalences, both etiologies had similar metabolic characteristics.
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Yang C, He Z, Zhang Q, Lu M, Zhao J, Chen W, Gao L. TSH Activates Macrophage Inflammation by G13- and G15-dependent Pathways. Endocrinology 2021; 162:6225351. [PMID: 33851697 DOI: 10.1210/endocr/bqab077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Indexed: 12/17/2022]
Abstract
Thyroid-stimulating hormone (TSH) treatment activates inhibitor of NF-κB/nuclear factor κB (IκB/NFκB) and extracellular signal-regulated kinase (ERK)-P38 in macrophages, but how these pathways are activated, and how they contribute to the proinflammatory effect of TSH on macrophages remain unknown. The TSH receptor (TSHR) is coupled to 4 subfamilies of G proteins (Gs, Gi/o, Gq/11, and G12/13) for its downstream signaling. This study investigated the G protein subtypes responsible for the proinflammatory effect of TSH on macrophages. qPCR showed that Gi2, Gi3, Gas, Gq, G11, G12, G13, and G15 are abundantly expressed by macrophages. The contribution of different G protein pathways to the proinflammatory effect was studied by the corresponding inhibitors or siRNA interference. While TSH-induced IκB phosphorylation was not inhibited by Gs inhibitor NF449, Gi inhibitor pertussis toxin, or Gq or G11 siRNA, it was blocked by phospholipase C inhibitor U73122 or G15 siRNA interference. TSH-induced ERK and P38 phosphorylation was blocked by G13 but not G12 siRNA interference. Interference of either G13 or G15 could block the proinflammatory effect of TSH on macrophages. The present study demonstrate that TSH activates macrophage inflammation by the G13/ERK-P38/Rho GTPase and G15/phospholipase C (PLC)/protein kinases C (PKCs)/IκB pathways.
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Affiliation(s)
- Chongbo Yang
- Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, China
| | - Zhao He
- Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, China
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qunye Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Ministry of Public Health, the State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ming Lu
- Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, China
| | - Wenbin Chen
- Scientific Center, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Ling Gao
- Scientific Center, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China
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Li J, Kong D, Gao X, Tian Z, Wang X, Guo Q, Wang Z, Zhang Q. TSH attenuates fatty acid oxidation in hepatocytes by reducing the mitochondrial distribution of miR-449a/449b-5p/5194. Mol Cell Endocrinol 2021; 530:111280. [PMID: 33862186 DOI: 10.1016/j.mce.2021.111280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 12/30/2022]
Abstract
The elevated thyroid-stimulating hormone (TSH) levels contribute to the abnormal expression/activity of several key hepatic lipid metabolism enzymes. Although miRNAs have been shown to play key roles in hepatic lipid metabolism and are found in isolated mitochondria, very little is known about the pathological and physiological significance of their mitochondrial distributions in regulating liver lipid metabolism. Here, we found that TSH significantly reduced the distribution of some miRNAs in mitochondria of hepatocytes, especially miR-449a, miR-449b-5p, and miR-5194. These three miRNAs inhibited their target genes PGC1B, ABCD1, ADIPOR1 and the downstream molecule PPARA. These effects synergistically suppressed fatty acid (FA) β-oxidation in mitochondria and peroxisomes and decreased the translocation of cytosolic very long chain fatty acids to peroxisomes, which noticeably reduced FA catabolism and promoted triglyceride accumulation in hepatocytes. This study reveals the functional significance of changed miRNA mitochondrial-cytoplasmic distribution in the regulation of hepatic lipid metabolism.
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Affiliation(s)
- Jiaxuan Li
- Division of Geriatrics, Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, 250012, China; Shandong Institute of Endocrine and Metabolic Disease, Jinan, Shandong, 250021, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
| | - Danxia Kong
- Division of Geriatrics, Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, 250012, China; Shandong Institute of Endocrine and Metabolic Disease, Jinan, Shandong, 250021, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
| | - Xueying Gao
- Division of Geriatrics, Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China; Shandong Institute of Endocrine and Metabolic Disease, Jinan, Shandong, 250021, China
| | - Zhenyu Tian
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Xiaowei Wang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Qianqian Guo
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Zhe Wang
- Division of Geriatrics, Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China; Shandong Institute of Endocrine and Metabolic Disease, Jinan, Shandong, 250021, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China.
| | - Qunye Zhang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, 250012, China.
