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Roh E, Hwang SY, Kim M, Won CW, Choi KM. Plasma Leukocyte Cell-Derived Chemotaxin-2 as a Risk Factor of Sarcopenia: Korean Frailty and Aging Cohort Study. Nutrients 2025; 17:1342. [PMID: 40284206 PMCID: PMC12029840 DOI: 10.3390/nu17081342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/29/2025] [Accepted: 04/13/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objective: Leukocyte cell-derived chemotaxin-2 (LECT2), a hepatokine, is implicated in non-alcoholic fatty liver disease (NAFLD). Although NAFLD and sarcopenia are closely linked, the relationship between plasma LECT2 levels and sarcopenia remains unclear. Methods: We analyzed plasma LECT2 levels in 400 older adults aged 70-84 years old living in the community enrolled in the Korean Frailty and Aging Cohort Study. The appendicular skeletal muscle mass (ASM) and handgrip strength (HGS), both adjusted for the BMI, were used to evaluate the muscle mass and strength. A low muscle mass (LMM) was defined using the sex-specific lowest quintile of ASM/BMI as the cutoff value, while a low muscle strength (LMS) was determined based on the lowest quintile of the HGS/BMI. Sarcopenia was defined by the coexistence of an LMM and LMS. Results: NAFLD was identified using a fatty liver index > 30. The participants with NAFLD had significantly higher plasma LECT2 levels compared to their non-NAFLD counterparts (34.4 [29.3-41.1] vs. 29.0 [24.7-36.7] ng/mL, p < 0.001). Circulating LECT2 levels were inversely correlated with ASM/BMI (r = -0.506, p < 0.001) and HGS/BMI (r = -0.474, p < 0.001), as determined by Spearman correlation analysis. Among the study participants, 79 (19.8%) were categorized as having either an LMM or LMS, and 31 (7.8%) were identified as having sarcopenia. In multivariate logistic regression, the highest LECT2 quartile had markedly greater odds of an LMM (OR 3.31, 95% CI 1.41-7.75), LMS (OR 2.85, 95% CI 1.29-6.26), and sarcopenia (OR 5.48, 95% CI 1.57-19.05) relative to the lowest quartile. Conclusions: Our results indicate that elevated plasma LECT2, a hepatokine increased in NAFLD, contributes to an increased risk of sarcopenia in older adults.
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Affiliation(s)
- Eun Roh
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
| | - Soon Young Hwang
- Department of Biostatistics, Korea University College of Medicine, Seoul 08308, Republic of Korea
| | - Miji Kim
- Department of Health Sciences and Technology, Kyung Hee University College of Medicine, Seoul 02447, Republic of Korea
| | - Chang Won Won
- Elderly Frailty Research Center, Department of Family Medicine, Kyung Hee University College of Medicine, Seoul 02447, Republic of Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Republic of Korea
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Suzuki K, Tsujiguchi H, Hara A, Takeshita Y, Goto H, Nakano Y, Yamamoto R, Takayama H, Tajima A, Yamashita T, Honda M, Nakamura H, Takamura T. Hepatokine leukocyte cell-derived chemotaxin 2 as a biomarker of insulin resistance, liver enzymes, and metabolic dysfunction-associated steatotic liver disease in the general population. J Diabetes Investig 2025; 16:298-308. [PMID: 39570764 PMCID: PMC11786172 DOI: 10.1111/jdi.14351] [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: 06/19/2024] [Revised: 10/20/2024] [Accepted: 10/27/2024] [Indexed: 02/02/2025] Open
Abstract
AIMS/INTRODUCTION Leukocyte cell-derived chemotaxin 2 (LECT2) is an obesity-associated hepatokine that causes skeletal muscle insulin resistance. Since LECT2 is up-regulated by the inactivation of the energy sensor AMPK in the liver, we hypothesized that LECT2 has potential as a biomarker for metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, we investigated whether circulating LECT2 levels are associated with insulin sensitivity, liver enzymes, and MASLD. MATERIALS AND METHODS This cross-sectional study included 138 Japanese individuals. Plasma LECT2 levels were measured using fasting blood samples. B-mode ultrasonography was used to assess hepatic steatosis. RESULTS The mean age and body mass index (BMI) of participants were 63.5 ± 10.2 years and 23.0 ± 3.1 kg/m2, respectively. Higher LECT2 levels positively correlated with homeostatic model assessment for insulin resistance (HOMA-IR) values and negatively correlated with the quantitative insulin sensitivity check index (QUICKI) among all participants (HOMA-IR; non-standardized β (B) = 6.38, P < 0.01: QUICKI; B = -161, P < 0.01). These correlations were stronger in the low BMI group (HOMA-IR; B = 13.85, P < 0.01: QUICKI; B = -180, P < 0.01). LECT2 levels also positively correlated with gamma-glutamyl transferase levels (B = 0.01, P = 0.01) and alanine aminotransferase levels (B = 0.33, P = 0.02). Higher LECT2 levels correlated with the prevalence of MASLD (odds ratio = 1.14, P = 0.02). CONCLUSIONS The present results suggest the potential of plasma LECT2 levels as a biomarker for insulin resistance in individuals who are not overweight and the prevalence of MASLD in the general population.
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Affiliation(s)
- Keita Suzuki
- Kanazawa University Advanced Preventive Medical Sciences Research CenterKanazawaIshikawaJapan
| | - Hiromasa Tsujiguchi
- Kanazawa University Advanced Preventive Medical Sciences Research CenterKanazawaIshikawaJapan
- Department of Public Health, Graduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaIshikawaJapan
- Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaIshikawaJapan
| | - Akinori Hara
- Kanazawa University Advanced Preventive Medical Sciences Research CenterKanazawaIshikawaJapan
- Department of Public Health, Graduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaIshikawaJapan
- Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaIshikawaJapan
| | - Yumie Takeshita
- Department of Endocrinology and MetabolismKanazawa University Graduate School of Medical SciencesKanazawaIshikawaJapan
| | - Hisanori Goto
- Department of Endocrinology and MetabolismKanazawa University Graduate School of Medical SciencesKanazawaIshikawaJapan
| | - Yujiro Nakano
- Department of Endocrinology and MetabolismKanazawa University Graduate School of Medical SciencesKanazawaIshikawaJapan
| | - Reina Yamamoto
- Department of Endocrinology and MetabolismKanazawa University Graduate School of Medical SciencesKanazawaIshikawaJapan
| | - Hiroaki Takayama
- Department of Endocrinology and MetabolismKanazawa University Graduate School of Medical SciencesKanazawaIshikawaJapan
| | - Atsushi Tajima
- Kanazawa University Advanced Preventive Medical Sciences Research CenterKanazawaIshikawaJapan
- Faculty of Medicine, Department of Bioinformatics and Genomics, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaIshikawaJapan
| | - Tatsuya Yamashita
- Department of GastroenterologyKanazawa University Graduate School of Medical SciencesKanazawaIshikawaJapan
| | - Masao Honda
- Department of GastroenterologyKanazawa University Graduate School of Medical SciencesKanazawaIshikawaJapan
| | - Hiroyuki Nakamura
- Kanazawa University Advanced Preventive Medical Sciences Research CenterKanazawaIshikawaJapan
- Department of Public Health, Graduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaIshikawaJapan
- Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaIshikawaJapan
| | - Toshinari Takamura
- Department of Endocrinology and MetabolismKanazawa University Graduate School of Medical SciencesKanazawaIshikawaJapan
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Crişan D, Avram L, Morariu-Barb A, Grapa C, Hirişcau I, Crăciun R, Donca V, Nemeş A. Sarcopenia in MASLD-Eat to Beat Steatosis, Move to Prove Strength. Nutrients 2025; 17:178. [PMID: 39796612 PMCID: PMC11722590 DOI: 10.3390/nu17010178] [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: 11/23/2024] [Revised: 12/26/2024] [Accepted: 12/31/2024] [Indexed: 01/13/2025] Open
Abstract
The connections between sarcopenia and various chronic conditions, including type 2 diabetes (T2DM), metabolic syndrome (MetS), and liver disease have been highlighted recently. There is also a high occurrence of sarcopenia in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, who are often disregarded. Both experimental and clinical findings suggest a complex, bidirectional relationship between MASLD and sarcopenia. While vitamin D, testosterone, and specific drug therapies show promise in mitigating sarcopenia, consensus on effective treatments is lacking. Recent focus on lifestyle interventions emphasizes dietary therapy and exercise for sarcopenic obesity in MASLD. Challenges arise as weight loss, a primary MASLD treatment, may lead to muscle mass reduction. The therapeutic approach to sarcopenia in morbidly obese MASLD patients also includes bariatric surgery (BS). BS induces weight loss and stabilizes metabolic imbalances, but its impact on sarcopenia is nuanced, underscoring the need for further research. Our aim is to provide a comprehensive review of the interplay between sarcopenia and MASLD and offer insight into the most recent therapeutic challenges and discoveries, as sarcopenia is often overlooked or unrecognized and poses significant challenges for managing these patients.
