Endocrinology and Metabolism

Original Article

Diabetes, Obesity and Metabolism
The Effects of Irisin on the Interaction between Hepatic Stellate Cell and Macrophage in Liver Fibrosis: Dinh Vinh Do, So Young Park, Giang Thi Nguyen, Dae Hee Choi, Eun-Hee Cho; Endocrinol Metab. 2022;37(4):620-629. Published online July 22, 2022; DOI: https://doi.org/10.3803/EnM.2022.1412

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Background
Hepatic stellate cells (HSCs) are the central players interacting with multiple cell types in liver fibrosis. The crosstalk between HSCs and macrophages has recently become clearer. Irisin, an exercise-responsive myokine, was known to have a potentially protective role in liver and renal fibrosis, especially in connection with stellate cells. This study investigated the effects of irisin on the interaction between HSCs and macrophages.
Methods
Tamm-Horsfall protein-1 (THP-1) human monocytes were differentiated into macrophages, polarized into the inflammatory M1 phenotype with lipopolysaccharide. Lieming Xu-2 (LX-2) cells, human HSCs, were treated with conditioned media (CM) from M1 macrophages, with or without recombinant irisin. HSCs responses to CM from M1 macrophages were evaluated regarding activation, proliferation, wound healing, trans-well migration, contractility, and related signaling pathway.
Results
CM from M1 macrophages significantly promoted HSC proliferation, wound healing, transwell migration, and contractility, but not activation of HSCs. Irisin co-treatment attenuated these responses of HSCs to CM. However, CM and irisin treatment did not induce any changes in HSC activation. Further, irisin co-treatment alleviated CM-induced increase of phopho-protein kinase B (pAKT), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1).
Conclusion
These findings suggested that irisin may play a protective role in the pathogenesis of liver fibrosis, especially when working in the crosstalk between HSCs and macrophages.

Citations

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Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis
Liang Shan, Fengling Wang, Dandan Zhai, Xiangyun Meng, Jianjun Liu, Xiongwen Lv
Biomedicine & Pharmacotherapy.2023; 161: 114472. CrossRef
Potential role of irisin in digestive system diseases
Yueming Zhang, Linxian Zhao, Huan Gao, Jinghui Zhai, Yanqing Song
Biomedicine & Pharmacotherapy.2023; 166: 115347. CrossRef
The effect of sarcopenia and serum myokines on prognosis and survival in cirrhotic patients: a multicenter cross-sectional study
Salih Boga, Abdullah Emre Yildirim, Enver Ucbilek, Ali Riza Koksal, Sevil Tokdemir Sisman, Ibrahim Durak, Ilker Sen, Beril Dogu, Erdinc Serin, Ayse Bolat Ucbilek, Makbule Ozge Yildirim, Sukru Mehmet Erturk, Huseyin Alkim, Canan Alkim
European Journal of Gastroenterology & Hepatology.2022; 34(12): 1261. CrossRef

Namgok Lecture 2020

Obesity and Metabolism
Cellular and Intercellular Homeostasis in Adipose Tissue with Mitochondria-Specific Stress: Min Jeong Choi, Saet-Byel Jung, Joon Young Chang, Minho Shong; Endocrinol Metab. 2021;36(1):1-11. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2021.956

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Paracrine interactions are imperative for the maintenance of adipose tissue intercellular homeostasis, and intracellular organelle dysfunction results in local and systemic alterations in metabolic homeostasis. It is currently accepted that mitochondrial proteotoxic stress activates the mitochondrial unfolded protein response (UPR^mt) in vitro and in vivo. The induction of mitochondrial chaperones and proteases during the UPR^mt is a key cell-autonomous mechanism of mitochondrial quality control. The UPR^mt also affects systemic metabolism through the secretion of cell non-autonomous peptides and cytokines (hereafter, metabokines). Mitochondrial function in adipose tissue plays a pivotal role in whole-body metabolism and human diseases. Despite continuing interest in the role of the UPR^mt and quality control pathways of mitochondria in energy metabolism, studies on the roles of the UPR^mt and metabokines in white adipose tissue are relatively sparse. Here, we describe the role of the UPR^mt in adipose tissue, including adipocytes and resident macrophages, and the interactive roles of cell non-autonomous metabokines, particularly growth differentiation factor 15, in local adipose cellular homeostasis and systemic energy metabolism.

