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Miyake T, Furukawa S, Matsuura B, Yoshida O, Kanamoto A, Miyazaki M, Shiomi A, Nakaguchi H, Okazaki Y, Nakamura Y, Imai Y, Koizumi M, Watanabe T, Yamamoto Y, Koizumi Y, Tokumoto Y, Hirooka M, Kumagi T, Abe M, Hiasa Y. Association Between Serum Remnant Cholesterol Level and Metabolic Dysfunction-associated Steatotic Liver Histology. J Clin Endocrinol Metab 2025; 110:e2064-e2070. [PMID: 39193707 DOI: 10.1210/clinem/dgae597] [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: 03/06/2024] [Revised: 05/29/2024] [Accepted: 08/27/2024] [Indexed: 08/29/2024]
Abstract
CONTEXT Estimated remnant cholesterol (Rem-C) level, a risk factor for cardiovascular disease, is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosed via ultrasonography. However, the relationship between accurate serum Rem-C level measurements and histological findings of MASLD remains unclear. OBJECTIVE We aimed to elucidate the relationship between accurately measured serum Rem-C levels and histological findings of MASLD. DESIGN Cross-sectional single-center observational study. METHODS We assessed 222 patients (94 men and 128 women; age 20-80) who were diagnosed with MASLD via liver biopsy with available medical history, physical examination, and biochemical measurement data. Serum ester-type cholesterol and free cholesterol contents in the remnant lipoproteins were measured using an enzymatic method. RESULTS Serum Rem-C levels were significantly higher in patients with NAFLD activity score (NAS) 5 to 8, >66% steatosis grade, lobular inflammation with ≥5 foci, and many cells/prominent ballooning cells (a contiguous patch of hepatocytes showing prominent ballooning injury) than in patients with NAS 1 to 4, < 33% steatosis grade, lobular inflammation with <2 foci, and few ballooning cells (several scattered balloon cells), respectively. While univariate analysis revealed no significant association between Rem-C levels and advanced fibrosis, a significant association between Rem-C levels and NAS was evident. This relationship remained significant in multivariate analysis adjusted for confounders. Furthermore, in the analysis by sex, these relationships were significant for men but not for women. CONCLUSION High serum Rem-C levels were associated with high NAS but not with fibrosis stage, particularly in men. Controlling serum Rem-C level may improve MASLD activity.
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Affiliation(s)
- Teruki Miyake
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Shinya Furukawa
- Health Services Center, Ehime University, 3 Bunkyocho, Matsuyama City, Ehime 790-0826, Japan
| | - Bunzo Matsuura
- Department of Lifestyle-related Medicine and Endocrinology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Ayumi Kanamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Masumi Miyazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Akihito Shiomi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Hironobu Nakaguchi
- Department of Lifestyle-related Medicine and Endocrinology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Yuki Okazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Yoshiko Nakamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Yusuke Imai
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Mitsuhito Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Yasunori Yamamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Teru Kumagi
- Postgraduate Medical Education Center, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon City, Ehime 791-0295, Japan
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Ye X, Toyama T, Yinuo W, Kudo R, Stephanie S, Arisawa K, Saito Y. Inhibition of selenium supply function of selenoprotein p through adduct formation by sulforaphane. J Nutr Biochem 2025; 135:109781. [PMID: 39419192 DOI: 10.1016/j.jnutbio.2024.109781] [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: 07/25/2024] [Revised: 10/08/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Selenium is a potent nucleophile essential for selenoenzymes, such as glutathione peroxidase (also known as GSH-Px; GPX; GPx) and selenoprotein P (also known as SelP; SEPP1; SELENOP; SeP). SeP is predominantly secreted from the liver and functions as a selenium carrier in plasma. We previously found that sulforaphane (SFN), an electrophilic phytochemical, reduces SeP production in cultured hepatocytes and mouse liver, however, the effect of electrophilic modification of SeP by SFN on selenium transport and metabolism remains unclear. In the present study, we demonstrate that sulforaphane covalently modifies selenocysteine/cysteine residues of SeP using an acidic biotin PAEC5 maleimide labeling assay, which allows for focused-labeling of selenocysteine residues. Although the SFN-SeP adduct can be taken up by HepG2 cells and degraded by the lysosome, it was less effective in inducing GPx expression. Our findings indicate that SFN disrupts the selenium supply pathway through the formation of the SeP-SFN adduct.
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Affiliation(s)
- Xinying Ye
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Takashi Toyama
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
| | - Wang Yinuo
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Runa Kudo
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Siu Stephanie
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Kotoko Arisawa
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Yoshiro Saito
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
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Letsiou S, Damigou E, Nomikos T, Pergantis SA, Pitsavos C, Panagiotakos D, Antonopoulou S. Deciphering the associations of selenium distribution in serum GPx-3 and selenoprotein P with cardiovascular risk factors in a healthy population with moderate levels of selenium: The ATTICA study. J Trace Elem Med Biol 2024; 86:127509. [PMID: 39190954 DOI: 10.1016/j.jtemb.2024.127509] [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: 06/18/2024] [Revised: 08/14/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024]
Abstract
BACKGROUND Selenium (Se) is an essential micronutrient, important for human health. The relationship of Se with cardiovascular risk factors is still inconclusive, especially regarding the role of different selenoproteins. The present study evaluated the relation of total serum Se as well as its distribution in plasma selenoproteins, namely glutathione peroxidase 3 (GPx3) and selenoprotein P (SelP) with cardiovascular risk factors in a sex-specific manner, in a healthy population with moderate levels of Se. METHODS A sub-sample from the ATTICA Study's database, consisting of 398 participants (160 females and 238 males) with data on Se and selenoproteins levels, was considered. GPx3, SelP and the main non-specific serum selenium containing protein, selenoalbumin (SeAlb) were simultaneously determined in human plasma by high-performance liquid chromatography (HPLC) coupled with inductively coupled plasma mass spectrometry (ICP-MS) at baseline. RESULTS Participants that belong to the highest tertiles of GPx3 and SelP presented the lowest blood pressure. Homocysteine was inversely associated with SelP and its ratio SelP/TSe in both sexes. In males, the lowest tertile of GPx3 showed lower adiponectin levels (0.66 ± 0.21 μg/mL) in comparison to the 2nd tertile of GPx3 (p=0.002), SelP was inversely associated with visceral adipose index (VAI) (-2.29 ± 0.81, p=0.005). Particularly, in males, the middle tertile of SelP had the lowest VAI values. Regarding females, lower Lp(a) concentration by 11.96 ± 5.84 mg/dL was observed in low SelP levels while higher leptin concentration by 2.30 ± 0.73 μg/L and lower fibrinogen concentration by 27.32 ± 13.30 mg/dL was detected in low GPx3 levels. CONCLUSION Circulating selenoproteins exert differentiated effects on cardiovascular risk factors, some of them in a sex-specific manner.
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Affiliation(s)
- Sophia Letsiou
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
| | - Evangelia Damigou
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
| | - Tzortzis Nomikos
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
| | | | - Christos Pitsavos
- First Cardiology Clinic, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece
| | - Demosthenes Panagiotakos
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
| | - Smaragdi Antonopoulou
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece.
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Alves HPDM, Duarte GBS, Souza Junior ACD, Pereira Batista LDS, Rogero MM, Barbosa F, Cozzolino SMF, Dantas-Komatsu RCS, Marinho Costa KZS, Reis BZ. Selenium biomarkers and miR-7-5p in overweight/obese women. J Trace Elem Med Biol 2024; 86:127499. [PMID: 39084121 DOI: 10.1016/j.jtemb.2024.127499] [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: 04/29/2024] [Revised: 06/25/2024] [Accepted: 07/18/2024] [Indexed: 08/02/2024]
Abstract
INTRODUCTION Chronic low-grade inflammation and oxidative stress are pivotal contributors to the metabolic complications associated with obesity. Selenoprotein P (SELENOP) and glutathione peroxidase 1 (GPx1) are selenoproteins involved in the reduction of reactive oxygen species and pro-inflammatory cytokines levels. Nutritional epigenomics revealed the interaction of microRNAs and nutrients with an important impact on metabolic pathways involved in obesity. However, the knowledge regarding the influence of microRNA on selenium biomarkers and its impact on metabolic pathways related to obesity remains scarce. Thus, the aim of this study was to investigate the association of plasma miR-7-5p expression with selenium and inflammatory biomarkers in women with overweight/obesity. MATERIAL AND METHODS Anthropometric evaluations were performed and blood samples were collected for the analysis of fasting glucose, insulin, inflammatory and selenium biomarkers, and miR-7-5p expression in 54 women with overweight/obesity. Gene expression of SELENOP and GPX1 were evaluated in peripheral mononuclear blood cells. RESULTS This study observed a negative correlation between SELENOP levels and miR-7-5p (rho = -0.350; p = 0.018). Additionally, it was observed that body fat (OR = 0.737; p = 0.011), age (OR = 1.214; p = 0.007), and miR-7-5p (OR = 0.990; p = 0.015) emerged as significant predictors of SELENOP levels. CONCLUSIONS In conclusion, we observed a significant inverse association between miR-7-5p expression and SELENOP concentration in overweight/obese women, suggesting that age and percentage of body fat are also associated. TRIAL REGISTRATION NUMBER Brazilian Registry of Clinical Trials (ReBEC) number RBR-2nfy5q.
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Affiliation(s)
- Higor Paiva de Mendonça Alves
- Postgraduate Program in Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Rio Grande do Norte, Avenida Senador Salgado Filho, 3000. University Campus - Lagoa Nova, Natal, RN 59078-970, Brazil.
| | - Graziela Biude Silva Duarte
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Science, University of São Paulo, Avenida Prof. Lineu Prestes, 580, Bloco 14 - Butantã, São Paulo, SP 05508-000, Brazil.
| | - Adriano Carlos de Souza Junior
- Postgraduate Program in Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Rio Grande do Norte, Avenida Senador Salgado Filho, 3000. University Campus - Lagoa Nova, Natal, RN 59078-970, Brazil.
| | - Leonam da Silva Pereira Batista
- Postgraduate Program in Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Rio Grande do Norte, Avenida Senador Salgado Filho, 3000. University Campus - Lagoa Nova, Natal, RN 59078-970, Brazil.
| | - Marcelo Macedo Rogero
- Department of Nutrition, School of Public Health, University of São Paulo, Avenida Dr. Arnaldo, 715 - Cerqueira César, São Paulo, SP 01246-904, Brazil; Food Research Center (FoRC), CEPID-FAPESP, Research Innovation and Dissemination Centers São Paulo Research Foundation, Laboratory of Food Engineering, Semi Industrial Ed. - R. do Lago, 250 - Bloco C, São Paulo, SP 05468-140, Brazil.
| | - Fernando Barbosa
- Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café, s/nº - Vila Monte Alegre, Ribeirão Preto, SP 14040903, Brazil.
| | - Silvia Maria Franciscato Cozzolino
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Science, University of São Paulo, Avenida Prof. Lineu Prestes, 580, Bloco 14 - Butantã, São Paulo, SP 05508-000, Brazil.
| | - Raquel Costa Silva Dantas-Komatsu
- Postgraduate Program in Pharmaceutical Sciences, Center for Health Sciences, Federal University of Rio Grande do Norte, Rio Grande do Norte, Rua General Gustavo Cordeiro de Faria, s/nº - Petrópolis, Natal, RN 59012-570, Brazil.
| | - Karina Zaira Silva Marinho Costa
- Brazilian Company of Hospital Services (EBSERH), Onofre Lopes University Hospital, Av. Nilo Peçanha, 620 - Petrópolis, Natal, RN 59012-300, Brazil.
| | - Bruna Zavarize Reis
- Postgraduate Program in Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Rio Grande do Norte, Avenida Senador Salgado Filho, 3000. University Campus - Lagoa Nova, Natal, RN 59078-970, Brazil; Department of Nutrition, Federal University of Rio Grande do Norte, Rio Grande do Norte, Avenida Senador Salgado Filho, 3000, University Campus - Lagoa Nova, Natal, RN 59078-970, Brazil.