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Affiliation(s)
- Dana Crişan
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.C.); (L.A.); (I.H.); (R.C.); (V.D.); (A.N.)
- Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
| | - Lucreţia Avram
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.C.); (L.A.); (I.H.); (R.C.); (V.D.); (A.N.)
- Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
| | - Andreea Morariu-Barb
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.C.); (L.A.); (I.H.); (R.C.); (V.D.); (A.N.)
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400162 Cluj-Napoca, Romania
| | - Cristiana Grapa
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.C.); (L.A.); (I.H.); (R.C.); (V.D.); (A.N.)
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400162 Cluj-Napoca, Romania
| | - Ioana Hirişcau
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.C.); (L.A.); (I.H.); (R.C.); (V.D.); (A.N.)
| | - Rareş Crăciun
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.C.); (L.A.); (I.H.); (R.C.); (V.D.); (A.N.)
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400162 Cluj-Napoca, Romania
| | - Valer Donca
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.C.); (L.A.); (I.H.); (R.C.); (V.D.); (A.N.)
- Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
| | - Andrada Nemeş
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.C.); (L.A.); (I.H.); (R.C.); (V.D.); (A.N.)
- Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
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Miao X, Alidadipour A, Saed V, Sayyadi F, Jadidi Y, Davoudi M, Amraee F, Jadidi N, Afrisham R. Hepatokines: unveiling the molecular and cellular mechanisms connecting hepatic tissue to insulin resistance and inflammation. Acta Diabetol 2024; 61:1339-1361. [PMID: 39031190 DOI: 10.1007/s00592-024-02335-9] [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: 05/04/2024] [Accepted: 07/06/2024] [Indexed: 07/22/2024]
Abstract
Insulin resistance arising from Non-Alcoholic Fatty Liver Disease (NAFLD) stands as a prevalent global ailment, a manifestation within societies stemming from individuals' suboptimal dietary habits and lifestyles. This form of insulin resistance emerges as a pivotal factor in the development of type 2 diabetes mellitus (T2DM). Emerging evidence underscores the significant role of hepatokines, as hepatic-secreted hormone-like entities, in the genesis of insulin resistance and eventual onset of type 2 diabetes. Hepatokines exert influence over extrahepatic metabolism regulation. Their principal functions encompass impacting adipocytes, pancreatic cells, muscles, and the brain, thereby playing a crucial role in shaping body metabolism through signaling to target tissues. This review explores the most important hepatokines, each with distinct influences. Our review shows that Fetuin-A promotes lipid-induced insulin resistance by acting as an endogenous ligand for Toll-like receptor 4 (TLR-4). FGF21 reduces inflammation in diabetes by blocking the nuclear translocation of nuclear factor-κB (NF-κB) in adipocytes and adipose tissue, while also improving glucose metabolism. ANGPTL6 enhances AMPK and insulin signaling in muscle, and suppresses gluconeogenesis. Follistatin can influence insulin resistance and inflammation by interacting with members of the TGF-β family. Adropin show a positive correlation with phosphoenolpyruvate carboxykinase 1 (PCK1), a key regulator of gluconeogenesis. This article delves into hepatokines' impact on NAFLD, inflammation, and T2DM, with a specific focus on insulin resistance. The aim is to comprehend the influence of these recently identified hormones on disease development and their underlying physiological and pathological mechanisms.
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Affiliation(s)
- Xiaolei Miao
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Arian Alidadipour
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Vian Saed
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Firooze Sayyadi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Yasaman Jadidi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Davoudi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Amraee
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Nastaran Jadidi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Afrisham
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
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Milani I, Codini M, Guarisco G, Chinucci M, Gaita C, Leonetti F, Capoccia D. Hepatokines and MASLD: The GLP1-Ras-FGF21-Fetuin-A Crosstalk as a Therapeutic Target. Int J Mol Sci 2024; 25:10795. [PMID: 39409124 PMCID: PMC11477334 DOI: 10.3390/ijms251910795] [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: 09/04/2024] [Revised: 10/04/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
The introduction of the term "Metabolic Steatotic Liver Disease" (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver's increased production of proteins known as "hepatokines" has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD.
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Affiliation(s)
- Ilaria Milani
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Michela Codini
- Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, Italy;
| | - Gloria Guarisco
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Marianna Chinucci
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Chiara Gaita
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Frida Leonetti
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Danila Capoccia
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
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Zhou Y, Su J, Dong Y, He Z, Wang Y, Chen S, Lv G. Buddleoside-rich Chrysanthemum indicum L. extract modulates macrophage-mediated inflammation to prevent metabolic syndrome induced by unhealthy diet. BMC Complement Med Ther 2024; 24:315. [PMID: 39179999 PMCID: PMC11344343 DOI: 10.1186/s12906-024-04583-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 07/09/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is a precursor to the development of many diseases (atherosclerosis, diabetes, etc.). It is marked by disruptions in glucose and lipid metabolism, along with hypertension. Numerous types of risk factors contribute to the development of the MetS, inflammation and insulin resistance are present throughout the metabolic abnormalities. Chrysanthemum indicum L. is a traditional Chinese plant used for both tea and medicine, known for its high content of total flavonoids, which are important secondary metabolites. Our research led to the extraction of a Buddleoside-Rich Chrysanthemum indicum L. extract (BUDE) which has demonstrated anti-inflammatory properties. Nonetheless, the specific role and mechanism of BUDE in preventing MetS remain unclear. METHODS The study initially evaluated the role of BUDE in preventing MetS. Subsequently, it investigated the anti-inflammatory properties of BUDE in the liver and pancreas in response to unhealthy diets. It then examined the level of insulin resistance and pancreatic β-cell function induced by inflammation. Additionally, an lipopolysaccharide (LPS)-induced macrophage inflammation model was used to further investigate the ameliorative effects of BUDE in inflammation. RESULTS BUDE has hypotensive, hypoglycemic and hypolipidemic effects. It can also resolve the imbalance between macrophage subpopulations, impede the triggering of the NF-κB signaling pathway, reduce the secretion of inflammatory mediators, ameliorate insulin resistance, and safeguard organs such as the liver and pancreas from inflammatory damage. These effects collectively contribute to preventing the development of MetS. DISCUSSION BUDE has the ability to modulate macrophage-mediated inflammation, leading to improved insulin resistance. Additionally, it delivers antihypertensive, hypoglycemic, and hypolipidemic effects, offering a potential for preventing MetS.
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Affiliation(s)
- Yiqing Zhou
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, China
| | - Jie Su
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, China
| | - Yingjie Dong
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, China
| | - Ziwen He
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, China
| | - Yajun Wang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, China
| | - Suhong Chen
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, No. 18, Chaowang Road, Xiacheng District, Hangzhou, Zhejiang, 310014, China.
- Zhejiang Provincial Key Laboratory of TCM for Innovative R & D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, 313200, China.
| | - Guiyuan Lv
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, China.
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Tobaruela-Resola AL, Milagro FI, Elorz M, Benito-Boillos A, Herrero JI, Mogna-Peláez P, Tur JA, Martínez JA, Abete I, Zulet MÁ. Circulating miR-122-5p, miR-151a-3p, miR-126-5p and miR-21-5p as potential predictive biomarkers for Metabolic Dysfunction-Associated Steatotic Liver Disease assessment. J Physiol Biochem 2024:10.1007/s13105-024-01037-8. [PMID: 39138826 DOI: 10.1007/s13105-024-01037-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 07/19/2024] [Indexed: 08/15/2024]
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a worldwide leading cause of liver-related associated morbidities and mortality. Currently, there is a lack of reliable non-invasive biomarkers for an accurate of MASLD. Hence, this study aimed to evidence the functional role of miRNAs as potential biomarkers for MASLD assessment. Data from 55 participants with steatosis (MASLD group) and 45 without steatosis (control group) from the Fatty Liver in Obesity (FLiO) Study (NCT03183193) were analyzed. Anthropometrics and body composition, biochemical and inflammatory markers, lifestyle factors and liver status were evaluated. Circulating miRNA levels were measured by RT-PCR. Circulating levels of miR-122-5p, miR-151a-3p, miR-126-5p and miR-21-5p were significantly increased in the MASLD group. These miRNAs were significantly associated with steatosis, liver stiffness and hepatic fat content. Logistic regression analyses revealed that miR-151a-3p or miR-21-5p in combination with leptin showed a significant diagnostic accuracy for liver stiffness obtaining an area under the curve (AUC) of 0.76 as well as miR-151a-3p in combination with glucose for hepatic fat content an AUC of 0.81. The best predictor value for steatosis was obtained by combining miR-126-5p with leptin, presenting an AUC of 0.95. Circulating miRNAs could be used as a non-invasive biomarkers for evaluating steatosis, liver stiffness and hepatic fat content, which are crucial in determining MASLD. CLINICAL TRIAL REGISTRATION: • Trial registration number: NCT03183193 ( www.clinicaltrials.gov ). • Date of registration: 12/06/2017.