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Wang Y, Guo P, Liu L, Zhang Y, Zeng P, Yuan Z. Mendelian Randomization Highlights the Causal Role of Normal Thyroid Function on Blood Lipid Profiles. Endocrinology 2021; 162:6136226. [PMID: 33587120 DOI: 10.1210/endocr/bqab037] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Indexed: 12/13/2022]
Abstract
The association between thyroid function and dyslipidemia has been well documented in observational studies. However, observational studies are prone to confounding, making it difficult to conduct causal inference. We performed a 2-sample bidirectional Mendelian randomization (MR) using summary statistics from large-scale genome-wide association studies of thyroid stimulating hormone (TSH), free T4 (FT4), and blood lipids. We chose the inverse variance-weighted (IVW) method for the main analysis, and consolidated results through various sensitivity analyses involving 6 different MR methods under different model specifications. We further conducted genetic correlation analysis and colocalization analysis to deeply reflect the causality. The IVW method showed per 1 SD increase in normal TSH was significantly associated with a 0.048 SD increase in total cholesterol (TC; P < 0.001) and a 0.032 SD increase in low-density lipoprotein cholesterol (LDL; P = 0.021). A 1 SD increase in normal FT4 was significantly associated with a 0.056 SD decrease in TC (P = 0.014) and a 0.072 SD decrease in LDL (P = 0.009). Neither TSH nor FT4 showed causal associations with high-density lipoprotein cholesterol and triglycerides. No significant causal effect of blood lipids on normal TSH or FT4 can be detected. All results were largely consistent when using several alternative MR methods, and were reconfirmed by both genetic correlation analysis and colocalization analysis. Our study suggested that, even within reference range, higher TSH or lower FT4 are causally associated with increased TC and LDL, whereas no reverse causal association can be found.
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Affiliation(s)
- Yanjun Wang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Ping Guo
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Lu Liu
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Yanan Zhang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Ping Zeng
- Department of Epidemiology and Biostatistics, Xuzhou Medical University, Xuzhou 221004, China
| | - Zhongshang Yuan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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Negi CK, Khan S, Dirven H, Bajard L, Bláha L. Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms22084282. [PMID: 33924165 PMCID: PMC8074384 DOI: 10.3390/ijms22084282] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/14/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing concern worldwide, affecting 25% of the global population. NAFLD is a multifactorial disease with a broad spectrum of pathology includes steatosis, which gradually progresses to a more severe condition such as nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually leads to hepatic cancer. Several risk factors, including exposure to environmental toxicants, are involved in the development and progression of NAFLD. Environmental factors may promote the development and progression of NAFLD by various biological alterations, including mitochondrial dysfunction, reactive oxygen species production, nuclear receptors dysregulation, and interference in inflammatory and immune-mediated signaling. Moreover, environmental contaminants can influence immune responses by impairing the immune system’s components and, ultimately, disease susceptibility. Flame retardants (FRs) are anthropogenic chemicals or mixtures that are being used to inhibit or delay the spread of fire. FRs have been employed in several household and outdoor products; therefore, human exposure is unavoidable. In this review, we summarized the potential mechanisms of FRs-associated immune and inflammatory signaling and their possible contribution to the development and progression of NAFLD, with an emphasis on FRs-mediated interferon signaling. Knowledge gaps are identified, and emerging pharmacotherapeutic molecules targeting the immune and inflammatory signaling for NAFLD are also discussed.
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Affiliation(s)
- Chander K. Negi
- Faculty of Science, RECETOX, Masaryk University, Kamenice 5, CZ62500 Brno, Czech Republic; (L.B.); (L.B.)
- Correspondence: or
| | - Sabbir Khan
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA;
| | - Hubert Dirven
- Department of Environmental Health, Section for Toxicology and Risk Assessment, Norwegian Institute of Public Health, 0456 Oslo, Norway;
| | - Lola Bajard
- Faculty of Science, RECETOX, Masaryk University, Kamenice 5, CZ62500 Brno, Czech Republic; (L.B.); (L.B.)
| | - Luděk Bláha
- Faculty of Science, RECETOX, Masaryk University, Kamenice 5, CZ62500 Brno, Czech Republic; (L.B.); (L.B.)