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Mladenović D, Vesković M, Šutulović N, Hrnčić D, Stanojlović O, Radić L, Macut JB, Macut D. Adipose-derived extracellular vesicles - a novel cross-talk mechanism in insulin resistance, non-alcoholic fatty liver disease, and polycystic ovary syndrome. Endocrine 2024; 85:18-34. [PMID: 38285412 DOI: 10.1007/s12020-024-03702-w] [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: 11/17/2023] [Accepted: 01/14/2024] [Indexed: 01/30/2024]
Abstract
Obesity is the best described risk factor for the development of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) while the major pathogenic mechanism linking these entities is insulin resistance (IR). IR is primarily caused by increased secretion of proinflammatory cytokines, adipokines, and lipids from visceral adipose tissue. Increased fatty acid mobilization results in ectopic fat deposition in the liver which causes endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress resulting in increased cytokine production and subsequent inflammation. Similarly, IR with hyperinsulinemia cause hyperandrogenism, the hallmark of PCOS, and inflammation in the ovaries. Proinflammatory cytokines from both liver and ovaries aggravate IR thus providing a complex interaction between adipose tissue, liver, and ovaries in inducing metabolic abnormalities in obese subjects. Although many pathogenic mechanisms of IR, NAFLD/MASLD, and PCOS are known, there is still no effective therapy for these entities suggesting the need for further evaluation of their pathogenesis. Extracellular vesicles (EVs) represent a novel cross-talk mechanism between organs and include membrane-bound vesicles containing proteins, lipids, and nucleic acids that may change the phenotype and function of target cells. Adipose tissue releases EVs that promote IR, the development of all stages of NAFLD/MASLD and PCOS, while mesenchymal stem cell-derived AVs may alleviate metabolic abnormalities and may represent a novel therapeutic device in NAFLD/MASLD, and PCOS. The purpose of this review is to summarize the current knowledge on the role of adipose tissue-derived EVs in the pathogenesis of IR, NAFLD/MASLD, and PCOS.
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Affiliation(s)
- Dušan Mladenović
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
| | - Milena Vesković
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Nikola Šutulović
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dragan Hrnčić
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Olivera Stanojlović
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Lena Radić
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Jelica Bjekić Macut
- University of Belgrade Faculty of Medicine, Department of Endocrinology, UMC Bežanijska kosa, Belgrade, Serbia
| | - Djuro Macut
- University of Belgrade Faculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Belgrade, Serbia
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Tinkov AA, Korobeinikova TV, Morozova GD, Aschner M, Mak DV, Santamaria A, Rocha JBT, Sotnikova TI, Tazina SI, Skalny AV. Association between serum trace element, mineral, and amino acid levels with non-alcoholic fatty liver disease (NAFLD) in adult women. J Trace Elem Med Biol 2024; 83:127397. [PMID: 38290269 DOI: 10.1016/j.jtemb.2024.127397] [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: 11/30/2023] [Revised: 12/29/2023] [Accepted: 01/13/2024] [Indexed: 02/01/2024]
Abstract
The objective of the present study is assessment of serum trace element and amino acid levels in non-alcoholic fatty liver disease (NAFLD) patients with subsequent evaluation of its independent associations with markers of liver injury and metabolic risk. MATERIALS AND METHODS 140 women aged 20-90 years old with diagnosed NAFLD and 140 healthy women with a respective age range were enrolled in the current study. Analysis of serum and hair levels of trace elements and minerals was performed with inductively-coupled plasma mass-spectrometry (ICP-MS). Serum amino acid concentrations were evaluated by high-pressure liquid chromatography (HPLC) with UV-detection. In addition, routine biochemical parameters including liver damage markers, alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT), were assessed spectrophotometrically. RESULTS The findings demonstrated that patients with NAFLD were characterized by higher ALT, GGT, lactate dehydrogenase (LDH) and cholinesterase (CE) activity, as well as increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid. NAFLD patients were characterized by reduced serum and hair Co, Se, and Zn levels, as well as hair Cu content and serum Mn concentrations in comparison to controls. Circulating Ala, Cit, Glu, Gly, Ile, Leu, Phe, and Tyr levels in NAFLD patients exceeded those in the control group. Multiple linear regression demonstrated that serum and hair trace element levels were significantly associated with circulating amino acid levels after adjustment for age, BMI, and metabolic parameters including liver damage markers. CONCLUSION It is proposed that altered trace element handling may contribute to NAFLD pathogenesis through modulation of amino acid metabolism.
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Affiliation(s)
- Alexey A Tinkov
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia.
| | - Tatiana V Korobeinikova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Galina D Morozova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, 10461 Bronx, NY, USA
| | - Daria V Mak
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Abel Santamaria
- Faculty of Sciencies, National Autonomous University of Mexico, 04510 Mexico City, Mexico
| | - Joao B T Rocha
- Departamento de Bioquímica e Biologia Molecular, CCNE, Universidade Federal de Santa Maria, Santa Maria 97105-900 RS, Brazil
| | - Tatiana I Sotnikova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; City Clinical Hospital n. a. S.P. Botkin of the Moscow City Health Department, 125284 Moscow, Russia
| | - Serafima Ia Tazina
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; City Clinical Hospital n. a. S.P. Botkin of the Moscow City Health Department, 125284 Moscow, Russia
| | - Anatoly V Skalny
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
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Xu Q, Zhang J, Lu Y, Wu L. Association of metabolic-dysfunction associated steatotic liver disease with polycystic ovary syndrome. iScience 2024; 27:108783. [PMID: 38292434 PMCID: PMC10825666 DOI: 10.1016/j.isci.2024.108783] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), which has a prevalence of over 25% in adults, encompasses a wide spectrum of liver diseases. Metabolic-dysfunction associated steatotic liver disease (MASLD), the new term for NAFLD, is characterized by steatotic liver disease accompanied by cardiometabolic criteria, showing a strong correlation with metabolic diseases. Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease affecting 4-21% of women of reproductive age. Numerous studies have indicated that NAFLD and PCOS often occur together. However, as MASLD is a new term, there is still a lack of reports describing the effects of MASLD on the development of PCOS. In this review article, we have summarized the complex and multifaceted connections between MASLD and PCOS. Understanding the pathogenesis and treatment methods could not only guide the clinical prevention, diagnosis, and treatment of PCOS in patients with MASLD, but also increase the clinical attention of reproductive doctors to MASLD.
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Affiliation(s)
- Qiuyu Xu
- Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Zhang
- Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Lu
- Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Wu
- Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Henin G, Loumaye A, Leclercq IA, Lanthier N. Myosteatosis: Diagnosis, pathophysiology and consequences in metabolic dysfunction-associated steatotic liver disease. JHEP Rep 2024; 6:100963. [PMID: 38322420 PMCID: PMC10844870 DOI: 10.1016/j.jhepr.2023.100963] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 02/08/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of multisystemic complications, including muscle changes such as sarcopenia and myosteatosis that can reciprocally affect liver function. We conducted a systematic review to highlight innovative assessment tools, pathophysiological mechanisms and metabolic consequences related to myosteatosis in MASLD, based on original articles screened from PUBMED, EMBASE and COCHRANE databases. Forty-six original manuscripts (14 pre-clinical and 32 clinical studies) were included. Microscopy (8/14) and tissue lipid extraction (8/14) are the two main assessment techniques used to measure muscle lipid content in pre-clinical studies. In clinical studies, imaging is the most used assessment tool and included CT (14/32), MRI (12/32) and ultrasound (4/32). Assessed muscles varied across studies but mainly included paravertebral (4/14 in pre-clinical; 13/32 in clinical studies) and lower limb muscles (10/14 in preclinical; 13/32 in clinical studies). Myosteatosis is already highly prevalent in non-cirrhotic stages of MASLD and correlates with disease activity when using muscle density assessed by CT. Numerous pathophysiological mechanisms were found and included: high-fat and high-fructose diet, dysregulation in fatty acid transport and ketogenesis, endocrine disorders and impaired microRNA122 pathway signalling. In this review we also uncover several potential consequences of myosteatosis in MASLD, such as insulin resistance, MASLD progression from steatosis to metabolic steatohepatitis and loss of muscle strength. In conclusion, data on myosteatosis in MASLD are already available. Screening for myosteatosis could be highly relevant in the context of MASLD, considering its correlation with MASLD activity as well as its related consequences.
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Affiliation(s)
- Guillaume Henin
- Service d’Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
- Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Audrey Loumaye
- Service d’Endocrinologie, Diabétologie et Nutrition, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Isabelle A. Leclercq
- Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Nicolas Lanthier
- Service d’Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
- Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
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9
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Driessen S, Francque SM, Anker SD, Castro Cabezas M, Grobbee DE, Tushuizen ME, Holleboom AG. Metabolic dysfunction-associated steatotic liver disease and the heart. Hepatology 2023:01515467-990000000-00699. [PMID: 38147315 DOI: 10.1097/hep.0000000000000735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 11/13/2023] [Indexed: 12/27/2023]
Abstract
The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with cardiometabolic disease, including atherosclerotic cardiovascular disease (asCVD). This raises questions on co-occurrence, causality, and the need for screening and multidisciplinary care for MASLD in patients with asCVD, and vice versa. Here, we review the interrelations of MASLD and heart disease and formulate answers to these matters. Epidemiological studies scoring proxies for atherosclerosis and actual cardiovascular events indicate increased atherosclerosis in patients with MASLD, yet no increased risk of asCVD mortality. MASLD and asCVD share common drivers: obesity, insulin resistance and type 2 diabetes mellitus (T2DM), smoking, hypertension, and sleep apnea syndrome. In addition, Mendelian randomization studies support that MASLD may cause atherosclerosis through mixed hyperlipidemia, while such evidence is lacking for liver-derived procoagulant factors. In the more advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction by reduced filling of the right ventricle, which may induce fatigue upon exertion, often mentioned by patients with MASLD. Some evidence points to an association between MASLD and cardiac arrhythmias. Regarding treatment and given the strong co-occurrence of MASLD and asCVD, pharmacotherapy in development for advanced stages of MASLD would ideally also reduce cardiovascular events, as has been demonstrated for T2DM treatments. Given the common drivers, potential causal factors and especially given the increased rate of cardiovascular events, comprehensive cardiometabolic risk management is warranted in patients with MASLD, preferably in a multidisciplinary approach.
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Affiliation(s)
- Stan Driessen
- Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - Stefan D Anker
- Department of Cardiology (CVK) of German Heart Center Charité, Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Manuel Castro Cabezas
- Julius Clinical, Zeist, The Netherlands
- Department of Internal Medicine, Franciscus Gasthuis and Vlietland, Rotterdam, The Netherlands
- Department of Internal Medicine and Endocrinology, Erasmus MC, Rotterdam, The Netherlands
| | - Diederick E Grobbee
- Julius Clinical, Zeist, The Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Maarten E Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Adriaan G Holleboom
- Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
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10
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Vesković M, Šutulović N, Hrnčić D, Stanojlović O, Macut D, Mladenović D. The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease-The Transition from an Adipocentric to Liver-Centric Approach. Curr Issues Mol Biol 2023; 45:9084-9102. [PMID: 37998747 PMCID: PMC10670061 DOI: 10.3390/cimb45110570] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/01/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023] Open
Abstract
The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.
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Affiliation(s)
- Milena Vesković
- Institute of Pathophysiology “Ljubodrag Buba Mihailovic”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Nikola Šutulović
- Institute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (N.Š.); (D.H.); (O.S.)
| | - Dragan Hrnčić
- Institute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (N.Š.); (D.H.); (O.S.)
| | - Olivera Stanojlović
- Institute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (N.Š.); (D.H.); (O.S.)
| | - Djuro Macut
- Clinic of Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Dušan Mladenović
- Institute of Pathophysiology “Ljubodrag Buba Mihailovic”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
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11
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Ye X, Toyama T, Taguchi K, Arisawa K, Kaneko T, Tsutsumi R, Yamamoto M, Saito Y. Sulforaphane decreases serum selenoprotein P levels through enhancement of lysosomal degradation independent of Nrf2. Commun Biol 2023; 6:1060. [PMID: 37857700 PMCID: PMC10587141 DOI: 10.1038/s42003-023-05449-y] [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: 04/11/2023] [Accepted: 10/11/2023] [Indexed: 10/21/2023] Open
Abstract
Selenoprotein P (SeP) is a major selenoprotein in serum predominantly produced in the liver. Excess SeP impairs insulin secretion from the pancreas and insulin sensitivity in skeletal muscle, thus inhibition of SeP could be a therapeutic strategy for type 2 diabetes. In this study, we examine the effect of sulforaphane (SFN), a phytochemical of broccoli sprouts and an Nrf2 activator, on SeP expression in vitro and in vivo. Treatment of HepG2 cells with SFN decreases inter- and intra-cellular SeP levels. SFN enhances lysosomal acidification and expression of V-ATPase, and inhibition of this process cancels the decrease of SeP by SFN. SFN activates Nrf2 in the cells, while Nrf2 siRNA does not affect the decrease of SeP by SFN or lysosomal acidification. These results indicate that SFN decreases SeP by enhancing lysosomal degradation, independent of Nrf2. Injection of SFN to mice results in induction of cathepsin and a decrease of SeP in serum. The findings from this study are expected to contribute to developing SeP inhibitors in the future, thereby contributing to treating and preventing diseases related to increased SeP.