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Affiliation(s)
- Ana Luz Tobaruela-Resola
- Department of Nutrition, Food Sciences and Physiology and Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - Fermín I Milagro
- Department of Nutrition, Food Sciences and Physiology and Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Biomedical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Mariana Elorz
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Department of Radiology, Clínica Universidad de Navarra, 31008, Pamplona, Spain
| | - Alberto Benito-Boillos
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Department of Radiology, Clínica Universidad de Navarra, 31008, Pamplona, Spain
| | - José I Herrero
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Liver Unit, Clínica Universidad de Navarra, 31008, Pamplona, Spain
- Biomedical Research Centre Network in Hepatic and Digestive Diseases (CIBERehd), 28029, Madrid, Spain
| | - Paola Mogna-Peláez
- Department of Nutrition, Food Sciences and Physiology and Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - Josep A Tur
- Biomedical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Research Group On Community Nutrition and Oxidative Stress, University of Balearic Islands, 07122, Palma, Spain
| | - J Alfredo Martínez
- Biomedical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Precision Nutrition and Cardiovascular Health Program, IMDEA Food, CEI UAM + CSIC, Madrid, Spain
| | - Itziar Abete
- Department of Nutrition, Food Sciences and Physiology and Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Biomedical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - M Ángeles Zulet
- Department of Nutrition, Food Sciences and Physiology and Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain.
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain.
- Biomedical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain.
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Teng J, Zhao Y, Li YB, Xue LY, Zhai YX, Liu JR, Wang H, Ji XS. LECT2 mediates antibacterial immune response induced by Nocardia seriolae infection in the northern snakehead. FISH & SHELLFISH IMMUNOLOGY 2024; 151:109708. [PMID: 38908810 DOI: 10.1016/j.fsi.2024.109708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/12/2024] [Accepted: 06/17/2024] [Indexed: 06/24/2024]
Abstract
Leukocyte-derived chemotaxin-2 (LECT2) is a multifunctional immunoregulator that plays several pivotal roles in the host's defense against pathogens. This study aimed to elucidate the specific functions and mechanisms of LECT2 (CaLECT2) in the northern snakehead (Channa argus) during infections with pathogens such as Nocardia seriolae (N. seriolae). We identified CaLECT2 in the northern snakehead, demonstrating its participation in the immune response to N. seriolae infection. CaLECT2 contains an open reading frame (ORF) of 459 bp, encoding a peptide of 152 amino acids featuring a conserved peptidase M23 domain. The CaLECT2 protein shares 62%-84 % identities with proteins from various other fish species. Transcriptional expression analysis revealed that CaLECT2 was constitutively expressed in all examined tissues, with the highest expression observed in the liver. Following intraperitoneal infection with N. seriolae, CaLECT2 transcription increased in the spleen, trunk kidney, and liver. In vivo challenge experiments showed that injecting recombinant CaLECT2 (rCaLECT2) could protect the snakehead against N. seriolae infection by reducing bacterial load, enhancing serum antibacterial activity and antioxidant capacity, and minimizing tissue damage. Moreover, in vitro analysis indicated that rCaLECT2 significantly enhanced the migration, respiratory burst, and microbicidal activity of the head kidney-derived phagocytes. These findings provide new insights into the role of LECT2 in the antibacterial immunity of fish.
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Affiliation(s)
- Jian Teng
- Phage Research Center, Liaocheng University, Liaocheng, Shandong, 252000, China; Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction By Ministry and Province) of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, Shandong, 271000, China
| | - Yan Zhao
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction By Ministry and Province) of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, Shandong, 271000, China
| | - Yu Bao Li
- Phage Research Center, Liaocheng University, Liaocheng, Shandong, 252000, China
| | - Liang Yi Xue
- College of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315832, China
| | - Yi Xiang Zhai
- Phage Research Center, Liaocheng University, Liaocheng, Shandong, 252000, China
| | - Jian Ru Liu
- Phage Research Center, Liaocheng University, Liaocheng, Shandong, 252000, China
| | - Hui Wang
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction By Ministry and Province) of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, Shandong, 271000, China
| | - Xiang Shan Ji
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction By Ministry and Province) of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, Shandong, 271000, China.
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9
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Umemura A, Sasaki A, Takamura T, Takayama H, Takeshita Y, Toya Y, Kakisaka K, Hasegawa Y, Ishigaki Y. Relationship between the changes in hepatokine levels and metabolic effects after laparoscopic sleeve gastrectomy in severely obese patients. Surg Today 2024; 54:581-590. [PMID: 37957316 PMCID: PMC11102872 DOI: 10.1007/s00595-023-02767-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/25/2023] [Indexed: 11/15/2023]
Abstract
PURPOSE To clarify the relationships between the changes in hepatokines and weight loss, and between these changes and the metabolic effects, and the roles played by these changes, after laparoscopic sleeve gastrectomy (LSG). METHODS We recruited 25 Japanese patients with severe obesity, who underwent LSG. We measured two hepatokines: selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2), at the baseline, and then 6 months and 1 year after LSG. Finally, we compared the changes in the hepatokines with the parameters of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). RESULTS Changes in LECT2 were correlated with the percentage of total weight loss (ρ = - 0.499, P = 0.024) and the decrease in total fat area (ρ = 0.559, P = 0.003). The changes in SeP were correlated with those in hemoglobin A1c (ρ = 0.526, P = 0.043) and the insulinogenic index (ρ = 0.638, P = 0.010) in T2D patients. In patients with NASH, the LECT2 levels were correlated with liver steatosis (ρ = 0.601). CONCLUSIONS SeP levels decrease in association with HbA1c reduction, whereas LECT2 levels are associated with reductions in fat mass and NASH scores after LSG. Hepatokines may be involved in the pathology of obesity and its complications.
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Affiliation(s)
- Akira Umemura
- Department of Surgery, Iwate Medical University School of Medicine, 2-1-1 Idaidori, Yahaba, Iwate, 028-3695, Japan.
| | - Akira Sasaki
- Department of Surgery, Iwate Medical University School of Medicine, 2-1-1 Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Hiroaki Takayama
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yumie Takeshita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yosuke Toya
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Iwate, 028-3695, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Iwate, 028-3695, Japan
| | - Yutaka Hasegawa
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Iwate, 028-3695, Japan
| | - Yasushi Ishigaki
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Iwate, 028-3695, Japan
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10
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Tanida R, Goto H, Takayama H, Nakano Y, Oo HK, Galicia-Medina CM, Takahashi K, Ishii KA, Goli AS, Matsuzaka T, Harada K, Takamura T. LECT2 Deletion Exacerbates Liver Steatosis and Macrophage Infiltration in a Male Mouse Model of LPS-mediated NASH. Endocrinology 2024; 165:bqae059. [PMID: 38781447 DOI: 10.1210/endocr/bqae059] [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: 12/31/2023] [Revised: 04/19/2024] [Accepted: 05/21/2024] [Indexed: 05/25/2024]
Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2) is a protein initially isolated as a neutrophil chemotactic factor. We previously found that LECT2 is an obesity-associated hepatokine that senses liver fat and induces skeletal muscle insulin resistance. In addition, hepatocyte-derived LECT2 activates macrophage proinflammatory activity by reinforcing the lipopolysaccharide (LPS)-induced c-Jun N-terminal kinase signaling. Based on these findings, we examined the effect of LECT2 deletion on nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) caused by bacterial translocation. We created the bacterial translocation-mediated NAFLD/NASH model using LECT2 knockout mice (LECT2 KO) with 28 times a low-dose LPS injection under high-fat diet feeding conditions. LECT2 deletion exacerbated steatosis and significantly reduced p38 phosphorylation in the liver. In addition, LECT2 deletion increased macrophage infiltration with decreased M1/M2 ratios. LECT2 might contribute to protecting against lipid accumulation and macrophage activation in the liver under pathological conditions, which might be accomplished via p38 phosphorylation. This study provides novel aspects of LECT2 in the bacterial translocation-mediated NAFLD/NASH model.