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Ma S, Shao S, Yang C, Yao Z, Gao L, Chen W. A preliminary study: proteomic analysis of exosomes derived from thyroid-stimulating hormone-stimulated HepG2 cells. J Endocrinol Invest 2020; 43:1229-1238. [PMID: 32166700 DOI: 10.1007/s40618-020-01210-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/02/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Thyroid-stimulating hormone (TSH) plays an important role in the regulation of lipid metabolism. However, little is known about the role that exosomes play in the process of TSH-induced lipotoxicity in non-alcoholic fatty liver disease (NAFLD). As a preliminary step, the present study set out to investigate alterations in protein expression in exosomes derived from TSH-stimulated HepG2 cells. METHODS HepG2 cells were treated with TSH, exosomes were collected, and proteins were identified by mass spectrometry (MS). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis were performed to analyze the identified proteins. RESULTS TSH treatment significantly increased exosomal production and changed the exosomal proteomic profile in HepG2 cells. Among the 1728 proteins, 140 identified proteins were upregulated and seven proteins were downregulated. GO analysis and KEGG analysis revealed that these proteins were involved in multiple processes including metabolism, apoptosis, and inflammation. CONCLUSION Our preliminary study demonstrated that exosomes derived from TSH-stimulated hepatocytes were increased and showed a specific altered spectrum of proteins, many of which were involved in metabolism, signal transduction, apoptosis, and inflammation. This study offers new insights into the pathogenesis of TSH-induced lipotoxicity in NAFLD.
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Affiliation(s)
- S Ma
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, 250021, China
| | - S Shao
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, 250021, China
| | - C Yang
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, 250021, China
| | - Z Yao
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, 250021, China
| | - L Gao
- Scientific Center, Shandong Provincial Hospital Affiliated to, Shandong First Medical University, 324 Jing 5 Road, Jinan, 250021, Shandong, China.
- Scientific Center, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, 250021, China.
| | - W Chen
- Scientific Center, Shandong Provincial Hospital Affiliated to, Shandong First Medical University, 324 Jing 5 Road, Jinan, 250021, Shandong, China.
- Scientific Center, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, 250021, China.
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Hypothyroidism-Induced Nonalcoholic Fatty Liver Disease (HIN): Mechanisms and Emerging Therapeutic Options. Int J Mol Sci 2020; 21:ijms21165927. [PMID: 32824723 PMCID: PMC7460638 DOI: 10.3390/ijms21165927] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/14/2020] [Accepted: 08/16/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an emerging worldwide problem and its association with other metabolic pathologies has been one of the main research topics in the last decade. The aim of this review article is to provide an up-to-date correlation between hypothyroidism and NAFLD. We followed evidence regarding epidemiological impact, immunopathogenesis, thyroid hormone-liver axis, lipid and cholesterol metabolism, insulin resistance, oxidative stress, and inflammation. After evaluating the influence of thyroid hormone imbalance on liver structure and function, the latest studies have focused on developing new therapeutic strategies. Thyroid hormones (THs) along with their metabolites and thyroid hormone receptor β (THR-β) agonist are the main therapeutic targets. Other liver specific analogs and alternative treatments have been tested in the last few years as potential NAFLD therapy. Finally, we concluded that further research is necessary as well as the need for an extensive evaluation of thyroid function in NAFLD/NASH patients, aiming for better management and outcome.
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Wei S, Ma X, Zhao Y. Mechanism of Hydrophobic Bile Acid-Induced Hepatocyte Injury and Drug Discovery. Front Pharmacol 2020; 11:1084. [PMID: 32765278 PMCID: PMC7378542 DOI: 10.3389/fphar.2020.01084] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 07/03/2020] [Indexed: 12/13/2022] Open
Abstract
Cholestatic liver disease is caused by the obstruction of bile synthesis, transport, and excretion in or outside the liver by a variety of reasons. Long-term persistent cholestasis in the liver can trigger inflammation, necrosis, or apoptosis of hepatocytes. Bile acid nuclear receptors have received the most attention for the treatment of cholestasis, while the drug development for bile acid nuclear receptors has made considerable progress. However, the targets regulated by bile acid receptor drugs are limited. Thus, as anticipated, intervention in the expression of bile acid nuclear receptors alone will not yield satisfactory clinical results. Therefore, this review comprehensively summarized the literature related to cholestasis, analyzed the molecular mechanism that bile acid damages cells, and status of drug development. It is hoped that this review will provide some reference for the research and development of drugs for cholestasis treatment in the future.