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Affiliation(s)
- Xinying Ye
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Takashi Toyama
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
| | - Keiko Taguchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Kotoko Arisawa
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Takayuki Kaneko
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Ryouhei Tsutsumi
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Yoshiro Saito
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
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12
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Dogaru CB, Duță C, Muscurel C, Stoian I. "Alphabet" Selenoproteins: Implications in Pathology. Int J Mol Sci 2023; 24:15344. [PMID: 37895024 PMCID: PMC10607139 DOI: 10.3390/ijms242015344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/08/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Selenoproteins are a group of proteins containing selenium in the form of selenocysteine (Sec, U) as the 21st amino acid coded in the genetic code. Their synthesis depends on dietary selenium uptake and a common set of cofactors. Selenoproteins accomplish diverse roles in the body and cell processes by acting, for example, as antioxidants, modulators of the immune function, and detoxification agents for heavy metals, other xenobiotics, and key compounds in thyroid hormone metabolism. Although the functions of all this protein family are still unknown, several disorders in their structure, activity, or expression have been described by researchers. They concluded that selenium or cofactors deficiency, on the one hand, or the polymorphism in selenoproteins genes and synthesis, on the other hand, are involved in a large variety of pathological conditions, including type 2 diabetes, cardiovascular, muscular, oncological, hepatic, endocrine, immuno-inflammatory, and neurodegenerative diseases. This review focuses on the specific roles of selenoproteins named after letters of the alphabet in medicine, which are less known than the rest, regarding their implications in the pathological processes of several prevalent diseases and disease prevention.
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Affiliation(s)
| | | | - Corina Muscurel
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania (I.S.)
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13
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Giannouli A, Stefanaki C, Kouskoutis C, Konidari M, Mani I, Konidari K, Markantonis SL, Mantzou A, Dourakis SP, Deligeoroglou E, Bacopoulou F. Hepatokine Profile in Adolescents with Polycystic Ovary Syndrome: A Case-Control Study. J Clin Med 2023; 12:5744. [PMID: 37685811 PMCID: PMC10489115 DOI: 10.3390/jcm12175744] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
The current guidelines suggest routine screening for non-alcoholic fatty liver disease (NAFLD) in patients with polycystic ovary syndrome (PCOS). Hepatokines seem to be promising surrogate endpoints for the diagnosis and severity of NAFLD. PCOS has its onset in adolescence and its metabolic sequalae begin during the same period. There are scarce data on the hepatokine profile of adolescent PCOS patients. This case-control study examined the serum profile of the hepatokines sex hormone-binding globulin (SHBG), selenoprotein P, fibroblast growth factor 21 (FGF21), and fetuin A in a sample of adolescent PCOS patients, and their association to metabolic and hormonal parameters. The selenoprotein P and SHBG serum concentrations were significantly decreased in PCOS patients vs. the controls (median (IQR), 2.47 (0.40) vs. 2.66 (0.36) μg/mL, p = 0.025; mean ± SD, 41.71 ± 19.41 vs. 54.94 ± 22.12 nmol/L, p = 0.011, respectively), whereas selenoprotein P was significantly and positively associated with testosterone (r = 0.325, p = 0.007) and the free androgen index (r = 0.361, p = 0.002). The SHBG demonstrated multiple significant negative correlations with adverse metabolic parameters. Among the PCOS patients, the FGF21 concentrations were significantly higher in those with NAFLD, whereas a 1 pg/mL increase in the FGF21 concentration increased the odds of NAFLD diagnosis by liver ultrasound by 1%, suggesting FGF21 as a potential biomarker for hepatic disease in females with PCOS in adolescence. Fetuin A was the least differentiated hepatokine between the PCOS patients and controls with the least associations with metabolic and hormonal parameters.
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Affiliation(s)
- Aikaterini Giannouli
- Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, 11527 Athens, Greece; (A.G.); (C.S.); (K.K.)
| | - Charikleia Stefanaki
- Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, 11527 Athens, Greece; (A.G.); (C.S.); (K.K.)
| | - Christos Kouskoutis
- Laboratory of Biopharmaceutics and Pharmacokinetics, Department of Pharmaceutical Technology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece; (C.K.); (S.L.M.)
| | - Marianna Konidari
- Department of Radiology, Medical School, National and Kapodistrian University of Athens, Aretaieio Hospital, 11528 Athens, Greece;
| | - Iliana Mani
- Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokratio Hospital, 11527 Athens, Greece; (I.M.); (S.P.D.)
| | - Konstantina Konidari
- Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, 11527 Athens, Greece; (A.G.); (C.S.); (K.K.)
| | - Sophia L. Markantonis
- Laboratory of Biopharmaceutics and Pharmacokinetics, Department of Pharmaceutical Technology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece; (C.K.); (S.L.M.)
| | - Aimilia Mantzou
- Division of Endocrinology, Metabolism, and Diabetes, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, 11527 Athens, Greece;
| | - Spyridon P. Dourakis
- Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokratio Hospital, 11527 Athens, Greece; (I.M.); (S.P.D.)
| | - Efthymios Deligeoroglou
- Department of Pediatric & Adolescent Gynecology, Mitera Children’s Hospital, 15123 Athens, Greece;
| | - Flora Bacopoulou
- Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, 11527 Athens, Greece; (A.G.); (C.S.); (K.K.)
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14
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Lim JY, Kim E. The Role of Organokines in Obesity and Type 2 Diabetes and Their Functions as Molecular Transducers of Nutrition and Exercise. Metabolites 2023; 13:979. [PMID: 37755259 PMCID: PMC10537761 DOI: 10.3390/metabo13090979] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023] Open
Abstract
Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D). Strategies aimed at remodeling organokines may be effective therapeutic interventions. Diet modification and exercise have been established as the first-line therapeutic intervention to prevent or treat metabolic diseases. This review summarizes the current knowledge on organokines secreted by the liver, muscle, and adipose tissues in obesity and T2D. Additionally, we highlighted the effects of diet/nutrition and exercise on the remodeling of organokines in obesity and T2D. Specifically, we investigated the ameliorative effects of caloric restriction, selective nutrients including ω3 PUFAs, selenium, vitamins, and metabolites of vitamins, and acute/chronic exercise on the dysregulation of organokines in obesity and T2D. Finally, this study dissected the underlying molecular mechanisms by which nutrition and exercise regulate the expression and secretion of organokines in specific tissues.
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Affiliation(s)
- Ji Ye Lim
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin St., Houston, TX 77030, USA
| | - Eunju Kim
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin St., Houston, TX 77030, USA
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15
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Qin L, Wu J, Sun X, Huang X, Huang W, Weng C, Cai J. The regulatory role of metabolic organ-secreted factors in the nonalcoholic fatty liver disease and cardiovascular disease. Front Cardiovasc Med 2023; 10:1119005. [PMID: 37180779 PMCID: PMC10169694 DOI: 10.3389/fcvm.2023.1119005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/13/2023] [Indexed: 05/16/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease characterized by an excessive accumulation of fat in the liver, which is becoming a major global health problem, affecting about a quarter of the population. In the past decade, mounting studies have found that 25%-40% of NAFLD patients have cardiovascular disease (CVD), and CVD is one of the leading causes of death in these subjects. However, it has not attracted enough awareness and emphasis from clinicians, and the underlying mechanisms of CVD in NAFLD patients remain unclear. Available research reveals that inflammation, insulin resistance, oxidative stress, and glucose and lipid metabolism disorders play indispensable roles in the pathogenesis of CVD in NAFLD. Notably, emerging evidence indicates that metabolic organ-secreted factors, including hepatokines, adipokines, cytokines, extracellular vesicles, and gut-derived factors, are also involved in the occurrence and development of metabolic disease and CVD. Nevertheless, few studies have focused on the role of metabolic organ-secreted factors in NAFLD and CVD. Therefore, in this review, we summarize the relationship between metabolic organ-secreted factors and NAFLD as well as CVD, which is beneficial for clinicians to comprehensive and detailed understanding of the association between both diseases and strengthen management to improve adverse cardiovascular prognosis and survival.
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Affiliation(s)
| | | | | | | | | | - Chunyan Weng
- Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
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16
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Stefan N, Schick F, Birkenfeld AL, Häring HU, White MF. The role of hepatokines in NAFLD. Cell Metab 2023; 35:236-252. [PMID: 36754018 PMCID: PMC10157895 DOI: 10.1016/j.cmet.2023.01.006] [Citation(s) in RCA: 135] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/18/2022] [Accepted: 01/13/2023] [Indexed: 02/09/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is not only a consequence of insulin resistance, but it is also an important cause of insulin resistance and major non-communicable diseases (NCDs). The close relationship of NAFLD with visceral obesity obscures the role of fatty liver from visceral adiposity as the main pathomechanism of insulin resistance and NCDs. To overcome this limitation, in analogy to the concept of adipokines, in 2008 we introduced the term hepatokines to describe the role of fetuin-A in metabolism. Since then, several other hepatokines were tested for their effects on metabolism. Here we address the dysregulation of hepatokines in people with NAFLD. Then, we discuss pathophysiological mechanisms of cardiometabolic diseases specifically related to NAFLD by focusing on hepatokine-related organ crosstalk. Finally, we propose how the determination of major hepatokines and adipokines can be used for pathomechanism-based clustering of insulin resistance in NAFLD and visceral obesity to better implement precision medicine in clinical practice.
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Affiliation(s)
- Norbert Stefan
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Fritz Schick
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section of Experimental Radiology, Department of Radiology, University Hospital of Tübingen, Tübingen, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Morris F White
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
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17
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Scherbakov VI, Skosyreva GA, Ryabichenko TI, Obukhova OO. Cytokines and regulation of glucose and lipid metabolism in the obesity. OBESITY AND METABOLISM 2022. [DOI: 10.14341/omet12863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The article presents data of the influence of cytokines of different directions of glucose and lipid metabolism in obesity. A change of the basic paradigm regarding adipose tissue has contributed to a number of recent discoveries. This concerns such basic concepts as healthy and diseased adipocytes, and, as a consequence, changes of their metabolism under the influence of cytokins. Distinguishing the concept of organokines demonstrates that despite the common features of cytokine regulation, each organ has its own specifics features of cytokine regulation, each organ has its own specific an important section of this concept is the idea of the heterogeneity of adipose tissue. Knowledge of the function of adipose tissue localized in different compartments of the body is expanding. There are date about the possibility of transition of one type of adipose tissue to another. A possible mechanism linking adipose tissue inflammation and the formation of insulin resistance (IR) is presented in this paper. The mechanism of IR development is closely connected with to proinflammatory cytokins disordering the insulin signal, accompanied by a decrease of the work of glucose transporters. A decrease of the income of glucose into cells leads to a change of glycolysis level to an increase of the fatty acids oxidation. Cytokins are able to participate in the process of the collaboration of some cells with others, that occurs both during physiological and pathological process.
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Affiliation(s)
- V. I. Scherbakov
- Federal Research Center of Fundamental and Translational Medicine
| | - G. A. Skosyreva
- Federal Research Center of Fundamental and Translational Medicine
| | | | - O. O. Obukhova
- Federal Research Center of Fundamental and Translational Medicine
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18
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Yang B, Lu L, Zhou D, Fan W, Barbier-Torres L, Steggerda J, Yang H, Yang X. Regulatory network and interplay of hepatokines, stellakines, myokines and adipokines in nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis. Front Endocrinol (Lausanne) 2022; 13:1007944. [PMID: 36267567 PMCID: PMC9578007 DOI: 10.3389/fendo.2022.1007944] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/05/2022] [Indexed: 11/29/2022] Open
Abstract
Fatty liver disease is a spectrum of liver pathologies ranging from simple hepatic steatosis to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and culminating with the development of cirrhosis or hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is complex and diverse, and there is a lack of effective treatment measures. In this review, we address hepatokines identified in the pathogenesis of NAFLD and NASH, including the signaling of FXR/RXR, PPARα/RXRα, adipogenesis, hepatic stellate cell activation/liver fibrosis, AMPK/NF-κB, and type 2 diabetes. We also highlight the interaction between hepatokines, and cytokines or peptides secreted from muscle (myokines), adipose tissue (adipokines), and hepatic stellate cells (stellakines) in response to certain nutritional and physical activity. Cytokines exert autocrine, paracrine, or endocrine effects on the pathogenesis of NAFLD and NASH. Characterizing signaling pathways and crosstalk amongst muscle, adipose tissue, hepatic stellate cells and other liver cells will enhance our understanding of interorgan communication and potentially serve to accelerate the development of treatments for NAFLD and NASH.
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Affiliation(s)
- Bing Yang
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liqing Lu
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Dongmei Zhou
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wei Fan
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Lucía Barbier-Torres
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Justin Steggerda
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Heping Yang
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Xi Yang
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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19
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Vachher M, Bansal S, Kumar B, Yadav S, Arora T, Wali NM, Burman A. Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma. J Cell Biochem 2022; 123:1553-1584. [PMID: 35818831 DOI: 10.1002/jcb.30252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 12/16/2022]
Abstract
Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.