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Affiliation(s)
- Ryota Tanida
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
- Department of Nutrition, Faculty of Wellness, Shigakkan University, Obu 474-8651, Japan
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Hisanori Goto
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
| | - Hiroaki Takayama
- Life Sciences Division, Engineering and Technology Department, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
| | - Yujiro Nakano
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
| | - Hein Ko Oo
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
| | - Cynthia Monserrat Galicia-Medina
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
| | - Kenta Takahashi
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
| | - Kiyo-Aki Ishii
- Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan
| | - Arman Syah Goli
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Takashi Matsuzaka
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
- Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan
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11
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Zheng X, Lu J, Xiang S, Zou P, Chen H, Liu J, Zeng C, He Y. Elevated serum levels of leukocyte cell-derived chemotaxin 2 are associated with the prevalence of metabolic syndrome. Acta Diabetol 2024; 61:643-655. [PMID: 38383671 DOI: 10.1007/s00592-024-02242-z] [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: 11/22/2023] [Accepted: 01/18/2024] [Indexed: 02/23/2024]
Abstract
AIMS Inflammation is central to the pathogenesis of metabolic syndrome (MetS). Leukocyte cell-derived chemotaxin 2 (LECT2) is constitutively secreted in response to inflammatory stimuli and oxidative stress contributing to tissue or systemic inflammation. We explored the relationship between LECT2 levels and MetS severity in humans and mice. METHODS Serum LECT2 levels were measured in 210 participants with MetS and 114 without MetS (non-MetS). LECT2 expression in the liver and adipose tissue was also examined in mice fed a high-fat diet (HFD) and genetically obese (ob/ob) mice. RESULTS Serum LECT2 levels were significantly higher in MetS participants than in non-MetS participants (7.47[3.36-17.14] vs. 3.74[2.61-5.82], P < 0.001). Particularly, serum LECT2 levels were significantly elevated in participants with hypertension, central obesity, diabetes mellitus (DM), hyperglycaemia, elevated triglyceride (TG) levels, and reduced high-density lipoprotein cholesterol (HDL-C) levels compared to those in participants without these conditions. Pearson's correlation analysis showed that serum LECT2 levels were positively associated with conventional risk factors in all patients. Moreover, LECT2 was positively associated with the number of MetS components (r = 0.355, P < 0.001), indicating that higher serum LECT2 levels reflected MetS severity. Multivariate regression analysis revealed that a one standard deviation increase in LECT2 was associated with an odds ratio of 1.52 (1.01-2.29, P = 0.044) for MetS prevalence after adjusting for age, sex, body mass index, waist circumference, smoking status, white blood cell count, fasting blood glucose, TG, total cholesterol, HDL-C, blood urea nitrogen, and alanine aminotransferase. Receiver operating characteristic curve analysis confirmed the strong predictive ability of serum LECT2 levels for MetS. The optimum serum LECT2 cut-off value was 9.05. The area under the curve was 0.73 (95% confidence interval 0.68-0.78, P < 0.001), with a sensitivity and specificity of 45.71% and 95.61%, respectively. Additionally, LECT2 expression levels were higher at baseline and dramatically enhanced in metabolic organs (e.g. the liver) and adipose tissue in HFD-induced obese mice and ob/ob mice. CONCLUSIONS Increased LECT2 levels were significantly and independently associated with the presence and severity of MetS, indicating that LECT2 could be used as a novel biomarker and clinical predictor of MetS.
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Affiliation(s)
- Xialei Zheng
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Junmi Lu
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Shaojun Xiang
- Department of Cardiology, Hong Jiang Hospital of Traditional Chinese Medicine, Huaihua, 418200, Hunan, China
| | - Pu Zou
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Hao Chen
- Department of Cardiology, The Second Affiliated Hospital of University of South China, Hengyang, 421200, Hunan, China
| | - Jing Liu
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Cheng Zeng
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Yuhu He
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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12
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Chen C, Xie L, Zhang M, Shama, Cheng KKY, Jia W. The interplay between the muscle and liver in the regulation of glucolipid metabolism. J Mol Cell Biol 2024; 15:mjad073. [PMID: 38095440 PMCID: PMC11078061 DOI: 10.1093/jmcb/mjad073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 09/24/2023] [Indexed: 05/09/2024] Open
Affiliation(s)
- Cheng Chen
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Liping Xie
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Mingliang Zhang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Shama
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Kenneth King Yip Cheng
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Weiping Jia
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
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13
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Hirako S, Wada N, Iizuka Y, Hirabayashi T, Kageyama H, Kim H, Kaibara N, Yanagisawa N, Takenoya F, Shioda S. Effect of Intracerebroventricular Administration of Galanin-Like Peptide on Hepatokines in C57BL/6 J Mice. J Mol Neurosci 2024; 74:25. [PMID: 38386221 DOI: 10.1007/s12031-024-02200-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: 12/21/2023] [Accepted: 02/06/2024] [Indexed: 02/23/2024]
Abstract
Galanin-like peptide (GALP) is a neuropeptide that was first isolated and identified from the porcine hypothalamus. Studies have described an anti-obesity effect of GALP. We previously found that intracerebroventricular administration of GALP in mice resulted in an increase in respiratory exchange rate 12 to 16 h later. GALP may also affect glucose metabolism, but the detailed mechanism has not been elucidated. In this study, we investigated the effects of GALP on glucose and lipid metabolism in the liver. Nine-week-old male C57BL / 6 J mice were administered a single intracerebroventricular dose of saline or GALP and dissected 16 h later. There were no significant between-group differences in body weight and blood glucose levels. With regard to gene and protein expression, G6Pase associated with hepatic gluconeogenesis was significantly reduced in the GALP group. In addition, the hepatokines selenoprotein P and fetuin-A, which induce insulin resistance in the liver, were significantly decreased in the GALP group. These results suggest that intracerebroventricular administration of GALP decreases the expression of key hepatokines, thereby enhancing glucose metabolism.
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Affiliation(s)
- Satoshi Hirako
- Department of Health and Nutrition, University of Human Arts and Sciences, 1288 Magome, Iwatsuki-ku, Saitama-shi, Saitama, 339-8539, Japan
| | - Nobuhiro Wada
- Department of Anatomy, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Yuzuru Iizuka
- Department of Microbiology and Immunology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Takahiro Hirabayashi
- Clinical Medicine Research Laboratory, Shonan University of Medical Sciences, 16-48 Kamishinano, Totsuka-ku, Yokohama-shi, Kanagawa, 244-0806, Japan
| | - Haruaki Kageyama
- Department of Nutrition and Dietetics, Faculty of Family and Consumer Sciences, Kamakura Women's University, 6-1-3 Ofuna, Kamakura-shi, Kanagawa, 247-8512, Japan
| | - Hyounju Kim
- Department of Nutrition and Health Sciences, Faculty of Food and Nutritional Sciences, Toyo University, 1-1-1 Izumino, Itakura-machi, Ora-gun, Gunma, 374-0193, Japan
| | - Naoko Kaibara
- Department of Health and Nutrition, University of Human Arts and Sciences, 1288 Magome, Iwatsuki-ku, Saitama-shi, Saitama, 339-8539, Japan
| | - Naoko Yanagisawa
- Department of Microbiology and Immunology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Fumiko Takenoya
- Department of Sport Sciences, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
| | - Seiji Shioda
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, 16-10, Kamishinano, Totsuka-ku, Yokohama-shi, Kanagawa, 244-0806, Japan
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14
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Paine‐Cabrera D, Harvey LK, Robarts DR, Pritchard MT, Thyfault J, Weinman SA, Apte U, Slowik V. Leukocyte cell-derived chemotaxin 2 correlates with pediatric non-alcoholic fatty liver disease. Clin Transl Sci 2023; 16:2719-2728. [PMID: 37877453 PMCID: PMC10719457 DOI: 10.1111/cts.13666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 09/07/2023] [Accepted: 10/03/2023] [Indexed: 10/26/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), newly renamed metabolic dysfunction-associated liver disease (MASLD), is a leading cause of liver disease in children and adults. There is a paucity of data surrounding potential biomarkers and therapeutic targets, especially in pediatric NAFLD. Leukocyte cell-derived chemotaxin 2 (LECT2) is a chemokine associated with both liver disease and skeletal muscle insulin resistance. Our aim was to determine associations between LECT2 and common clinical findings of NAFLD in pediatric patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum LECT2 concentrations in children (aged 2-17 years) with and without NAFLD. LECT2 concentrations were then correlated to clinical parameters in NAFLD. Mean LECT2 was significantly elevated in children with NAFLD versus healthy controls (n = 63 vs. 42, 5.83 ± 1.98 vs. 4.02 ± 2.02 ng/mL, p < 0.005). Additionally, LECT2 had strong correlations with body mass index (BMI) (Pearson r = 0.301, p = 0.002). A LECT2 concentration of 3.76 mg/mL predicts NAFLD with a sensitivity of 90.5% and specificity of 54.8%. Principal component analysis and logistic regression models further confirmed associations between LECT2 and NAFLD status. This study demonstrates increased serum LECT2 concentrations in pediatric NAFLD, which correlates with BMI and shows strong predictive value within these patients. Our data indicate that LECT2 is a potential diagnostic biomarker of disease and should be further investigated in pediatric as well as adult NAFLD.