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Mitochondrial stress-induced GFRAL signaling controls diurnal food intake and anxiety-like behavior
Carla Igual Gil, Bethany M Coull, Wenke Jonas, Rachel N Lippert, Susanne Klaus, Mario Ost
Life Science Alliance.2022; 5(11): e202201495. CrossRef
Stress-induced FGF21 and GDF15 in obesity and obesity resistance
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Original Article

Clinical Study
Mechanisms of the Impact of Hashimoto Thyroiditis on Papillary Thyroid Carcinoma Progression: Relationship with the Tumor Immune Microenvironment: Oksana Sulaieva, Olena Chernenko, Oleksiy Selesnov, Oleksandr Nechay, Oleksandr Maievskyi, Tetyana Falalyeyeva, Nazarii Kobyliak, Olena Tsyryuk, Yurii Penchuk, Dmytro Shapochka; Endocrinol Metab. 2020;35(2):443-455. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.443

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Background
The relationship between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma (PTC) remains uncertain. We assessed the impact of HT on the tumor immune microenvironment (TIME) in PTC.
Methods
Thirty patients with PTC (group 1) and 30 patients with PTC and HT (group 2) were enrolled in this pilot study. The distribution and number of CD8+ lymphocytes, plasma cells (CD138+), regulatory T cells (forkhead box P3 [FOXP3+)], mast cell tryptase (MCT+), and M2 macrophages (CD163+) were evaluated. To test the hypothesis that HT impacts PTC development via signal transducer and activator of transcription 6 (STAT6) activation and M2 macrophage polarization, we investigated STAT6 expression in tumor and stromal cells. We also evaluated vascular endothelial growth factor (VEGF) expression by lymph node metastasis (LNM) status.
Results
TIME showed significant between-group differences. Group 1 patients demonstrated immune desert or immune-excluded immunophenotypes, while an inflamed phenotype with more CD8+ cells (P<0.001) predominated in group 2. Immune-excluded TIME was associated with the highest LNM rate. In PTC, LNM was associated with more numerous CD163+ cells. Moreover, LNM in group 1 was associated with increased numbers of mast cells peritumorally and FOXP3+ cells intratumorally and peritumorally. Group 2 demonstrated higher STAT6 but not higher VEGF expression in tumor cells. High VEGF expression was associated with LNM regardless of HT status.
Conclusion
Concomitant HT impacted PTC signaling via STAT6 and TIME by increasing the number of CD8+ cells. LNM is associated with increases in CD163+ cells and VEGF expression in PTC, whereas HT affected LNM through different mechanisms.

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Prevalence of Hashimoto Thyroiditis in Adults With Papillary Thyroid Cancer and Its Association With Cancer Recurrence and Outcomes
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Review Article

The Role of Macrophage Lipophagy in Reverse Cholesterol Transport: Se-Jin Jeong, Mi-Ni Lee, Goo Taeg Oh; Endocrinol Metab. 2017;32(1):41-46. Published online March 20, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.1.41

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Macrophage cholesterol efflux is a central step in reverse cholesterol transport, which helps to maintain cholesterol homeostasis and to reduce atherosclerosis. Lipophagy has recently been identified as a new step in cholesterol ester hydrolysis that regulates cholesterol efflux, since it mobilizes cholesterol from lipid droplets of macrophages via autophagy and lysosomes. In this review, we briefly discuss recent advances regarding the mechanisms of the cholesterol efflux pathway in macrophage foam cells, and present lipophagy as a therapeutic target in the treatment of atherosclerosis.