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Affiliation(s)
- Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Savita Bansal
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Sandeep Yadav
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Taruna Arora
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Nalini Moza Wali
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
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20
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Yu R, Wang Z, Ma M, Xu P, Liu L, Tinkov AA, Lei XG, Zhou JC. Associations between Circulating SELENOP Level and Disorders of Glucose and Lipid Metabolism: A Meta-Analysis. Antioxidants (Basel) 2022; 11:1263. [PMID: 35883754 PMCID: PMC9311835 DOI: 10.3390/antiox11071263] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/15/2022] [Accepted: 06/23/2022] [Indexed: 02/01/2023] Open
Abstract
Selenoprotein P (SELENOP) is an extracellular antioxidant, selenium transporter, and hepatokine interfering with glucose and lipid metabolism. To study the association between the circulating SELENOP concentration and glucose and lipid metabolic diseases (GLMDs), including gestational diabetes (GD), metabolic syndrome (MetS), non-alcoholic fatty liver disease, obesity, and type 2 diabetes, as well as the individual markers, a meta-analysis was conducted by searching multiple databases from their establishment through March 2022 and including 27 articles published between October 2010 and May 2021, involving 4033 participants. Participants with GLMDs had higher levels of SELENOP than those without GLMDs (standardized mean difference = 0.84, 95% CI: 0.16 to 1.51), and the SELENOP levels were positively correlated with the markers of GLMDs (pooled effect size = 0.09, 95% CI: 0.02 to 0.15). Subgroup analyses showed that the SELENOP concentrations were higher in women with GD and lower in individuals with MetS than their counterparts, respectively. Moreover, SELENOP was positively correlated with low-density lipoprotein cholesterol, but not with the other markers of GLMDs. Thus, the heterogenicity derived from diseases or disease markers should be carefully considered while interpreting the overall positive association between SELENOP and GLMDs. Studies with a larger sample size and advanced design are warranted to confirm these findings.
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Affiliation(s)
- Ruirui Yu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (R.Y.); (Z.W.); (M.M.)
| | - Zhoutian Wang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (R.Y.); (Z.W.); (M.M.)
| | - Miaomiao Ma
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (R.Y.); (Z.W.); (M.M.)
| | - Ping Xu
- Shenzhen Health Development Research and Data Management Center, Shenzhen 518028, China;
| | - Longjian Liu
- Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA 19104, USA;
| | - Alexey A. Tinkov
- Laboratory of Molecular Dietetics, IM Sechenov First Moscow State Medical University, 119146 Moscow, Russia;
- Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia
| | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA;
| | - Ji-Chang Zhou
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (R.Y.); (Z.W.); (M.M.)
- Guangdong Province Engineering Laboratory for Nutrition Translation, Guangzhou 510080, China
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21
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Sak JJ, Prystupa A, Kiciński P, Luchowska-Kocot D, Kurys-Denis E, Bis-Wencel H. Leukocyte cell-derived chemotaxin-2 and fibroblast growth factor 21 in alcohol-induced liver cirrhosis. World J Hepatol 2021; 13:2071-2080. [PMID: 35070009 PMCID: PMC8727211 DOI: 10.4254/wjh.v13.i12.2071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 07/22/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The importance of early diagnosis of alcoholic liver disease underscores the need to seek better and especially non-invasive diagnostic procedures. Leukocyte cell-derived chemotaxin-2 (LECT2) has been widely studied to determine its usefulness in monitoring the course of non-alcoholic fatty liver disease but not for alcoholic liver cirrhosis (ALC).
AIM To determine the concentration of LECT2 in the blood serum of patients in relation to progressive stages of ALC, its relation to fibroblast growth factor 1 (FGF-1) and FGF-21, and to examine the possible wider use of LECT2 in diagnosing ALC.
METHODS A retrospective case-control study was conducted with 69 ALC cases and 17 controls with no ALC. Subjects were recruited from the region of Lublin (eastern Poland). Liver cirrhosis was diagnosed based on clinical features, history of heavy alcohol consumption, laboratory tests, and abdominal ultrasonography. The degree of ALC was evaluated according to Pugh-Child criteria (the Pugh-Child score). Blood was drawn and, after centrifugation, serum was collected for analysis. LECT2, FGF-1, and FGF-21 were determined using enzyme-linked immunosorbent assay kits.
RESULTS The LECT2 Levels in the control group were 18.99 ± 5.36 ng/mL. In the study groups, they declined with the progression of cirrhosis to 11.06 ± 6.47 ng/mL in one group and to 8.06 ± 5.74 ng/mL in the other (P < 0.0001). Multiple comparison tests confirmed the statistically significant differences in LECT2 Levels between the control group and both test groups (P = 0.006 and P < 0.0001). FGF-21 Levels were 44.27 ± 64.19 pg/mL in the first test group, 45.4 ± 51.69 pg/mL in the second (P = 0.008), and 13.52 ± 7.51 pg/mL in the control group. The difference between the control group and the second test group was statistically significant (P = 0.007).
CONCLUSION We suggest that LECT2 may be a non-invasive diagnostic factor for alcohol-induced liver cirrhosis. The usefulness of LECT2 for non-invasive monitoring of alcohol-induced liver cirrhosis was indirectly confirmed by the multiple regression model developed on the basis of our statistical analysis.
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Affiliation(s)
- Jarosław Jerzy Sak
- Chair and Department of Humanities and Social Medicine, Medical University of Lublin, Lublin 20-093, Poland
| | - Andrzej Prystupa
- Department of Internal Medicine, Medical University of Lublin, Lublin 20-081, Poland
| | - Paweł Kiciński
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin 20-080, Poland
| | | | - Ewa Kurys-Denis
- The Second Department of Radiology, Medical University of Lublin, Lublin 20-081, Poland
| | - Hanna Bis-Wencel
- Department of Microbiology and Reproductive Biology, University of Life Sciences in Lublin, Lublin 20-950, Poland
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22
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Kim TH, Hong DG, Yang YM. Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism. Biomedicines 2021; 9:biomedicines9121903. [PMID: 34944728 PMCID: PMC8698516 DOI: 10.3390/biomedicines9121903] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/12/2021] [Accepted: 12/12/2021] [Indexed: 12/16/2022] Open
Abstract
The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.
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Affiliation(s)
- Tae Hyun Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Korea;
| | - Dong-Gyun Hong
- Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea;
- KNU Researcher Training Program for Developing Anti-Viral Innovative Drugs, Kangwon National University, Chuncheon 24341, Korea
| | - Yoon Mee Yang
- Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea;
- KNU Researcher Training Program for Developing Anti-Viral Innovative Drugs, Kangwon National University, Chuncheon 24341, Korea
- Correspondence: ; Tel.: +82-33-250-6909
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23
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Day K, Seale LA, Graham RM, Cardoso BR. Selenotranscriptome Network in Non-alcoholic Fatty Liver Disease. Front Nutr 2021; 8:744825. [PMID: 34869521 PMCID: PMC8635790 DOI: 10.3389/fnut.2021.744825] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Observational studies indicate that selenium may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Transcriptomic exploration of the aetiology and progression of NAFLD may offer insight into the role selenium plays in this disease. This study compared gene expression levels of known selenoprotein pathways between individuals with a healthy liver to those with NAFLD. Publicly available gene expression databases were searched for studies that measured global gene expression in liver samples from patients with steatosis and non-alcoholic steatohepatitis (NASH) and healthy controls (with [HOC] or without [HC] obesity). A subset of five selenoprotein-related pathways (164 genes) were assessed in the four datasets included in this analysis. The gene TXNRD3 was less expressed in both disease groups when compared with HOC. SCLY and SELENOO were less expressed in NASH when compared with HC. SELENOM, DIO1, GPX2, and GPX3 were highly expressed in NASH when compared to HOC. Disease groups had lower expression of iron-associated transporters and higher expression of ferritin-encoding sub-units, consistent with dysregulation of iron metabolism often observed in NAFLD. Our bioinformatics analysis suggests that the NAFLD liver may have lower selenium levels than a disease-free liver, which may be associated with a disrupted iron metabolism. Our findings indicate that gene expression variation may be associated with the progressive risk of NAFLD.
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Affiliation(s)
- Kaitlin Day
- Department of Nutrition, Dietetics, and Food, Monash University, Notting Hill, VIC, Australia
| | - Lucia A Seale
- Pacific Biosciences Research Center, School of Ocean and Earth Science and Technology, University of Hawaii, Honolulu, HI, United States
| | - Ross M Graham
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Barbara R Cardoso
- Department of Nutrition, Dietetics, and Food, Monash University, Notting Hill, VIC, Australia
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24
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Urbano T, Filippini T, Lasagni D, De Luca T, Grill P, Sucato S, Polledri E, Djeukeu Noumbi G, Malavolti M, Santachiara A, Pertinhez TA, Baricchi R, Fustinoni S, Michalke B, Vinceti M. Association of Urinary and Dietary Selenium and of Serum Selenium Species with Serum Alanine Aminotransferase in a Healthy Italian Population. Antioxidants (Basel) 2021; 10:1516. [PMID: 34679651 PMCID: PMC8532767 DOI: 10.3390/antiox10101516] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/17/2021] [Accepted: 09/22/2021] [Indexed: 01/23/2023] Open
Abstract
The trace element selenium is of considerable interest due to its toxic and nutritional properties, which markedly differ according to the dose and the chemical form. It has been shown that excess selenium intake increases the risk of type 2 diabetes and, possibly, other metabolic diseases like hyperlipidemia and non-alcoholic fatty liver disease (NAFLD). For the latter, however, epidemiologic evidence is still limited. We carried out a cross-sectional study recruiting 137 healthy blood donors living in Northern Italy and assessed their exposure to selenium through different methods and measuring serum selenium species. We performed linear and spline regression analyses to assess the relation of selenium and its forms with serum alanine aminotransferase (ALT) levels, a marker of NAFLD. Urinary selenium levels were positively and somewhat linearly correlated with ALT (beta regression coefficient (β) 0.11). Conversely, the association of dietary selenium intake with ALT was positive up to 100 µg/day and null above that amount (β 0.03). Total serum selenium was inversely associated with ALT up to 120 µg/L, and slightly positive above that amount. Concerning the different serum selenium species, ALT positively correlated with two organic forms, selenocysteine (β 0.27) and glutathione peroxidase-bound selenium (β 0.09), showed a U-shaped relation with the inorganic tetravalent form, selenite, and an inverse association with human serum albumin-bound selenium (β -0.56). Our results suggest that overall exposure to selenium, and more specifically to some of its chemical forms, is positively associated with ALT, even at levels so far generally considered to be safe. Our findings add to the evidence suggesting that low-dose selenium overexposure is associated with NAFLD.
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Affiliation(s)
- Teresa Urbano
- CREAGEN—Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (T.U.); (T.F.); (G.D.N.); (M.M.)
| | - Tommaso Filippini
- CREAGEN—Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (T.U.); (T.F.); (G.D.N.); (M.M.)
| | - Daniela Lasagni
- Transfusion Medicine Unit, Azienda USL-IRCCS of Reggio Emilia, 42123 Reggio Emilia, Italy; (D.L.); (T.D.L.); (T.A.P.); (R.B.)
| | - Tiziana De Luca
- Transfusion Medicine Unit, Azienda USL-IRCCS of Reggio Emilia, 42123 Reggio Emilia, Italy; (D.L.); (T.D.L.); (T.A.P.); (R.B.)
| | - Peter Grill
- Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health, Helmholtz Center Munich, 85764 Neuherberg, Germany; (P.G.); (B.M.)
| | - Sabrina Sucato
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy; (S.S.); (E.P.); (S.F.)
| | - Elisa Polledri
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy; (S.S.); (E.P.); (S.F.)
| | - Guy Djeukeu Noumbi
- CREAGEN—Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (T.U.); (T.F.); (G.D.N.); (M.M.)
| | - Marcella Malavolti
- CREAGEN—Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (T.U.); (T.F.); (G.D.N.); (M.M.)
| | | | - Thelma A. Pertinhez
- Transfusion Medicine Unit, Azienda USL-IRCCS of Reggio Emilia, 42123 Reggio Emilia, Italy; (D.L.); (T.D.L.); (T.A.P.); (R.B.)
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
| | - Roberto Baricchi
- Transfusion Medicine Unit, Azienda USL-IRCCS of Reggio Emilia, 42123 Reggio Emilia, Italy; (D.L.); (T.D.L.); (T.A.P.); (R.B.)
| | - Silvia Fustinoni
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy; (S.S.); (E.P.); (S.F.)
- IRCCS Ca’ Granda Foundation Maggiore Policlinico Hospital, 20122 Milan, Italy
| | - Bernhard Michalke
- Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health, Helmholtz Center Munich, 85764 Neuherberg, Germany; (P.G.); (B.M.)
| | - Marco Vinceti
- CREAGEN—Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (T.U.); (T.F.); (G.D.N.); (M.M.)
- Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA
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25
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Chen Y, He X, Chen X, Li Y, Ke Y. SeP is elevated in NAFLD and participates in NAFLD pathogenesis through AMPK/ACC pathway. J Cell Physiol 2021; 236:3800-3807. [PMID: 33094480 DOI: 10.1002/jcp.30121] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is prevalent chronic liver diseases with unknown mechanism and no curative treatment. Hepatokines have demonstrated importance in NAFLD but, role of selenoprotein P (SeP) in NAFLD is unknown. A total of 79 patients with NAFLD and 79 healthy controls were included in this case-control study. SeP is elevated in patients with NAFLD. With elevating level of SeP, NAFLD prevalence, and detecting rate increases. As NAFLD aggravated, serum SeP increases. Correlation analysis demonstrates that SeP is positively associated with NAFLD risk factors including body mass index, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and serum uric acid. Both NAFLD in vivo and in vitro models, SeP protein level is higher in liver. Small interfering RNA of SEPP1 inhibited TG accumulation by activating adenosine monophosphate activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC), and overexpression of SEPP1 aggravated lipid accumulation and inhibited AMPK/ACC phosphorylation. SeP expression is activated in NAFLD and exacerbated NAFLD through AMPK/ACC, providing insight into new diagnostic, therapeutic target in NAFLD.
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Affiliation(s)
- Yi Chen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xinjue He
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xueyang Chen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Youming Li
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yini Ke
- Department of Rheumatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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26
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Oh S, Tsujimoto T, Kim B, Uchida F, Suzuki H, Iizumi S, Isobe T, Sakae T, Tanaka K, Shoda J. Weight-loss-independent benefits of exercise on liver steatosis and stiffness in Japanese men with NAFLD. JHEP Rep 2021; 3:100253. [PMID: 33898958 PMCID: PMC8059085 DOI: 10.1016/j.jhepr.2021.100253] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 01/21/2021] [Accepted: 01/23/2021] [Indexed: 02/07/2023] Open
Abstract
Background & Aims A weight-loss-independent beneficial effect of exercise on non-alcoholic fatty liver disease (NAFLD) management has been reported, but the underlying mechanism is unknown. To help determine this mechanism, the effects of exercise on individual tissues (liver, adipose tissue, and skeletal muscle) were retrospectively studied. Methods Data from Japanese obese men with NAFLD in a 3-month exercise regimen were analysed and compared with those in a 3-month dietary restriction program designed to achieve weight loss. The underlying mechanism was studied in a smaller subcohort. Results Independent of the effect of weight loss, the exercise regimen reduced liver steatosis by 9.5% and liver stiffness by 6.8% per 1% weight loss, and resulted in a 16.4% reduction in FibroScan-AST score. Improvements in these hepatic parameters were closely associated with anthropometric changes (reduction in adipose tissue and preservation of muscle mass), increases in muscle strength (+11.6%), reductions in inflammation and oxidative stress (ferritin: -22.3% and thiobarbituric acid: -12.3%), and changes in organokine concentrations (selenoprotein-P: -11.2%, follistatin: +17.1%, adiponectin: +8.9%, and myostatin: -21.6%) during the exercise regimen. Moreover, the expression of target genes of the transcription factor Nrf2, an oxidative stress sensor, was higher in monocytes, suggesting that Nrf2 is activated. Large amounts of high-intensity exercise were effective at further reducing liver steatosis and potentiating improvements in pathophysiological parameters (liver enzyme activities and organokine profiles). Conclusions The weight-loss-independent benefits of exercise include anti-steatotic and anti-stiffness effects in the livers of patients with NAFLD. These benefits seem to be acquired through the modification of inter-organ crosstalk, which is characterised by improvements in organokine imbalance and reductions in inflammation and oxidative stress. Lay summary We investigated the effects of exercise on non-alcoholic fatty liver disease (NAFLD) that were not related to weight loss. We found that exercise had considerable weight-loss-independent benefits for the liver through a number of mechanisms. This suggests that exercise is important for NAFLD patients, regardless of whether they lose weight.
Exercise has effects on liver steatosis and stiffness, independent of weight loss. Exercise maintains muscle mass and alters the secretion of organokines. Exercise increases the phagocytic capacity of Kupffer cells and activates Nrf2. Exercise, especially vigorous exercise, should be used aggressively to manage non-alcoholic fatty liver disease (NAFLD).
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Key Words
- ALT, alanine aminotransferase
- ANGPTL6, angiopoietin-like 6
- AST, aspartate aminotransferase
- Aerobic exercise
- BDNF, brain-derived neurotrophic factor
- CAP, controlled attenuation parameter
- Dietary restriction
- Elarge, large amount of exercise group
- Esmall, small amount of exercise group
- Esub, exercise (subset for which biological samples were available) group
- Etotal, exercise group
- FAST-Score, FibroScan-AST score
- FGF-21, fibroblast growth factor-21
- FPG, fasting plasma glucose
- GCLC, glutamate-cysteine ligase catalytic subunit
- GCLM, glutamate-cysteine ligase modifier subunit
- GGT, gamma-glutamyl transpeptidase
- GPx, glutathione peroxidase
- HO1, heme oxygenase 1
- HOMA-IR, homeostasis model assessment-insulin resistance
- Hepatokine
- KC, Kupffer cells
- LPS, lipopolysaccharide
- LSM, liver stiffness measured using transient elastography
- Liver fat
- Liver stiffness
- MVPA, moderate-to-vigorous intensity physical activity
- Myokine
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NEFAs, non-esterified fatty acids
- NF-Score, NAFLD fibrosis score
- NQO1, NAD(P)H quinone oxidoreductase
- Nrf2, nuclear factor E2-related factor 2
- Nuclear factor-erythroid 2-related factor 2
- PBMCs, peripheral blood mononuclear cells
- SPARC, secreted protein acidic and rich in cysteine
- Se-P, selenoprotein-P
- TBARS, thiobarbituric acid-reactive substances
- TEI, total energy intake
- TG, triglycerides
- TNF-α, tumour necrosis factor alpha
- VAT, visceral adipose tissue
- WC, waist circumference
- WFA+-M2BP, Wisteria floribunda agglutinin-positive human Mac-2 binding protein
- Wsub, weight-loss (subset for which biological samples were available) group
- Wtotal, weight-loss group
- mnSOD, manganese superoxide dismutase
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Affiliation(s)
- Sechang Oh
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | | | - Bokun Kim
- Department of Sports Health Care, Inje University, Gimhae, Republic of Korea
| | - Fumihiko Uchida
- Department of Oral and Maxillofacial Surgery, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan
| | - Hideo Suzuki
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Seiichiro Iizumi
- Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tomonori Isobe
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Takeji Sakae
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kiyoji Tanaka
- Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Junichi Shoda
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Friesen CS, Hosey-Cojocari C, Chan SS, Csanaky IL, Wagner JB, Sweeney BR, Friesen A, Fraser JD, Shakhnovich V. Efficacy of Weight Reduction on Pediatric Nonalcoholic Fatty Liver Disease: Opportunities to Improve Treatment Outcomes Through Pharmacotherapy. Front Endocrinol (Lausanne) 2021; 12:663351. [PMID: 33927697 PMCID: PMC8076784 DOI: 10.3389/fendo.2021.663351] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity is the single greatest risk factor for nonalcoholic fatty liver disease (NAFLD). Without intervention, most pediatric patients with NAFLD continue to gain excessive weight, making early, effective weight loss intervention key for disease treatment and prevention of NAFLD progression. Unfortunately, outside of a closely monitored research setting, which is not representative of the real world, lifestyle modification success for weight loss in children is low. Bariatric surgery, though effective, is invasive and can worsen NAFLD postoperatively. Thus, there is an evolving and underutilized role for pharmacotherapy in children, both for weight reduction and NAFLD management. In this perspective article, we provide an overview of the efficacy of weight reduction on pediatric NAFLD treatment, discuss the pros and cons of currently approved pharmacotherapy options, as well as drugs commonly used off-label for weight reduction in children and adolescents. We also highlight gaps in, and opportunities for, streamlining obesity trials to include NAFLD assessment as a valuable, secondary, therapeutic outcome measure, which may aid drug repurposing. Finally, we describe the already available, and emerging, minimally-invasive biomarkers of NAFLD that could offer a safe and convenient alternative to liver biopsy in pediatric obesity and NAFLD trials.
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Affiliation(s)
- Chance S. Friesen
- University of Kansas School of Medicine, Kansas City, KS, United States
| | | | - Sherwin S. Chan
- Children’s Mercy Kansas City, Kansas City, MO, United States
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
| | - Iván L. Csanaky
- Children’s Mercy Kansas City, Kansas City, MO, United States
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
- University of Kansas Medical Center, Kansas City, KS, United States
| | - Jonathan B. Wagner
- Children’s Mercy Kansas City, Kansas City, MO, United States
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
| | - Brooke R. Sweeney
- Children’s Mercy Kansas City, Kansas City, MO, United States
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
- Center for Children’s Healthy Lifestyles & Nutrition, Kansas City, MO, United States
| | - Alec Friesen
- University of Kansas School of Medicine, Kansas City, KS, United States
| | - Jason D. Fraser
- Children’s Mercy Kansas City, Kansas City, MO, United States
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
| | - Valentina Shakhnovich
- Children’s Mercy Kansas City, Kansas City, MO, United States
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
- University of Kansas Medical Center, Kansas City, KS, United States
- Center for Children’s Healthy Lifestyles & Nutrition, Kansas City, MO, United States
- *Correspondence: Valentina Shakhnovich,
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28
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Jensen-Cody SO, Potthoff MJ. Hepatokines and metabolism: Deciphering communication from the liver. Mol Metab 2020; 44:101138. [PMID: 33285302 PMCID: PMC7788242 DOI: 10.1016/j.molmet.2020.101138] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/19/2020] [Accepted: 12/01/2020] [Indexed: 02/09/2023] Open
Abstract
Background The liver is a key regulator of systemic energy homeostasis and can sense and respond to nutrient excess and deficiency through crosstalk with multiple tissues. Regulation of systemic energy homeostasis by the liver is mediated in part through regulation of glucose and lipid metabolism. Dysregulation of either process may result in metabolic dysfunction and contribute to the development of insulin resistance or fatty liver disease. Scope of review The liver has recently been recognized as an endocrine organ that secretes hepatokines, which are liver-derived factors that can signal to and communicate with distant tissues. Dysregulation of liver-centered inter-organ pathways may contribute to improper regulation of energy homeostasis and ultimately metabolic dysfunction. Deciphering the mechanisms that regulate hepatokine expression and communication with distant tissues is essential for understanding inter-organ communication and for the development of therapeutic strategies to treat metabolic dysfunction. Major conclusions In this review, we discuss liver-centric regulation of energy homeostasis through hepatokine secretion. We highlight key hepatokines and their roles in metabolic control, examine the molecular mechanisms of each hepatokine, and discuss their potential as therapeutic targets for metabolic disease. We also discuss important areas of future studies that may contribute to understanding hepatokine signaling under healthy and pathophysiological conditions.
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Affiliation(s)
- Sharon O Jensen-Cody
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Matthew J Potthoff
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
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29
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Caviglia GP, Rosso C, Armandi A, Gaggini M, Carli F, Abate ML, Olivero A, Ribaldone DG, Saracco GM, Gastaldelli A, Bugianesi E. Interplay between Oxidative Stress and Metabolic Derangements in Non-Alcoholic Fatty Liver Disease: The Role of Selenoprotein P. Int J Mol Sci 2020; 21:8838. [PMID: 33266488 PMCID: PMC7700603 DOI: 10.3390/ijms21228838] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/12/2020] [Accepted: 11/19/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Pathogenetic mechanisms involved in the progression of non-alcoholic fatty liver disease (NAFLD) are complex and multifactorial. We investigated oxidative stress through the measurement of selenoprotein P (SeP) in serum and we explored its relation to metabolic derangements and liver damage in a group of non-diabetic NAFLD subjects. Methods: 57 NAFLD patients underwent a double-tracer oral glucose tolerance test (OGTT). Insulin resistance (IR) components were calculated at baseline as follows: hepatic-IR = (endogenous glucose production*insulin); peripheral-IR = (glucose rate of disappearance(Rd)); adipose-tissue(AT)-IR as Lipo-IR = (glycerol rate of appearance (Ra)*insulin) or AT-IR = (free fatty acids (FFAs)*insulin). The lipid and amino acid (AA) profiles were assessed by gas chromatography-mass spectrometry. SeP levels were measured by enzyme immunosorbent assay. Results: Circulating SeP correlated with insulin (rS = 0.28), FFAs (rS = 0.42), glucose Rd (rS = -0.33) and glycerol Ra (rS = -0.34); consistently, SeP levels correlated with Lipo-IR and AT-IR (rS > 0.4). Among the AA and lipid profiles, SeP inversely correlated with serine (rS = -0.31), glycine (rS = -0.44) and branched chain AA (rS = -0.32), and directly correlated with saturated (rS = 0.41) and monounsaturated FFAs (rS = 0.40). Hepatic steatosis and fibrosis increased in subjects with higher levels of SeP. In multivariable regression analysis, SeP was associated with the degree of hepatic fibrosis (t = 2.4, p = 0.022). Conclusions: SeP levels were associated with an altered metabolic profile and to the degree of hepatic fibrosis, suggesting a role in the pathogenesis of NAFLD.