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Affiliation(s)
- Shizhang Wei
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Pharmacy, PLA General Hospital, Beijing, China
| | - Xiao Ma
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanling Zhao
- Department of Pharmacy, PLA General Hospital, Beijing, China
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The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells. Cells 2020; 9:cells9071730. [PMID: 32698392 PMCID: PMC7407617 DOI: 10.3390/cells9071730] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/16/2020] [Accepted: 07/17/2020] [Indexed: 01/18/2023] Open
Abstract
The thyroid stimulating hormone (TSH) and its cognate receptor (TSHR) are of crucial importance for thyrocytes to proliferate and exert their functions. Although TSHR is predominantly expressed in thyrocytes, several studies have revealed that functional TSHR can also be detected in many extra-thyroid tissues, such as primary ovarian and hepatic tissues as well as their corresponding malignancies. Recent advances in cancer biology further raise the possibility of utilizing TSH and/or TSHR as a therapeutic target or as an informative index to predict treatment responses in cancer patients. The TSH/TSHR cascade has been considered a pivotal modulator for carcinogenesis and/or tumor progression in these cancers. TSHR belongs to a sub-group of family A G-protein-coupled receptors (GPCRs), which activate a bundle of well-defined signaling transduction pathways to enhance cell renewal in response to external stimuli. In this review, recent findings regarding the molecular basis of TSH/TSHR functions in either thyroid or extra-thyroid tissues and the potential of directly targeting TSHR as an anticancer strategy are summarized and discussed.
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Nichols PH, Pan Y, May B, Pavlicova M, Rausch JC, Mencin AA, Thaker VV. Effect of TSH on Non-Alcoholic Fatty Liver Disease (NAFLD) independent of obesity in children of predominantly Hispanic/Latino ancestry by causal mediation analysis. PLoS One 2020; 15:e0234985. [PMID: 32569304 PMCID: PMC7307750 DOI: 10.1371/journal.pone.0234985] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 06/05/2020] [Indexed: 12/29/2022] Open
Abstract
Background Nonalcoholic Fatty Liver Disease (NAFLD) is a common co-morbidity of obesity. Elevated TSH levels (eTSH), also associated with obesity, may contribute to the dysmetabolic state that predisposes to NAFLD. Objective To assess the relationship between TSH levels and NAFLD in children with biopsy-proven NAFLD compared to controls. Design and methods In this retrospective study of children with biopsy-proven NAFLD and age-matched controls, the association of eTSH with NAFLD was investigated and the role of TSH as a mediator between obesity and NAFLD was assessed. Results Sixty-six cases and 4067 controls (69.7 vs 59% Hispanic/Latino ancestry, p = 0.1) of the same age range seen in the same time duration at an urban Children’s Hospital were studied. Children with NAFLD were more likely to be male (74.6 vs 39.4%, p < 0.001), have higher modified BMI-z scores (median 2.4 (IQR 1.7) vs 1.9 (IQR 1.7), p < 0.001), and abnormal metabolic parameters (TSH, ALT, HDL-C, non-HDL-C, and TG). Multivariate analyses controlling for age, sex and severity of obesity showed significant association between the 4th quartile of TSH and NAFLD. Causal mediation analysis demonstrates that TSH mediates 33.8% of the effect of modified BMI-z score on NAFLD. This comprises of 16.0% (OR = 1.1, p = 0.002) caused by the indirect effect of TSH and its interaction with modified BMI-z, and 17.7% (OR = 1.1, p = 0.05) as an autonomous effect of TSH on NAFLD. Overall, 33.8% of the effect can be eliminated by removing the mediator, TSH (p = 0.001). Conclusions The association of eTSH and biopsy-proven NAFLD is demonstrated in children of Hispanic/Latino ancestry. Further, a causal mediation analysis implicates an effect of TSH on NAFLD, independent of obesity.
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Affiliation(s)
- Presley H. Nichols
- Department of Pediatrics, New York Presbyterian-Columbia University Irving Medical Center, New York, New York, United States of America
| | - Yue Pan
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, United States of America
| | - Benjamin May
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Martina Pavlicova
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, United States of America
| | - John C. Rausch
- Department of Pediatrics, New York Presbyterian-Columbia University Irving Medical Center, New York, New York, United States of America
- Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Ali A. Mencin
- Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Vidhu V. Thaker
- Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, United States of America
- * E-mail:
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Küçükçongar Yavaş A, Çavdarlı B, Ünal Uzun Ö, Uncuoğlu A, Gündüz M. A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis. J Pediatr Endocrinol Metab 2020; 33:665-669. [PMID: 32229667 DOI: 10.1515/jpem-2019-0314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 02/03/2020] [Indexed: 12/15/2022]
Abstract
Background Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C. Case presentation Here we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol. Conclusion This is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.