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Original Articles

Endocrine Research
Macrophage Densities Correlated with CXC Chemokine Receptor 4 Expression and Related with Poor Survival in Anaplastic Thyroid Cancer: Dae In Kim, Eunyoung Kim, Young A Kim, Sun Wook Cho, Jung Ah Lim, Young Joo Park; Endocrinol Metab. 2016;31(3):469-475. Published online August 2, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.3.469

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Background

Tumor associated macrophages (TAMs) and CXC chemokine receptor 4 (CXCR4) have emerged as potential biomarkers in various human cancers. The aims of this study were to investigate the clinical characteristics of anaplastic thyroid cancer (ATC) patients according to the TAM numbers in the tumor tissue, and to evaluate the associations between CXCR4 expressions and macrophage densities in ATC tumor microenvironment.

Methods

Total 14 ATC samples from thyroid tissue microarray were used. Immunohistochemical staining was performed using anti-CD163 and anti-CXCR4 antibodies. According to the immunoreactivity of CD163, all subjects were divided into two groups: low-CD163 (n=8) and high-CD163 (n=6) groups.

Results

The mean diagnostic age was 65±7 years and the median tumor size was 4.3 cm, ranging 2.5 to 15 cm. Clinicopathological characteristics were not significantly different between low-CD163 and high-CD163 groups, while age of diagnosis was younger in high-CD163 group than that of low-CD163 group with marginal significance (56.9±5.5 years vs. 67.5±6.8 years, P=0.09). However, overall survival was significantly reduced in high-CD163 group (5.5 months [range, 1 to 10]) compared with low-CD163 groups (8.8 months [range, 6 to 121); log-rank test, P=0.0443). Moreover, high-CD163 group showed strong CXCR4 expressions in both cancer and stromal compartments, while low-CD163 group showed relatively weak, stromal-dominant CXCR4 expressions. Additionally, CD163 and CXCR4 expressions showed a strong positive correlation (γ²=0.432, P=0.013).

Conclusion

Increased number of TAMs showed poor overall survival in ATC, suggesting TAMs are potentially a prognostic biomarker for ATC. CXCR4 expression was significantly correlated with CD163-positive TAM densities, which suggest the possible role of CXCR4 in TAM recruitments.

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Thyroid
The Expression of Tumor-Associated Macrophages in Papillary Thyroid Carcinoma: Seunghwan Kim, Sun Wook Cho, Hye Sook Min, Kang Min Kim, Gye Jeong Yeom, Eun Young Kim, Kyu Eun Lee, Yeo Gyu Yun, Do Joon Park, Young Joo Park; Endocrinol Metab. 2013;28(3):192-198. Published online September 13, 2013; DOI: https://doi.org/10.3803/EnM.2013.28.3.192

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Background

Tumor-associated macrophages (TAMs) play a tumorigenic role related to advanced staging and poor prognosis in many human cancers including thyroid cancers. Yet, a functional role of TAMs in papillary thyroid carcinoma (PTC) has not been established. The aim of this study was to investigate TAM expression in human PTC with lymph node (LN) metastasis.

Methods

Thirty-six patients who underwent surgery after being diagnosed with PTC with LN metastasis were included. Primary tumor tissues were immunohistochemically stained with an anti-CD68 antibody and clinical characteristics according to TAM density were evaluated.

Results

The TAM densities (CD68⁺ cells) varied from 5% to 70%, in all tumor areas, while few cells were stained in adjacent normal tissues. TAMs were identified as CD68⁺ cells with thin, elongated cytoplasmic extensions that formed a canopy structure over tumor cells. Comparing clinicopathologic characteristics between tumors with low (<25%) and high (25% to 70%) TAM densities, primary tumors were larger in the high density group than in the low density group (2.0±0.1 vs. 1.5±0.1; P=0.009).

Conclusion

TAMs were identified in primary PTC tumors with LN metastasis and higher TAM densities were related to larger tumor sizes, suggesting a tumorigenic role of TAMs in human PTCs.

Citations

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