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Affiliation(s)
- Diego Paine‐Cabrera
- Department of Pharmacology, Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKansasUSA
| | - Lisa K. Harvey
- Division of Gastroenterology, Hepatology, and NutritionChildren's Mercy – Kansas CityKansas CityMissouriUSA
| | - Dakota R. Robarts
- Department of Pharmacology, Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKansasUSA
| | - Michele T. Pritchard
- Department of Pharmacology, Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKansasUSA
- University of Kansas Liver CenterKansas CityKansasUSA
| | - John Thyfault
- Department of Molecular and Integrative PhysiologyUniversity of Kansas Medical CenterKansas CityKansasUSA
- Children's Center for Healthy Lifestyles and NutritionKansas CityMissouriUSA
| | - Steven A. Weinman
- University of Kansas Liver CenterKansas CityKansasUSA
- Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKansasUSA
| | - Udayan Apte
- Department of Pharmacology, Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKansasUSA
- University of Kansas Liver CenterKansas CityKansasUSA
- Children's Center for Healthy Lifestyles and NutritionKansas CityMissouriUSA
| | - Voytek Slowik
- Division of Gastroenterology, Hepatology, and NutritionChildren's Mercy – Kansas CityKansas CityMissouriUSA
- Children's Center for Healthy Lifestyles and NutritionKansas CityMissouriUSA
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15
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Zhang Y, Fang XM. The pan-liver network theory: From traditional chinese medicine to western medicine. CHINESE J PHYSIOL 2023; 66:401-436. [PMID: 38149555 DOI: 10.4103/cjop.cjop-d-22-00131] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
In traditional Chinese medicine (TCM), the liver is the "general organ" that is responsible for governing/maintaining the free flow of qi over the entire body and storing blood. According to the classic five elements theory, zang-xiang theory, yin-yang theory, meridians and collaterals theory, and the five-viscera correlation theory, the liver has essential relationships with many extrahepatic organs or tissues, such as the mother-child relationships between the liver and the heart, and the yin-yang and exterior-interior relationships between the liver and the gallbladder. The influences of the liver to the extrahepatic organs or tissues have been well-established when treating the extrahepatic diseases from the perspective of modulating the liver by using the ancient classic prescriptions of TCM and the acupuncture and moxibustion. In modern medicine, as the largest solid organ in the human body, the liver has the typical functions of filtration and storage of blood; metabolism of carbohydrates, fats, proteins, hormones, and foreign chemicals; formation of bile; storage of vitamins and iron; and formation of coagulation factors. The liver also has essential endocrine function, and acts as an immunological organ due to containing the resident immune cells. In the perspective of modern human anatomy, physiology, and pathophysiology, the liver has the organ interactions with the extrahepatic organs or tissues, for example, the gut, pancreas, adipose, skeletal muscle, heart, lung, kidney, brain, spleen, eyes, skin, bone, and sexual organs, through the circulation (including hemodynamics, redox signals, hepatokines, metabolites, and the translocation of microbiota or its products, such as endotoxins), the neural signals, or other forms of pathogenic factors, under normal or diseases status. The organ interactions centered on the liver not only influence the homeostasis of these indicated organs or tissues, but also contribute to the pathogenesis of cardiometabolic diseases (including obesity, type 2 diabetes mellitus, metabolic [dysfunction]-associated fatty liver diseases, and cardio-cerebrovascular diseases), pulmonary diseases, hyperuricemia and gout, chronic kidney disease, and male and female sexual dysfunction. Therefore, based on TCM and modern medicine, the liver has the bidirectional interaction with the extrahepatic organ or tissue, and this established bidirectional interaction system may further interact with another one or more extrahepatic organs/tissues, thus depicting a complex "pan-hepatic network" model. The pan-hepatic network acts as one of the essential mechanisms of homeostasis and the pathogenesis of diseases.
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Affiliation(s)
- Yaxing Zhang
- Department of Physiology; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong; Issue 12th of Guangxi Apprenticeship Education of Traditional Chinese Medicine (Shi-Cheng Class of Guangxi University of Chinese Medicine), College of Continuing Education, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xian-Ming Fang
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine (Guangxi Hospital of Integrated Chinese Medicine and Western Medicine, Ruikang Clinical Faculty of Guangxi University of Chinese Medicine), Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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16
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Ye W, Shi M, Chen S, Duan Y, Jiang Y, Cheng Y, Zhang W, Chen J, Wang Y, Xia XQ. Transcriptome analysis revealed the existence of family-specific regulation of growth traits in grass carp. Genomics 2023; 115:110706. [PMID: 37714387 DOI: 10.1016/j.ygeno.2023.110706] [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: 05/21/2023] [Revised: 07/31/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023]
Abstract
The grass carp (Ctenopharyngodon idella) is the world's most prolific freshwater fish. Little is known, however, about the functional genes and genetic regulatory networks that govern its growth traits. We created three grass carp families in this study by using two grass carp parents with fast-growing offspring and two grass carp parents with slow-growing offspring, namely the fast-growing × fast-growing family (FF), the slow-growing × slow-growing family (SS), and the fast-growing × slow-growing family (FS). Under the satiation and starvation feeding modes, the average body weight of these families' offspring exhibited a consistent ordering (FF > FS > SS). The transcriptomes of grass carp whole brain and hepatopancreas were then acquired for each family, and it was discovered that the number of differentially expressed genes (DEGs) in the different organs demonstrated family specificity. DEGs were mostly identified in the hepatopancreas of FF and the whole brain of SS, but they were more evenly distributed in FS. There were 14 DEGs that were found in all three families, including three that were negatively correlated in hepatopancreas (ahsg2, lect2) or in brain (drd5), and 11 that were positively connected in hepatopancreas (sycn, pabpc4, zgc:112294, cel, endou, ela2, prss3, zbtb41, ela3) or in brain (fabp7, endod1). The deletion of ahsg2 boosted the growth rate only in certain zebrafish, suggesting that the growth-promoting effects of ahsg2 varies among individuals. Furthermore, we examined the SNP in each family and conducted preliminary research on the probable genetic pathways of family-specific control of growth traits. The family specificity of the growth regulation mechanism of grass carp at the transcriptional level was revealed for the first time in this study, and it was discovered that growth differences among individuals in the FF family were primarily due to differences in nutrient metabolism, whereas growth differences among individuals in the SS family may be primarily due to differences in foraging ability caused by differences in brain development. This research adds to our understanding of the genetic regulatory mechanism of grass carp growth.
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Affiliation(s)
- Weidong Ye
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mijuan Shi
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; The Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China.
| | - Sijia Chen
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - You Duan
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanxin Jiang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yingyin Cheng
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; The Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China
| | - Wanting Zhang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; The Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiujiu Chen
- College of Life Science, Wuhan University, Wuhan 430072, China
| | - Yaping Wang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China; The Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiao-Qin Xia
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China; The Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China.
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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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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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Kawade S, Ogiso K, Shayo SC, Obo T, Arimura A, Hashiguchi H, Deguchi T, Nishio Y. Luseogliflozin and caloric intake restriction increase superoxide dismutase 2 expression, promote antioxidative effects, and attenuate aortic endothelial dysfunction in diet-induced obese mice. J Diabetes Investig 2023; 14:548-559. [PMID: 36729938 PMCID: PMC10034951 DOI: 10.1111/jdi.13981] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 01/06/2023] [Accepted: 01/11/2023] [Indexed: 02/03/2023] Open
Abstract
AIMS/INTRODUCTION The mechanisms underlying the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on aortic endothelial dysfunction in diet-induced obesity are not clearly understood. This study investigated whether SGLT2 inhibition by luseogliflozin improved free fatty acid (FFA)-induced endothelial dysfunction in high-fat diet (HFD)-induced obese mice. MATERIALS AND METHODS Mice were fed a control diet or high-fat diet for 8 weeks, and then each diet with or without luseogliflozin was provided for an additional 8 weeks under free or paired feeding. Afterward, the thoracic aortas were removed and utilized for the experiments. RESULTS Luseogliflozin treatment decreased body weight, fasting blood glucose, insulin, and total cholesterol in HFD-fed mice only under paired feeding but not under free feeding. Endothelial-dependent vasodilation under FFA exposure conditions was significantly lower in HFD-fed mice than in control diet-fed mice, and luseogliflozin treatment ameliorated FFA-induced endothelial dysfunction. Reactive oxygen species (ROS) production induced by FFA was significantly increased in HFD-induced obese mice. Luseogliflozin treatment increased the expression of superoxide dismutase 2 (SOD2), an antioxidative molecule, and reduced FFA-induced ROS production in the thoracic aorta. Superoxide dismutase reversed FFA-induced endothelial dysfunction in HFD-fed mice. CONCLUSIONS It was shown that caloric restriction is important for the effect of luseogliflozin on metabolic parameters and endothelial dysfunction. Furthermore, SGLT2 inhibition by luseogliflozin possibly ameliorates FFA-induced endothelial dysfunction by increasing SOD2 expression and decreasing reactive oxygen species production in the thoracic aorta.