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Affiliation(s)
- Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.P.C.); (A.A.); (M.L.A.); (A.O.); (D.G.R.); (G.M.S.); (E.B.)
| | - Chiara Rosso
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.P.C.); (A.A.); (M.L.A.); (A.O.); (D.G.R.); (G.M.S.); (E.B.)
| | - Angelo Armandi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.P.C.); (A.A.); (M.L.A.); (A.O.); (D.G.R.); (G.M.S.); (E.B.)
| | - Melania Gaggini
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy; (M.G.); (F.C.); (A.G.)
| | - Fabrizia Carli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy; (M.G.); (F.C.); (A.G.)
| | - Maria Lorena Abate
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.P.C.); (A.A.); (M.L.A.); (A.O.); (D.G.R.); (G.M.S.); (E.B.)
| | - Antonella Olivero
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.P.C.); (A.A.); (M.L.A.); (A.O.); (D.G.R.); (G.M.S.); (E.B.)
| | - Davide Giuseppe Ribaldone
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.P.C.); (A.A.); (M.L.A.); (A.O.); (D.G.R.); (G.M.S.); (E.B.)
- Division of Gastroenterology, Città della Salute e della Scienza University-Hospital, 10100 Turin, Italy
| | - Giorgio Maria Saracco
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.P.C.); (A.A.); (M.L.A.); (A.O.); (D.G.R.); (G.M.S.); (E.B.)
- Division of Gastroenterology, Città della Salute e della Scienza University-Hospital, 10100 Turin, Italy
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy; (M.G.); (F.C.); (A.G.)
| | - Elisabetta Bugianesi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.P.C.); (A.A.); (M.L.A.); (A.O.); (D.G.R.); (G.M.S.); (E.B.)
- Division of Gastroenterology, Città della Salute e della Scienza University-Hospital, 10100 Turin, Italy
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30
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Physiopathology of Lifestyle Interventions in Non-Alcoholic Fatty Liver Disease (NAFLD). Nutrients 2020; 12:nu12113472. [PMID: 33198247 PMCID: PMC7697937 DOI: 10.3390/nu12113472] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health problem, and its prevalence has increased in recent years. Diet and exercise interventions are the first-line treatment options, with weight loss via a hypocaloric diet being the most important therapeutic target in NAFLD. However, most NAFLD patients are not able to achieve such weight loss. Therefore, the requisite is the investigation of other effective therapeutic approaches. This review summarizes research on understanding complex pathophysiology underlying dietary approaches and exercise interventions with the potential to prevent and treat NAFLD.
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31
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Jung YM, Lee SM, Hong S, Koo JN, Oh IH, Kim BJ, Kim SM, Kim SY, Kim GM, Kyung Joo S, Shin S, Norwitz ER, Park CW, Jun JK, Kim W, Park JS. The risk of pregnancy-associated hypertension in women with nonalcoholic fatty liver disease. Liver Int 2020; 40:2417-2426. [PMID: 32558189 DOI: 10.1111/liv.14563] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of cardiovascular disease (CVD) in non-pregnant adults. Although the biological mechanisms underlying this association are not completely understood, metabolic factors, inflammation, and endothelial dysfunction are likely all involved. The association between NAFLD and pregnancy-associated hypertension (HTN) has not been systematically examined. The aim of this study is to assess the risk of pregnancy-associated HTN in pregnant women with NAFLD. METHODS This is secondary analysis of a prospective study of healthy pregnant women. Liver ultrasonography was performed at 10-14 weeks of gestation and maternal blood was taken for the measurement of selenoprotein P (SeP), a hepatokine independently associated with both NAFLD and CVD. Pregnancy-associated HTN was defined as the development of gestational HTN, preeclampsia, or eclampsia. RESULTS Among 877 pregnant women, the risk of developing pregnancy-associated HTN was significantly increased in women with NAFLD compared to those without NAFLD. Grade 2-3 steatosis was a significant predictor of pregnancy-associated HTN, even after adjustment for metabolic risk factors. Circulating levels of SeP were significantly higher in women with versus those without NAFLD (P = .001) and was significantly higher also in women who subsequently developed pregnancy-associated HTN compared with those who did not (P < .005). CONCLUSIONS Sonographic evidence of NAFLD at 10-14 weeks is an independent predictor of pregnancy-associated HTN. Circulating levels of SeP at that same gestational age are significantly increased in pregnant women with NAFLD who subsequently develop pregnancy-associated HTN.
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Affiliation(s)
- Young Mi Jung
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Seung Mi Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Subeen Hong
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | | | | | - Byoung Jae Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.,Department of Obstetrics and Gynecology, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Sun Min Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.,Department of Obstetrics and Gynecology, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Sang Youn Kim
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Gyoung Min Kim
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Sae Kyung Joo
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Sue Shin
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Laboratory Medicine, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Errol R Norwitz
- Department of Obstetrics and Gynecology, Tufts University School of Medicine, Boston, MA, USA
| | - Chan-Wook Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Jong Kwan Jun
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Joong Shin Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
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32
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Metabolic adaptations after bariatric surgery: adipokines, myokines and hepatokines. Curr Opin Pharmacol 2020; 52:67-74. [PMID: 32688292 DOI: 10.1016/j.coph.2020.06.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/13/2020] [Accepted: 06/15/2020] [Indexed: 12/23/2022]
Abstract
This review addresses the impact of bariatric surgery on the endocrine aspects of white adipose tissue, muscle and the liver. We describe literature supporting the notion that adipokines, myokines and hepatokines likely act in concert and drive many of the long-term metabolic improvements following surgery. Circulating adiponectin is increased while secretion of pro-inflammatory interleukins (1, 6 and 8) decreases, alongside leptin secretion. The metabolic improvements observed in the muscle might relate to reduction of myokines contributing to insulin resistance (including myostatin, brain-derived neurotrophic factor and fibroblast growth factor-21). Subject to exception, hepatokine secretion is generally increased (such as insulin-like growth factor-binding protein 2, adropin and sex hormone-binding globulin). In conclusion, bariatric surgery restores metabolic functions by enhancing the time-dependent secretion of anti-inflammatory, insulin-sensitizing and antilipemic factors. Further research is needed to understand the molecular mechanisms by which these factors may trigger the remission of obesity-related comorbidities following bariatric surgery.
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33
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Higher Serum Selenoprotein P Level as a Novel Inductor of Metabolic Complications in Psoriasis. Int J Mol Sci 2020; 21:ijms21134594. [PMID: 32605214 PMCID: PMC7370132 DOI: 10.3390/ijms21134594] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
Selenoprotein P (SeP), a member of hepatokines, is involved in the development of various metabolic diseases closely related to psoriasis, but it has not been explored in that dermatosis so far. The study aimed to evaluate the clinical value of serum SeP concentrations in patients with psoriasis and its interplay between disease activity, metabolic or inflammatory parameters and systemic therapy. The study included thirty-three patients with flared plaque-type psoriasis and fifteen healthy volunteers. Blood samples were collected before and after three months of treatment with methotrexate or acitretin. Serum SeP levels were evaluated using the immune–enzymatic method. SeP concentration was significantly higher in patients with psoriasis than in the controls (p < 0.05). Further, in patients with severe psoriasis, SeP was significantly increased, compared with the healthy volunteers before treatment, and significantly decreased after (p < 0.05, p = 0.041, respectively). SeP positively correlated with C-reactive protein and platelets and negatively with red blood counts (p = 0.008, p = 0.013, p = 0.022, respectively). Therapy resulted in a significant decrease in SeP level. Selenoprotein P may be a novel indicator of inflammation and the metabolic complications development in psoriatics, especially with severe form or with concomitant obesity. Classic systemic therapy has a beneficial effect on reducing the risk of comorbidities by inhibiting SeP.
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34
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Gonzalez-Gil AM, Elizondo-Montemayor L. The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review. Nutrients 2020; 12:E1899. [PMID: 32604889 PMCID: PMC7353393 DOI: 10.3390/nu12061899] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/18/2020] [Accepted: 06/18/2020] [Indexed: 12/17/2022] Open
Abstract
Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution of energy substrates, optimization of global energy expenditure, enhancement of hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an important role in the body's response to exercise. To our knowledge, no review has provided a comprehensive integrative overview of these novel molecular players and the mechanisms involved in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass, and reduced inflammation. In this review, we explain the potential role of these exercise-inducible factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines, in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin. We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways, and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation, and healthy weight induced by exercise.
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Affiliation(s)
- Adrian M. Gonzalez-Gil
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey N.L. 64710, Mexico;
- Tecnologico de Monterrey, Center for Research in Clinical Nutrition and Obesity, Ave. Morones Prieto 300, Monterrey N.L. 64710, Mexico
| | - Leticia Elizondo-Montemayor
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey N.L. 64710, Mexico;
- Tecnologico de Monterrey, Center for Research in Clinical Nutrition and Obesity, Ave. Morones Prieto 300, Monterrey N.L. 64710, Mexico
- Tecnologico de Monterrey, Cardiovascular and Metabolomics Research Group, Hospital Zambrano Hellion, San Pedro Garza Garcia P.C. 66278, Mexico
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35
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Bisaccia G, Ricci F, Mantini C, Tana C, Romani GL, Schiavone C, Gallina S. Nonalcoholic fatty liver disease and cardiovascular disease phenotypes. SAGE Open Med 2020; 8:2050312120933804. [PMID: 32612827 PMCID: PMC7307287 DOI: 10.1177/2050312120933804] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 05/21/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease is increasingly recognized as a major global health problem. Intertwined with diabetes, metabolic syndrome, and obesity, nonalcoholic fatty liver disease embraces a spectrum of liver conditions spanning from steatosis to inflammation, fibrosis, and liver failure. Compared with the general population, the prevalence of cardiovascular disease is higher among nonalcoholic fatty liver disease patients, in whom comprehensive cardiovascular risk assessment is highly desirable. Preclinical effects of nonalcoholic fatty liver disease on the heart include both metabolic and structural changes eventually preceding overt myocardial dysfunction. Particularly, nonalcoholic fatty liver disease is associated with enhanced atherosclerosis, heart muscle disease, valvular heart disease, and arrhythmias, with endothelial dysfunction, inflammation, metabolic dysregulation, and oxidative stress playing in the background. In this topical review, we aimed to summarize current evidence on the epidemiology of nonalcoholic fatty liver disease, discuss the pathophysiological links between nonalcoholic fatty liver disease and cardiovascular disease, illustrate nonalcoholic fatty liver disease-related cardiovascular phenotypes, and finally provide a glimpse on the relationship between nonalcoholic fatty liver disease and cardiac steatosis, mitochondrial (dys)function, and cardiovascular autonomic dysfunction.
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Affiliation(s)
- Giandomenico Bisaccia
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
| | - Fabrizio Ricci
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy.,Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Cesare Mantini
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
| | - Claudio Tana
- Internal Medicine and Critical Subacute Care Unit, Medicine Geriatric-Rehabilitation Department, and Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy
| | - Gian Luca Romani
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
| | - Cosima Schiavone
- Department of Internistic Ultrasound, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
| | - Sabina Gallina
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
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Willis SA, Sargeant JA, Yates T, Takamura T, Takayama H, Gupta V, Brittain E, Crawford J, Parry SA, Thackray AE, Varela-Mato V, Stensel DJ, Woods RM, Hulston CJ, Aithal GP, King JA. Acute Hyperenergetic, High-Fat Feeding Increases Circulating FGF21, LECT2, and Fetuin-A in Healthy Men. J Nutr 2020; 150:1076-1085. [PMID: 31919514 DOI: 10.1093/jn/nxz333] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 10/08/2019] [Accepted: 12/12/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Hepatokines such as fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B, and selenoprotein P (SeP) are liver-derived proteins that are modulated by chronic energy status and metabolic disease. Emerging data from rodent and cell models indicate that hepatokines may be sensitive to acute nutritional manipulation; however, data in humans are lacking. OBJECTIVE The aim was to investigate the influence of hyperenergetic, high-fat feeding on circulating hepatokine concentrations, including the time course of responses. METHODS In a randomized, crossover design, 12 healthy men [mean ± SD: age, 24 ± 4 y; BMI (kg/m2), 24.1 ± 1.5] consumed a 7-d hyperenergetic, high-fat diet [HE-HFD; +50% energy, 65% total energy as fat (32% saturated, 26% monounsaturated, 8% polyunsaturated)] and control diet (36% total energy as fat), separated by 3 wk. Whole-body insulin sensitivity was assessed before and after each diet using oral-glucose-tolerance tests. Fasting plasma concentrations of FGF21 (primary outcome), LECT2, fetuin-A, fetuin-B, SeP, and related metabolites were measured after 1, 3, and 7 d of each diet. Hepatokine responses were analyzed using 2-factor repeated-measures ANOVA and subsequent pairwise comparisons. RESULTS Compared with the control, the HE-HFD increased circulating FGF21 at 1 d (105%) and 3 d (121%; P ≤ 0.040), LECT2 at 3 d (17%) and 7 d (32%; P ≤ 0.004), and fetuin-A at 7 d (7%; P = 0.028). Plasma fetuin-B and SeP did not respond to the HE-HFD. Whole-body insulin sensitivity was reduced after the HE-HFD by 31% (P = 0.021). CONCLUSIONS Acute high-fat overfeeding augments circulating concentrations of FGF21, LECT2, and fetuin-A in healthy men. Notably, the time course of response varies between proteins and is transient for FGF21. These findings provide further insight into the nutritional regulation of hepatokines in humans and their interaction with metabolic homeostasis. This study was registered at clinicaltrials.gov as NCT03369145.