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Affiliation(s)
- Aynur Küçükçongar Yavaş
- Pediatric Metabolism, Ministry of Health Ankara City Hospital, University of Health Science, Ankara, Turkey
| | - Büşra Çavdarlı
- Medical Genetics, Ministry of Health, Ankara City Hospital, University of Health Science, Ankara, Turkey
| | - Özlem Ünal Uzun
- Pediatric Metabolism, Ministry of Health Ankara City Hospital, University of Health Science, Ankara, Turkey
| | - Ayşen Uncuoğlu
- Pediatric Gastroenterology, Sakarya University, Sakarya, Turkey
| | - Mehmet Gündüz
- Pediatric Metabolism, Ministry of Health Ankara City Hospital, University of Health Science, Ankara, Turkey
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Effect of rhTSH on Lipids. J Clin Med 2020; 9:jcm9020515. [PMID: 32074945 PMCID: PMC7073530 DOI: 10.3390/jcm9020515] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/02/2020] [Accepted: 02/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Subclinical hypothyroidism is associated with increased blood lipid levels. However, the exact role of thyrotropin (TSH) alone is not clear. In order to clarify this point, we analysed the acute effect of recombinant human TSH (rhTSH) administration on lipid levels. METHODS Sera of 27 premenopausal women with well-differentiated thyroid cancer were analysed. Patients that underwent a total thyroidectomy, ablation with 131I (Iodine 131) and rhTSH administration as a part of routine follow-up American Thyroid Association guidelines were included. The protocol consists of 2 intramuscular injections of 0.9 mg of rhTSH, performed on day 1 day and day 2, with blood collection on day 1 (before rhTSH administration), and day 5. TSH, free thyroxine, total cholesterol, low-density lipoprotein cholesterol (LDLc), high density lipoprotein cholesterol (HDLc), and triglycerides were assessed in all the samples, before and four days after the first administration of rhTSH. RESULTS Total cholesterol and triglycerides significantly increased after stimulation of rhTSH (respectively, 192 ± 33 vs. 207 ± 26, p = 0.036 and 72 ± 23 vs. 85 ± 23, p = 0.016). LDLc and HDLc showed comparable concentrations before and after the test (respectively, 115 ± 27 vs. 126 ± 22, p = 0.066, and 62 ± 15 vs. 64 ± 15, p = 0.339), while non-HDLc increased after stimulation (130 ± 30 vs. 143 ± 25, p = 0.045). CONCLUSION TSH has a direct effect on total cholesterol, triglycerides, and nonHDLc. Explanation of these phenomena will require additional studies.
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Wang X, Mao J, Zhou X, Li Q, Gao L, Zhao J. Thyroid Stimulating Hormone Triggers Hepatic Mitochondrial Stress through Cyclophilin D Acetylation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1249630. [PMID: 31998431 PMCID: PMC6970002 DOI: 10.1155/2020/1249630] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 09/01/2019] [Accepted: 09/14/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Oxidative stress-related liver diseases were shown to be associated with elevated serum thyroid stimulating hormone (TSH) levels. Mitochondria are the main source of cellular reactive oxygen species. However, the relationship between TSH and hepatic mitochondrial stress/dysfunction and the underlying mechanisms are largely unknown. Here, we focused on exploring the effects and mechanism of TSH on hepatic mitochondrial stress. METHODS As the function of TSH is mediated through the TSH receptor (TSHR), Tshr -/- mice and liver-specific Tshr -/- mice and liver-specific Tshr -/- mice and liver-specific. RESULTS A relatively lower degree of mitochondrial stress was observed in the livers of Tshr -/- mice and liver-specific in vitro. Microarray and RT-PCR analyses showed that Tshr -/- mice and liver-specific. CONCLUSIONS TSH stimulates hepatic CypD acetylation through the lncRNA-AK044604/SIRT1/SIRT3 signaling pathway, indicating an essential role for TSH in mitochondrial stress in the liver.
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Affiliation(s)
- Xiaolei Wang
- Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250014, China
| | - Jinbao Mao
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Xinli Zhou
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Qiu Li
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Ling Gao
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China
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