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Affiliation(s)
- Shigeru Kawade
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Kazuma Ogiso
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Sigfrid Casmir Shayo
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Takahiko Obo
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Aiko Arimura
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Hiroshi Hashiguchi
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Takahisa Deguchi
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Yoshihiko Nishio
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
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Zhang X, Sun K, Tang C, Cen L, Li S, Zhu W, Liu P, Chen Y, Yu C, Li L. LECT2 modulates dendritic cell function after Helicobacter pylori infection via the CD209a receptor. J Gastroenterol Hepatol 2023; 38:625-633. [PMID: 36740832 DOI: 10.1111/jgh.16138] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/06/2022] [Accepted: 01/31/2023] [Indexed: 02/07/2023]
Abstract
BACKGROUND Helicobacter pylori, a gram-negative bacterium persisting on the gastric mucosa, is involved in the pathogenesis of a variety of gastric diseases. Leukocyte cell-derived chemotaxin 2 (LECT2) treatment increased the phagocytic capacity of lymphocytes and improved immune function in bacterial infection. Whether the immune cells infected with H. pylori are affected by LECT2 is unclear. METHODS Bone marrow-derived dendritic cells (BMDCs) from wild-type C57BL/6 mice, CD209a knockout mice, or LECT2 knockout mice were exposed to H. pylori at a multiplicity of infection of 10 for 24 h. The maturity of DCs and the cytokines secreted by DCs were analyzed by flow cytometry, western blot, and real-time PCR. The signaling pathway underlying CD209a activation after LECT2 treatment were also detected. RESULTS LECT2 treatment promoted H. pylori-induced BMDC maturation and produced a high level of anti-inflammatory cytokine (IL-10) but a low level of pro-inflammatory cytokine (IL-23p40). Moreover, LECT2-pretreated DCs shifted the development of pro-inflammatory Th1/Th17 cells to Treg cells. CD209a mediated LECT2-induced maturation and secretion of DC in H. pylori-primed BMDCs. LECT2 was further confirmed to induce the secretion of certain cytokines via CD209a-JNK/P38 MAPK pathway. CONCLUSION This study reveals that LECT2 modulated the functions of H. pylori-primed DCs in a CD209a-dependent manner, which might hinder the clearance of H. pylori and contribute to its colonization.
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Affiliation(s)
- Xiaofen Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Kefang Sun
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Chenxi Tang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Li Cen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Sha Li
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Wei Zhu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Peihao Liu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Yishu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - Lan Li
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
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21
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Zhu MH, Liu YJ, Li CY, Tao F, Yang GJ, Chen J. The emerging roles of leukocyte cell-derived chemotaxin-2 in immune diseases: From mechanisms to therapeutic potential. Front Immunol 2023; 14:1158083. [PMID: 36969200 PMCID: PMC10034042 DOI: 10.3389/fimmu.2023.1158083] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Leukocyte cell-derived chemotaxin-2 (LECT2, also named ChM-II), initially identified as a chemokine mediating neutrophil migration, is a multifunctional secreted factor involved in diverse physiological and pathological processes. The high sequence similarity of LECT2 among different vertebrates makes it possible to explore its functions by using comparative biology. LECT2 is associated with many immune processes and immune-related diseases via its binding to cell surface receptors such as CD209a, Tie1, and Met in various cell types. In addition, the misfolding LECT2 leads to the amyloidosis of several crucial tissues (kidney, liver, and lung, etc.) by inducing the formation of insoluble fibrils. However, the mechanisms of LECT2-mediated diverse immune pathogenic conditions in various tissues remain to be fully elucidated due to the functional and signaling heterogeneity. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of LECT2 in immune diseases, as well as the potential applications of LECT2 in therapeutic interventions in preclinical or clinical trials. This review provides an integrated perspective on the current understanding of how LECT2 is associated with immune diseases, with the aim of facilitating the development of drugs or probes against LECT2 for the theranostics of immune-related diseases.
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Affiliation(s)
- Ming-Hui Zhu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Yan-Jun Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Chang-Yun Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Fan Tao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
- *Correspondence: Jiong Chen, ; ; Guan-Jun Yang,
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
- *Correspondence: Jiong Chen, ; ; Guan-Jun Yang,
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Yu B, Zhang Y, Wang T, Guo J, Kong C, Chen Z, Ma X, Qiu T. MAPK Signaling Pathways in Hepatic Ischemia/Reperfusion Injury. J Inflamm Res 2023; 16:1405-1418. [PMID: 37012971 PMCID: PMC10065871 DOI: 10.2147/jir.s396604] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023] Open
Abstract
The mitogen-activated protein kinase signaling pathway can be activated by a variety of growth factors, cytokines, and hormones, and mediates numerous intracellular signals related to cellular activities, including cell proliferation, motility, and differentiation. It has been widely studied in the occurrence and development of inflammation and tumor. Hepatic ischemia-reperfusion injury (HIRI) is a common pathophysiological phenomenon that occurs in surgical procedures such as lobectomy and liver transplantation, which is characterized by severe inflammatory reaction after ischemia and reperfusion. In this review, we mainly discuss the role of p38, ERK1/2, JNK in MAPK family and TAK1 and ASK1 in MAPKKK family in HIRI, and try to find an effective treatment for HIRI.
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Affiliation(s)
- Bo Yu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Yalong Zhang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Tianyu Wang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Jiayu Guo
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Chenyang Kong
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Zhongbao Chen
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Xiaoxiong Ma
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Tao Qiu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
- Correspondence: Tao Qiu, Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China, Tel +86-13995632367, Email
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23
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Hepatokines and Adipokines in Metabolic Syndrome. ANNALS OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES (INDIA) 2023. [DOI: 10.1055/s-0042-1760087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023] Open
Abstract
AbstractHepatokines and adipokines are secretory proteins derived from hepatocytes and adipocytes, respectively. These proteins play a main role in the pathogenesis of metabolic syndrome (MetS), characterized by obesity, dysglycemia, insulin resistance, dyslipidemia, and hypertension. Adipose tissue and liver are important endocrine organs because they regulate metabolic homeostasis as well as inflammation because they secrete adipokines and hepatokines, respectively. These adipokines and hepatokines communicate their action through different autocrine, paracrine and endocrine pathways. Liver regulates systemic homeostasis and also glucose and lipid metabolism through hepatokines. Dysregulation of hepatokines can lead to progression toward MetS, type 2 diabetes (T2D), inflammation, hypertension, and other diseases. Obesity is now a worldwide epidemic. Increasing cases of obesity and obesity-associated metabolic syndrome has brought the focus on understanding the biology of adipocytes and the mechanisms occurring in adipose tissue of obese individuals. A lot of facts are now available on adipose tissue as well. Adipose tissue is now given the status of an endocrine organ. Recent evidence indicates that obesity contributes to systemic metabolic dysfunction. Adipose tissue plays a significant role in systemic metabolism by communicating with other central and peripheral organs via the production and secretion of a group of proteins known as adipokines. Adipokine levels regulate metabolic state of our body and are potent enough to have a direct impact upon energy homeostasis and systemic metabolism. Dysregulation of adipokines contribute to obesity, T2D, hypertension and several other pathological changes in various organs. This makes characterization of hepatokines and adipokines extremely important to understand the pathogenesis of MetS. Hepatokines such as fetuin-A and leukocyte cell-derived chemotaxin 2, and adipokines such as resistin, leptin, TNF-α, and adiponectin are some of the most studied proteins and they can modulate the manifestations of MetS. Detailed insight into the function and mechanism of these adipokines and hepatokines in the pathogenesis of MetS can show the path for devising better preventative and therapeutic strategies against this present-day pandemic.