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Affiliation(s)
- Scott A Willis
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
- National Institute for Health Research(NIHR) Leicester Biomedical Research Centre, University Hospitals of Leicester National Health Service (NHS) Trust and the University of Leicester, Leicester, United Kingdom
| | - Jack A Sargeant
- National Institute for Health Research(NIHR) Leicester Biomedical Research Centre, University Hospitals of Leicester National Health Service (NHS) Trust and the University of Leicester, Leicester, United Kingdom
- Diabetes Research Centre, University of Leicester, Leicester, United Kingdom
| | - Thomas Yates
- National Institute for Health Research(NIHR) Leicester Biomedical Research Centre, University Hospitals of Leicester National Health Service (NHS) Trust and the University of Leicester, Leicester, United Kingdom
- Diabetes Research Centre, University of Leicester, Leicester, United Kingdom
| | - Toshinari Takamura
- Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hiroaki Takayama
- Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Vinay Gupta
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
| | - Emily Brittain
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
| | - Joe Crawford
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
| | - Siôn A Parry
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Alice E Thackray
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
- National Institute for Health Research(NIHR) Leicester Biomedical Research Centre, University Hospitals of Leicester National Health Service (NHS) Trust and the University of Leicester, Leicester, United Kingdom
| | - Veronica Varela-Mato
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
| | - David J Stensel
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
- National Institute for Health Research(NIHR) Leicester Biomedical Research Centre, University Hospitals of Leicester National Health Service (NHS) Trust and the University of Leicester, Leicester, United Kingdom
| | - Rachel M Woods
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
- National Institute for Health Research(NIHR) Leicester Biomedical Research Centre, University Hospitals of Leicester National Health Service (NHS) Trust and the University of Leicester, Leicester, United Kingdom
| | - Carl J Hulston
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
- National Institute for Health Research(NIHR) Leicester Biomedical Research Centre, University Hospitals of Leicester National Health Service (NHS) Trust and the University of Leicester, Leicester, United Kingdom
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom
| | - James A King
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
- National Institute for Health Research(NIHR) Leicester Biomedical Research Centre, University Hospitals of Leicester National Health Service (NHS) Trust and the University of Leicester, Leicester, United Kingdom
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Selenium and Selenoproteins in Adipose Tissue Physiology and Obesity. Biomolecules 2020; 10:biom10040658. [PMID: 32344656 PMCID: PMC7225961 DOI: 10.3390/biom10040658] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/13/2020] [Accepted: 04/20/2020] [Indexed: 12/14/2022] Open
Abstract
Selenium (Se) homeostasis is tightly related to carbohydrate and lipid metabolism, but its possible roles in obesity development and in adipocyte metabolism are unclear. The objective of the present study is to review the current data on Se status in obesity and to discuss the interference between Se and selenoprotein metabolism in adipocyte physiology and obesity pathogenesis. The overview and meta-analysis of the studies on blood Se and selenoprotein P (SELENOP) levels, as well as glutathione peroxidase (GPX) activity in obese subjects, have yielded heterogenous and even conflicting results. Laboratory studies demonstrate that Se may modulate preadipocyte proliferation and adipogenic differentiation, and also interfere with insulin signaling, and regulate lipolysis. Knockout models have demonstrated that the selenoprotein machinery, including endoplasmic reticulum-resident selenoproteins together with GPXs and thioredoxin reductases (TXNRDs), are tightly related to adipocyte development and functioning. In conclusion, Se and selenoproteins appear to play an essential role in adipose tissue physiology, although human data are inconsistent. Taken together, these findings do not support the utility of Se supplementation to prevent or alleviate obesity in humans. Further human and laboratory studies are required to elucidate associations between Se metabolism and obesity.
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Wang P, Lu Z, He M, Shi B, Lei X, Shan A. The Effects of Endoplasmic-Reticulum-Resident Selenoproteins in a Nonalcoholic Fatty Liver Disease Pig Model Induced by a High-Fat Diet. Nutrients 2020; 12:nu12030692. [PMID: 32143527 PMCID: PMC7146353 DOI: 10.3390/nu12030692] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 02/29/2020] [Accepted: 03/02/2020] [Indexed: 12/20/2022] Open
Abstract
The present study aimed to investigate the intervention of selenium in the oxidative stress and apoptosis of pig livers, which were induced by a high-fat diet, and the effects of four endoplasmic reticulum (ER)-resident selenoproteins in the process. A 2 × 4 design trial was conducted that included two dietary fat levels (BD = basal diet and HFD = high-fat diet) and four dietary Se supplementation levels (0, 0.3, 1.0, and 3.0 mg/kg of the diet, in the form of sodium selenite (Na2SeO3)). Our results indicated that the HFD significantly increased the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum, as well as the degree of steatosis, the content of malondialdehyde (MDA), the apoptotic rate, and the level of mRNA caspase-3 in the liver compared to their BD counterparts (p < 0.05). Moreover, these parameters in the HFD groups were more significantly reduced (p < 0.05) for a Se concentration of 1.0 mg/kg than for the other concentrations. Further, for both the BD and HFD, the groups supplemented with 1.0 mg/kg Se showed the highest mRNA level of selenoprotein S. In conclusion, the consumption of an HFD can induce oxidative damage and apoptosis in the liver. This shows that the supplementation of Se at 1.0 mg/kg may be the optimum concentration against damage induced by HFD, and Sels may play a key role in this process.
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Affiliation(s)
- Pengzu Wang
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, China; (P.W.); (Z.L.); (M.H.); (B.S.)
| | - Zhuang Lu
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, China; (P.W.); (Z.L.); (M.H.); (B.S.)
| | - Meng He
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, China; (P.W.); (Z.L.); (M.H.); (B.S.)
| | - Baoming Shi
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, China; (P.W.); (Z.L.); (M.H.); (B.S.)
| | - Xingen Lei
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA;
| | - Anshan Shan
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, China; (P.W.); (Z.L.); (M.H.); (B.S.)
- Correspondence: ; Tel./Fax: +86-0451-55190685
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Polyzos SA, Kountouras J, Goulas A, Duntas L. Selenium and selenoprotein P in nonalcoholic fatty liver disease. Hormones (Athens) 2020; 19:61-72. [PMID: 31493247 DOI: 10.1007/s42000-019-00127-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/02/2019] [Indexed: 02/07/2023]
Abstract
Conflicting data link nonalcoholic fatty liver disease (NAFLD), a disease with no currently approved treatment, with selenium (Se) and selenoprotein P (SELENOP), a glycoprotein synthesized and primarily secreted by the hepatocytes, functioning as a Se transporter from the liver to other tissues. This review aims to summarize the evidence between Se, SELENOP, and NAFLD, which may hopefully clarify whether current data on Se and SELENOP in NAFLD warrant further investigation for their diagnostic and therapeutic potential. Most, albeit not all, experimental data show a favorable effect of Se on hepatic steatosis, inflammation, and fibrosis. It seems that Se may exert an antioxidant effect on the liver, at least partly via increasing the activity of glutathione peroxidase, whose depletion contributes to the pathogenesis of hepatic inflammation and fibrosis. Se may also affect metalloproteinases, cytokines, and growth factors participating in the pathogenesis of NAFLD and, most importantly, may induce the apoptosis of hepatic stellate cells, the key players in hepatic fibrosis. However, the association between Se or SELENOP and insulin resistance, which is a principal pathogenetic factor of NAFLD, remains inconclusive. Clinical studies on Se or SELENOP in NAFLD are conflicting, apart from those in advanced liver disease (cirrhosis or hepatocellular carcinoma), in which lower circulating Se and SELENOP are constant findings. Existing data warrant further mechanistic studies in valid animal models of human NAFLD. Prospective cohort studies and possibly randomized controlled trials are also needed to elucidate the diagnostic and therapeutic potential of Se supplementation in selected NAFLD individuals with Se deficiency.
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Affiliation(s)
- Stergios A Polyzos
- First Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
| | - Jannis Kountouras
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Antonis Goulas
- First Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
| | - Leonidas Duntas
- Endocrine Unit, Evgenidion Hospital, National Kapodestrian University, Athens, Greece
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40
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Abstract
Selenoprotein P (SeP) is one of the 25 human selenocysteine (Sec)-containing proteins, and is generally thought to function as a plasma carrier of the trace element selenium in the body. Recent studies, however, indicate unsuspected pivotal roles of SeP in human diseases, particularly in type 2 diabetes mellitus (T2DM) and pulmonary arterial hypertension (PAH). In this review, we will summarize the characteristics of SeP and recent advances in the field, especially focusing on the emerging roles of SeP in pathophysiological conditions. We will also discuss potential medical/pharmaceutical applications targeting SeP.
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Affiliation(s)
- Ryouhei Tsutsumi
- Laboratory of Metabolism and Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Yoshiro Saito
- Laboratory of Metabolism and Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University
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41
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Wu HT, Chen SC, Fan KC, Kuo CH, Lin SY, Wang SH, Chang CJ, Li HY. Targeting fibrinogen-like protein 1 is a novel therapeutic strategy to combat obesity. FASEB J 2019; 34:2958-2967. [PMID: 31908014 DOI: 10.1096/fj.201901925r] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 12/06/2019] [Accepted: 12/15/2019] [Indexed: 12/16/2022]
Abstract
Fibrinogen-like-protein 1 (FGL1) is a novel hepatokine that plays an important role in hepatic steatosis and insulin resistance. Although FGL1 expression can be detected in adipose tissues, the functions of FGL1 in adipose tissues are still unknown. In this study, 356 participants with (body mass index (BMI) ≥25 kg/m2 ; n = 134) or without obesity (BMI <25 kg/m2 ; n = 222) were recruited, and we found that the plasma FGL1 concentrations were significantly higher in obese group than those of in the normal weight group, and were positively correlated with age, BMI, waist circumference, fat content, plasma glucose at 2 hours during an oral glucose tolerance test, and the insulin sensitivity index. In univariate analyses, BMI, waist circumference, total fat, visceral fat, and subcutaneous fat areas were positively correlated with FGL1 levels. After adjusting for age and gender, obesity indices, including the BMI and different fat areas, remained significantly associated with FGL1 levels. In order to investigate the causal relationship between FGL1 and obesity, animal and cell models were used. Overexpression of FGL1 in epididymal adipose tissue by lentiviral vector encoding FGL1 increased the fat pad size, whereas FGL1-knockdown by lentiviral vector encoding short-hairpin RNA targeted to FGL1 decreased high-fat diet-induced adiposity. In addition, 3T3-L1 adipocytes were used to clarify the possible mechanism of FGL1-induced adipogenesis. FGL1 induced adipogenesis through an ERK1/2-C/EBPβ-dependent pathway in 3T3-L1 adipocytes. These findings highlight the pathophysiological role of FGL1 in obesity, and FGL1 might be a novel therapeutic target to combat obesity.
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Affiliation(s)
- Hung-Tsung Wu
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan
| | - Szu-Chi Chen
- Division of Endocrinology, Department of Internal Medicine, Cardinal Tien Hospital, Xindian, Taiwan
| | - Kang-Chih Fan
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan
| | - Chun-Heng Kuo
- Department of Internal Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Shin-Yu Lin
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Shu-Huei Wang
- Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chih-Jen Chang
- Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Yuan Li
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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42
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Abstract
Maintenance of systemic homeostasis and the response to nutritional and environmental challenges require the coordination of multiple organs and tissues. To respond to various metabolic demands, higher organisms have developed a system of inter-organ communication through which one tissue can affect metabolic pathways in a distant tissue. Dysregulation of these lines of communication contributes to human pathologies, including obesity, diabetes, liver disease and atherosclerosis. In recent years, technical advances such as data-driven bioinformatics, proteomics and lipidomics have enabled efforts to understand the complexity of systemic metabolic cross-talk and its underlying mechanisms. Here, we provide an overview of inter-organ signals and their roles in metabolic control, and highlight recent discoveries in the field. We review peptide, small-molecule and lipid mediators secreted by metabolic tissues, as well as the role of the central nervous system in orchestrating peripheral metabolic functions. Finally, we discuss the contributions of inter-organ signalling networks to the features of metabolic syndrome.
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Affiliation(s)
- Christina Priest
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
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43
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Shi J, Fan J, Su Q, Yang Z. Cytokines and Abnormal Glucose and Lipid Metabolism. Front Endocrinol (Lausanne) 2019; 10:703. [PMID: 31736870 PMCID: PMC6833922 DOI: 10.3389/fendo.2019.00703] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 09/30/2019] [Indexed: 12/20/2022] Open
Abstract
Clear evidence indicates that cytokines, for instance, adipokines, hepatokines, inflammatory cytokines, myokines, and osteokines, contribute substantially to the development of abnormal glucose and lipid metabolism. Some cytokines play a positive role in metabolism action, while others have a negative metabolic role linking to the induction of metabolic dysfunction. The mechanisms involved are not fully understood, but are associated with lipid accumulation in organs and tissues, especially in the adipose and liver tissue, changes in energy metabolism, and inflammatory signals derived from various cell types, including immune cells. In this review, we describe the roles of certain cytokines in the regulation of metabolism and inter-organ signaling in regard to the pathophysiological aspects. Given the disease-related changes in circulating levels of relevant cytokines, these factors may serve as biomarkers for the early detection of metabolic disorders. Moreover, based on preclinical studies, certain cytokines that can induce improvements in glucose and lipid metabolism and immune response may emerge as novel targets of broader and more efficacious treatments and prevention of metabolic disease.
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Affiliation(s)
- Jie Shi
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiangao Fan
- Shanghai Key Laboratory of Children's Digestion and Nutrition, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhen Yang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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44
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Watt MJ, Miotto PM, De Nardo W, Montgomery MK. The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance. Endocr Rev 2019; 40:1367-1393. [PMID: 31098621 DOI: 10.1210/er.2019-00034] [Citation(s) in RCA: 389] [Impact Index Per Article: 64.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/04/2019] [Indexed: 02/06/2023]
Abstract
The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry "omics" approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of "hepatokine" biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.
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Affiliation(s)
- Matthew J Watt
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - Paula M Miotto
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - William De Nardo
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
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Flisiak-Jackiewicz M, Bobrus-Chociej A, Wasilewska N, Tarasow E, Wojtkowska M, Lebensztejn DM. Can hepatokines be regarded as novel non-invasive serum biomarkers of intrahepatic lipid content in obese children? Adv Med Sci 2019; 64:280-284. [PMID: 30921653 DOI: 10.1016/j.advms.2019.02.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 10/14/2018] [Accepted: 02/28/2019] [Indexed: 12/24/2022]
Abstract
PURPOSE Hepatokines are proteins produced by the liver and involved in regulating glucose and lipid metabolism. However, their role as the biomarkers of intrahepatic lipid content is not clear. The aim of the study was to evaluate the serum concentration of selected hepatokines: fibroblast growth factor-21 (FGF-21), selenoprotein P (SELENOP) and sex hormone-binding globulin (SHBG) in obese children. PATIENTS AND METHODS The cross-sectional study included 86 obese children with suspected liver disease. Nonalcoholic fatty liver disease (NAFLD) was diagnosed in children with liver steatosis in ultrasound with elevated alanine aminotransferase (ALT) serum activity and excluded other liver diseases. The total intrahepatic lipid content (TILC) was assessed by magnetic resonance proton spectroscopy (1H-MRS). RESULTS The concentration of FGF-21 and SELENOP was significantly higher and SHBG significantly lower in children with NAFLD compared to controls. Only FGF-21 level was significantly higher in NAFLD children than in obese patients without NAFLD. The significant positive correlation of FGF-21 with ALT, gamma glutamyltransferase (GGT), triglycerides, homeostatic model assessment-insulin resistance (HOMA-IR), the degree of liver steatosis in ultrasound and TILC in 1H-MRS were found. The ability of serum FGF-21 to diagnose severe liver steatosis was significant. CONCLUSIONS FGF-21 can be considered as a suitable biomarker in predicting TILC and fatty liver in obese children.
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Affiliation(s)
- Marta Flisiak-Jackiewicz
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland.
| | - Anna Bobrus-Chociej
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Natalia Wasilewska
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Eugeniusz Tarasow
- Department of Radiology, Medical University of Bialystok, Bialystok, Poland
| | | | - Dariusz Marek Lebensztejn
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
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Song P, Kwon Y, Joo JY, Kim DG, Yoon JH. Secretomics to Discover Regulators in Diseases. Int J Mol Sci 2019; 20:ijms20163893. [PMID: 31405033 PMCID: PMC6720857 DOI: 10.3390/ijms20163893] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/01/2019] [Accepted: 08/08/2019] [Indexed: 01/03/2023] Open
Abstract
Secretory proteins play important roles in the cross-talk of individual functional units, including cells. Since secretory proteins are essential for signal transduction, they are closely related with disease development, including metabolic and neural diseases. In metabolic diseases, adipokines, myokines, and hepatokines are secreted from respective organs under specific environmental conditions, and play roles in glucose homeostasis, angiogenesis, and inflammation. In neural diseases, astrocytes and microglia cells secrete cytokines and chemokines that play roles in neurotoxic and neuroprotective responses. Mass spectrometry-based secretome profiling is a powerful strategy to identify and characterize secretory proteins. This strategy involves stepwise processes such as the collection of conditioned medium (CM) containing secretome proteins and concentration of the CM, peptide preparation, mass analysis, database search, and filtering of secretory proteins; each step requires certain conditions to obtain reliable results. Proteomic analysis of extracellular vesicles has become a new research focus for understanding the additional extracellular functions of intracellular proteins. Here, we provide a review of the insights obtained from secretome analyses with regard to disease mechanisms, and highlight the future prospects of this technology. Continued research in this field is expected to provide valuable information on cell-to-cell communication and uncover new pathological mechanisms.
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Affiliation(s)
- Parkyong Song
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan 50612, Korea
| | - Yonghoon Kwon
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Korea
| | - Jae-Yeol Joo
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu 41062, Korea
| | - Do-Geun Kim
- Dementia Research Group, Korea Brain Research Institute, Daegu 41062, Korea
| | - Jong Hyuk Yoon
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu 41062, Korea.
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47
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Abstract
The health-promoting effects of physical activity to prevent and treat metabolic disorders are numerous. However, the underlying molecular mechanisms are not yet completely deciphered. In recent years, studies have referred to the liver as an endocrine organ, since it releases specific proteins called hepatokines. Some of these hepatokines are involved in whole body metabolic homeostasis and are theorized to participate in the development of metabolic disease. In this regard, the present review describes the role of Fibroblast Growth Factor 21, Fetuin-A, Angiopoietin-like protein 4, and Follistatin in metabolic disease and their production in response to acute exercise. Also, we discuss the potential role of hepatokines in mediating the beneficial effects of regular exercise and the future challenges to the discovery of new exercise-induced hepatokines.
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Affiliation(s)
- Gaël Ennequin
- PEPITE EA4267, EPSI, Université de Bourgogne Franche-Comté , Besançon , France
| | - Pascal Sirvent
- Université Clermont Auvergne, Laboratoire des Adaptations Métaboliques à l'Exercice en conditions Physiologiques et Pathologiques (AME2P), CRNH Auvergne, Clermont-Ferrand , France
| | - Martin Whitham
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham , Birmingham , United Kingdom
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48
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di Giuseppe R, Koch M, Nöthlings U, Kastenmüller G, Artati A, Adamski J, Jacobs G, Lieb W. Metabolomics signature associated with circulating serum selenoprotein P levels. Endocrine 2019; 64:486-495. [PMID: 30448992 DOI: 10.1007/s12020-018-1816-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 11/07/2018] [Indexed: 10/27/2022]
Abstract
PURPOSE Selenoprotein P (SELENOP) has been previously related to various metabolic traits with partially conflicting results. The identification of SELENOP-associated metabolites, using an untargeted metabolomics approach, may provide novel biological insights relevant to disentangle the role of SELENOP in human health. METHODS In this cross-sectional study, 572 serum metabolites were identified by comparing the obtained LC-MS/MS spectra with spectra stored in Metabolon's spectra library. Serum SELENOP levels were measured in 832 men and women using an ELISA kit. RESULTS Circulating SELENOP levels were associated with 24 out of 572 metabolites after accounting for the number of independent dimensions in the metabolomics data, including inverse associations with alanine, glutamate, leucine, isoleucine and valine, an unknown compound X-12063, urate and the peptides gamma-glutamyl-leucine, and N-acetylcarnosine. Positive associations were observed between SELENOP and several lipid compounds. Of the identified metabolites, each standard deviation increase in the branched-chain amino acids (isoleucine, leucine, valine), alanine and gamma-glutamyl-leucine was related to higher odds of having T2DM [OR (95% CI): 1.96 (1.41-2.73); 1.62 (1.15-2.28); 1.94 (1.45-2.60), 1.57 (1.17-2.11), and 1.52 (1.13-2.05), respectively]. CONCLUSIONS Higher serum SELENOP levels were associated with an overall healthy metabolomics profile, which may provide further insights into potential mechanisms of SELENOP-associated metabolic disorders.
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Affiliation(s)
| | - Manja Koch
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ute Nöthlings
- Department of Nutrition and Food Sciences, University of Bonn, Bonn, Germany
| | - Gabi Kastenmüller
- Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany
| | - Anna Artati
- Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany
| | - Jerzy Adamski
- Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany
- Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany
- Experimental Genetics, Technical University of Munich, Freising, Germany
| | - Gunnar Jacobs
- Institute of Epidemiology, Kiel University, Kiel, Germany
- Biobank PopGen, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Wolfgang Lieb
- Institute of Epidemiology, Kiel University, Kiel, Germany
- Biobank PopGen, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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49
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Montgomery MK, De Nardo W, Watt MJ. Impact of Lipotoxicity on Tissue "Cross Talk" and Metabolic Regulation. Physiology (Bethesda) 2019; 34:134-149. [PMID: 30724128 DOI: 10.1152/physiol.00037.2018] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Obesity-associated comorbidities include non-alcoholic fatty liver disease, Type 2 diabetes, and cardiovascular disease. These diseases are associated with accumulation of lipids in non-adipose tissues, which can impact many intracellular cellular signaling pathways and functions that have been broadly defined as "lipotoxic." This review moves beyond understanding intracellular lipotoxic outcomes and outlines the consequences of lipotoxicity on protein secretion and inter-tissue "cross talk," and the impact this exerts on systemic metabolism.
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Affiliation(s)
| | - William De Nardo
- Department of Physiology, The University of Melbourne , Melbourne, Victoria , Australia
| | - Matthew J Watt
- Department of Physiology, The University of Melbourne , Melbourne, Victoria , Australia
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50
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Oo SM, Misu H, Saito Y, Tanaka M, Kato S, Kita Y, Takayama H, Takeshita Y, Kanamori T, Nagano T, Nakagen M, Urabe T, Matsuyama N, Kaneko S, Takamura T. Serum selenoprotein P, but not selenium, predicts future hyperglycemia in a general Japanese population. Sci Rep 2018; 8:16727. [PMID: 30425271 PMCID: PMC6233151 DOI: 10.1038/s41598-018-35067-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 10/29/2018] [Indexed: 02/06/2023] Open
Abstract
We aimed to test the hypothesis that selenoprotein P (SELENOP), a hepatokine involved in the development of both insulin resistance and impaired insulin production in mice, is related to future onset of hyperglycemia in humans. 76 healthy non-pregnant human subjects without diabetes underwent oral glucose tolerance test (OGTT) at baseline and 4-years follow-up. Nine subjects developed either impaired glucose tolerance or type 2 diabetes at follow-up. At baseline, SELENOP concentrations correlated negatively with insulinogenic index, but not with homeostasis model assessment-estimated insulin resistance (HOMA-IR). Multivariate analysis showed that baseline SELENOP predicted fasting plasma glucose at follow-up independently of the other parameters. The receiver operating characteristic (ROC) curve analysis showed that baseline concentrations of serum SELENOP, but not of selenium, were a reliable test to predict future onset of glucose intolerance. In conclusion, elevation of circulating SELENOP, but not of circulating selenium, was positively and independently associated with future onset of glucose intolerance in a general Japanese population.
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Affiliation(s)
- Swe Mar Oo
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hirofumi Misu
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.
- PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
| | - Yoshiro Saito
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
| | - Mutsumi Tanaka
- Diagnostic R&D, R&D Headquarters, Alfresa Pharma Corporation, Ibaraki, Osaka, Japan
| | - Seiji Kato
- Diagnostic R&D, R&D Headquarters, Alfresa Pharma Corporation, Ibaraki, Osaka, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hiroaki Takayama
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Takehiro Kanamori
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Toru Nagano
- Department of Gastroenterology, Public Central Hospital of Matto Ishikawa, Matto, Ishikawa, Japan
| | - Masatoshi Nakagen
- Department of Gastroenterology, Public Central Hospital of Matto Ishikawa, Matto, Ishikawa, Japan
| | - Takeshi Urabe
- Department of Gastroenterology, Public Central Hospital of Matto Ishikawa, Matto, Ishikawa, Japan
| | - Naoto Matsuyama
- Diagnostic R&D, R&D Headquarters, Alfresa Pharma Corporation, Ibaraki, Osaka, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.
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