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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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Kitamura H. Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders. Int J Mol Sci 2023; 24:3219. [PMID: 36834633 PMCID: PMC9966627 DOI: 10.3390/ijms24043219] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and enzymatic activity. Ubiquitin-specific proteases (USPs) constitute the largest deubiquitinating enzyme family. To date, accumulating evidence indicates that several USPs positively and negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 in adipose tissue macrophages, USP9X, 20, and 33 in myocytes, USP4, 7, 10, and 18 in hepatocytes, and USP2 in hypothalamus improve hyperglycemia, whereas USP19 in adipocytes, USP21 in myocytes, and USP2, 14, and 20 in hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 14, 15, 22, 36, and 48 modulate the progression of diabetic nephropathy, neuropathy, and/or retinopathy. USP4, 10, and 18 in hepatocytes ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic USP2, 11, 14, 19, and 20 exacerbate it. The roles of USP7 and 22 in hepatic disorders are controversial. USP9X, 14, 17, and 20 in vascular cells are postulated to be determinants of atherosclerosis. Moreover, mutations in the Usp8 and Usp48 loci in pituitary tumors cause Cushing syndrome. This review summarizes the current knowledge about the modulatory roles of USPs in energy metabolic disorders.
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Affiliation(s)
- Hiroshi Kitamura
- Laboratory of Comparative Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan
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26
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Wang Q, Xu F, Chen J, Xie YQ, Xu SL, He WM. Serum Leukocyte Cell-Derived Chemotaxin 2 (LECT2) Level Is Associated with Osteoporosis. Lab Med 2023; 54:106-111. [PMID: 35976970 DOI: 10.1093/labmed/lmac080] [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] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE The aim of this study was to examine serum leukocyte cell-derived chemotaxin 2 (LECT2) levels in osteoporosis subjects to confirm its association with osteoporosis. METHODS A total of 204 adult subjects were recruited. Bone mineral densities (BMD) were assessed and blood samples were collected for measurements of biomedical parameters and the bone turnover markers. Serum LECT2 levels were measured by enzyme-linked immunosorbent assay. The relationships between serum LECT2 levels and other parameters were analyzed using the Spearman correlation coefficient. RESULTS Serum LECT2 levels were significantly increased in osteoporosis subjects over controls. We found a significantly negative correlation of serum LECT2 with BMD, 25-hydroxy-vitamin D, and creatinine and a significantly positive correlation with C-terminal telopeptide of type 1 collagen and total cholesterol. CONCLUSION Serum LECT2 levels were significantly upregulated in osteoporosis subjects and correlated with the severity of bone loss. Serum LECT2 could be a potential biomarker to assess the risk of bone loss.
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Affiliation(s)
- Qiang Wang
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Feng Xu
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Jiong Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang, China.,State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
| | - Yan-Qing Xie
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Su-Ling Xu
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Wen-Ming He
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
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de la Cruz Jasso MA, Mejía-Vilet JM, Del Toro-Cisneros N, Aguilar-León DE, Morales-Buenrostro LE, Herrera G, Uribe-Uribe NO. Leukocyte Chemotactic Factor 2 Amyloidosis (ALECT2) Distribution in a Mexican Population. Am J Clin Pathol 2023; 159:89-97. [PMID: 36370056 DOI: 10.1093/ajcp/aqac138] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 10/06/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES To assess the prevalence of leukocyte cell-derived chemotactic 2 (LECT2), its organ involvement, and its clinical association in autopsies from an ethnically biased population. METHODS The tissues from all autopsies of individuals diagnosed with amyloidosis were reassessed and typed for amyloid light chain (AL) amyloidosis, amyloid A (AA) amyloidosis, transthyretin amyloidosis (ATTR), and leukocyte chemotactic factor 2 amyloidosis (ALECT2) by immunohistochemistry. Organ involvement was described and correlated with its clinical associations. RESULTS Of 782 autopsies, 27 (3.5%) had a confirmed diagnosis of amyloidosis. Of these, 14 (52%) corresponded to ALECT2, 5 (19%) to AL amyloidosis, 2 (7%) to ATTR amyloidosis, 1 (4%) to AA amyloidosis, and 5 (21%) as undetermined-type amyloidosis. The LECT2 amyloid deposits were found in the kidneys, liver, spleen, and adrenal glands in most individuals. Except for the kidneys, there were no clinical signs suggestive of amyloid deposition in most of the affected organs. LECT2 amyloidosis was not associated with the cause of death in any case. No cases had heart or brain involvement. Potential subclinical effects of amyloid deposition in organs such as adrenal glands and spleen require further study. CONCLUSIONS This autopsy study confirms the high prevalence of LECT2 amyloidosis in the Mexican population, with frequent amyloid deposition in the kidneys, liver, spleen, and adrenal glands.
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Affiliation(s)
| | - Juan M Mejía-Vilet
- Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexicoand
| | - Noemí Del Toro-Cisneros
- Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexicoand
| | | | - Luis E Morales-Buenrostro
- Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexicoand
| | - Guillermo Herrera
- Department of Pathology, University of South Alabama, Mobile, AL, USA
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Xie Y, Zhong KB, Hu Y, Xi YL, Guan SX, Xu M, Lin Y, Liu FY, Zhou WJ, Gao Y. Liver infiltration of multiple immune cells during the process of acute liver injury and repair. World J Gastroenterol 2022; 28:6537-6550. [PMID: 36569272 PMCID: PMC9782841 DOI: 10.3748/wjg.v28.i46.6537] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/29/2022] [Accepted: 11/18/2022] [Indexed: 12/08/2022] Open
Abstract
BACKGROUND Immune cells, including neutrophils, natural killer (NK) cells, T cells, NKT cells and macrophages, participate in the progression of acute liver injury and hepatic recovery. To date, there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery.
AIM To investigate the infiltration changes of various immune cells in acute liver injury models over time, and to study the relationship between the changes in leukocyte cell-derived chemotaxin 2 (LECT2) and the infiltration of several immune cells.
METHODS Carbon tetrachloride- and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively. The quantitative changes in various immune cells were monitored at different time points. Serum samples were collected, and liver tissues were harvested. Ly6G, CD161, CD4, CD8 and F4/80 staining were used to indicate neutrophils, NK/NKT cells, CD4+ T cells, CD8+ T cells and macrophages, respectively. Lect2-KO mice were used to detect the function of LECT2.
RESULTS During the injury and repair process, different types of immune cells began to increase, reached their peaks and fell into decline at different time points. Furthermore, when the serum alanine transaminase (ALT) and aspartate transaminase (AST) indices reverted to normal levels 7 d after the injury, the infiltration of immune cells still existed even 14 d after the injury, showing an obvious lag effect. We found that the expression of LECT2 was upregulated in acute liver injury mouse models, and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice. Compared with wild-type mice, Lect2-KO mice had different immune cell infiltration.
CONCLUSION The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair. LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.
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Affiliation(s)
- Yuan Xie
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Ke-Bo Zhong
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Yang Hu
- State Key Laboratory of Organ Failure Research, Department of Pathology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yong-Lun Xi
- State Key Laboratory of Organ Failure Research, Department of Pathology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Shi-Xing Guan
- State Key Laboratory of Organ Failure Research, Department of Pathology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Meng Xu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yuan Lin
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Feng-Yong Liu
- Department of Interventional Radiology, Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing 100853, China
| | - Wei-Jie Zhou
- State Key Laboratory of Organ Failure Research, Department of Pathology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yi Gao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510280, Guangdong Province, China
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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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Qin J, Sun W, Zhang H, Wu Z, Shen J, Wang W, Wei Y, Liu Y, Gao Y, Xu H. Prognostic value of LECT2 and relevance to immune infiltration in hepatocellular carcinoma. Front Genet 2022; 13:951077. [PMID: 36160006 PMCID: PMC9500357 DOI: 10.3389/fgene.2022.951077] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/23/2022] [Indexed: 11/28/2022] Open
Abstract
Background: Previous studies have shown that Leukocyte cell-derived chemotaxin2 (LECT2) is associated with the development of HCC. However, there are still no studies with a comprehensive analysis of the role of LECT2 in hepatocellular carcinoma (HCC). Methods: TCGA data sets were used to analyze the expression of LECT2 in HCC. In addition, the prognostic value of LECT2 in HCC was also investigated. DriverDBv3 was used to analyze the Mutation, CNV, and methylation profiles of LECT2. And, validated by immunohistochemistry in 72 HCC samples. The prognostic value of LECT2 and the correlation with clinicopathological features were analyzed. The GO/KEGG enrichment analysis of LECT2 co-expression and gene set enrichment analysis (GSEA) was performed using the R software package. The PPI interaction network was constructed by Search Tool for the Retrieval of Interacting Genes (STRING) database. Immune infiltration was estimated by the XCELL, TIMER, QUANTISEQ, MCPCOUNTER, EPIC, CIBERSORT abs and CIBERSORT algorithms, and Spearman was used to analyzing their correlation with LECT2. Moreover, we analyzed the correlation of LECT2 expression with immune checkpoint molecules and HLA genes. Finally, we analyzed the IC50 values of six chemotherapeutic drugs by the pRRophetic package. Results: Reduced LECT2 expression levels found in HCC patients. Moreover, decreased levels of LECT2 were associated with poor overall survival, disease-free survival, disease-specific survival, and progression-free survival. Besides, methylation was significantly associated with LECT2 expression. The functional enrichment analysis revealed that LECT2 may affect HCC progression through various pathways such as JAK/STAT signaling pathway, cell cycle, and pathways in cancer. Additionally, the results showed that LECT2 expression was negatively correlated with immune infiltration of B cells, Neutrophil, Monocyte, Cancer-associated fibroblast, and Myeloid dendritic cell, and positively correlated with T cell CD8+ naive, Endothelial cell, and Hematopoietic stem cell. LECT2 expression was negatively correlated with multiple immune checkpoint molecules and HLA genes. Chemosensitivity analysis showed that chemosensitivity was lower in the LECT2 high expression group. We validated the prognostic value of LECT2 and analysis of clinicopathological features showed a lower TNM stage in the group with high expression of LECT2. Conclusion: Low expression of LECT2 in HCC is closely associated with poor prognosis, LECT2 may have potential clinical applications due to its unique immunological effects.
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Affiliation(s)
- Jiangfeng Qin
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Weijie Sun
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hui Zhang
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zihao Wu
- Department of Pathology, the Fourth Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jiapei Shen
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wenhai Wang
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuanyuan Wei
- Department of Hospital Infection Prevention and Control, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Center for Surveillance of Bacterial Resistance, Hefei, China
| | - Yanyan Liu
- Anhui Center for Surveillance of Bacterial Resistance, Hefei, China
- *Correspondence: Yanyan Liu, ; Yufeng Gao, ; Honghai Xu,
| | - Yufeng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Center for Surveillance of Bacterial Resistance, Hefei, China
- *Correspondence: Yanyan Liu, ; Yufeng Gao, ; Honghai Xu,
| | - Honghai Xu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Center for Surveillance of Bacterial Resistance, Hefei, China
- *Correspondence: Yanyan Liu, ; Yufeng Gao, ; Honghai Xu,
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Harris EN. Will inhibition of cellular crosstalk resolve liver fibrosis? Hepatology 2022; 76:558-560. [PMID: 35080050 PMCID: PMC9429820 DOI: 10.1002/hep.32361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 01/20/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Edward N. Harris
- Department of Biochemistry University of Nebraska Lincoln Nebraska USA
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Lin Y, Dong M, Liu Z, Xu M, Huang Z, Liu H, Gao Y, Zhou W. A strategy of vascular-targeted therapy for liver fibrosis. Hepatology 2022; 76:660-675. [PMID: 34940991 PMCID: PMC9543235 DOI: 10.1002/hep.32299] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof-of-concept strategy by combining the regulation of leukocyte cell-derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling. APPROACH AND RESULTS The CCl4 -induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno-associated viral vector serotype 9 (AAV9)-LECT2-short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9-LECT2-shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects. CONCLUSIONS Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9-LECT2-shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.
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Affiliation(s)
- Yuan Lin
- Department of PathologyShunde HospitalSouthern Medical University (The First People’s Hospital of Shunde Foshan)FoshanChina,State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Meng‐Qi Dong
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Zhi‐Min Liu
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Meng Xu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal TumorNanfang HospitalFirst Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina
| | - Zhi‐Hao Huang
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Hong‐Juan Liu
- Department of BioinformationSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yi Gao
- General Surgery CenterDepartment of Hepatobiliary Surgery IIGuangdong ProvincialResearch Center for Artificial Organ and Tissue EngineeringGuangzhou Clinical Research and Transformation Center for Artificial LiverInstitute of Regenerative MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Wei‐Jie Zhou
- Department of PathologyShunde HospitalSouthern Medical University (The First People’s Hospital of Shunde Foshan)FoshanChina,State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina,Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal TumorNanfang HospitalFirst Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina,General Surgery CenterDepartment of Hepatobiliary Surgery IIGuangdong ProvincialResearch Center for Artificial Organ and Tissue EngineeringGuangzhou Clinical Research and Transformation Center for Artificial LiverInstitute of Regenerative MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina,Microbiome Medicine CenterZhujiang HospitalSouthern Medical UniversityGuangzhouChina,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
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Sheng CY, Son YH, Jang J, Park SJ. In vitro skeletal muscle models for type 2 diabetes. BIOPHYSICS REVIEWS 2022; 3:031306. [PMID: 36124295 PMCID: PMC9478902 DOI: 10.1063/5.0096420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 08/18/2022] [Indexed: 06/15/2023]
Abstract
Type 2 diabetes mellitus, a metabolic disorder characterized by abnormally elevated blood sugar, poses a growing social, economic, and medical burden worldwide. The skeletal muscle is the largest metabolic organ responsible for glucose homeostasis in the body, and its inability to properly uptake sugar often precedes type 2 diabetes. Although exercise is known to have preventative and therapeutic effects on type 2 diabetes, the underlying mechanism of these beneficial effects is largely unknown. Animal studies have been conducted to better understand the pathophysiology of type 2 diabetes and the positive effects of exercise on type 2 diabetes. However, the complexity of in vivo systems and the inability of animal models to fully capture human type 2 diabetes genetics and pathophysiology are two major limitations in these animal studies. Fortunately, in vitro models capable of recapitulating human genetics and physiology provide promising avenues to overcome these obstacles. This review summarizes current in vitro type 2 diabetes models with focuses on the skeletal muscle, interorgan crosstalk, and exercise. We discuss diabetes, its pathophysiology, common in vitro type 2 diabetes skeletal muscle models, interorgan crosstalk type 2 diabetes models, exercise benefits on type 2 diabetes, and in vitro type 2 diabetes models with exercise.
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Affiliation(s)
- Christina Y. Sheng
- Biohybrid Systems Group, Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Young Hoon Son
- Biohybrid Systems Group, Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | | | - Sung-Jin Park
- Biohybrid Systems Group, Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, Georgia 30322, USA
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Chu TH, Ko CY, Tai PH, Chang YC, Huang CC, Wu TY, Chan HH, Wu PH, Weng CH, Lin YW, Kung ML, Fang CC, Wu JC, Wen ZH, Lee YK, Hu TH, Tai MH. Leukocyte cell-derived chemotaxin 2 regulates epithelial-mesenchymal transition and cancer stemness in hepatocellular carcinoma. J Biol Chem 2022; 298:102442. [PMID: 36055405 PMCID: PMC9530851 DOI: 10.1016/j.jbc.2022.102442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 08/07/2022] [Accepted: 08/08/2022] [Indexed: 11/27/2022] Open
Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2) acts as a tumor suppressor in hepatocellular carcinoma (HCC). However, the antineoplastic mechanism of LECT2, especially its influence on hepatic cancer stem cells (CSCs), remains largely unknown. In The Cancer Genome Atlas cohort, LECT2 mRNA expression was shown to be associated with stage, grade, recurrence, and overall survival in human HCC patients, and LECT2 expression was downregulated in hepatoma tissues compared with the adjacent nontumoral liver. Here, we show by immunofluorescence and immunoblot analyses that LECT2 was expressed at lower levels in tumors and in poorly differentiated HCC cell lines. Using functional assays, we also found LECT2 was capable of suppressing oncogenic behaviors such as cell proliferation, anchorage-independent growth, migration, invasiveness, and epithelial-mesenchymal transition in hepatoma cells. Moreover, we show exogenous LECT2 treatment inhibited CSC functions such as tumor sphere formation and drug efflux. Simultaneously, hepatic CSC marker expression was also downregulated, including expression of CD133 and CD44. This was supported by infection with adenovirus encoding LECT2 (Ad-LECT2) in HCC cells. Furthermore, in animal experiments, Ad-LECT2 gene therapy showed potent efficacy in treating HCC. We demonstrate LECT2 overexpression significantly promoted cell apoptosis and reduced neovascularization/CSC expansion in rat hepatoma tissues. Mechanistically, we showed using immunoblot and immunofluorescence analyses that LECT2 inhibited β-catenin signaling via the suppression of the hepatocyte growth factor/c-MET axis to diminish CSC properties in HCC cells. In summary, we reveal novel functions of LECT2 in the suppression of hepatic CSCs, suggesting a potential alternative strategy for HCC therapy.
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Affiliation(s)
- Tian-Huei Chu
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Chou-Yuan Ko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Po-Han Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yi-Chen Chang
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tung-Yang Wu
- Department of Chest Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Hoi-Hung Chan
- Division of Gastroenterology, Department of Medicine, Conde S. Januário Hospital, Macau, China
| | - Ping-Hsuan Wu
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chien-Hui Weng
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yu-Wei Lin
- Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Cheng-Chieh Fang
- Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Jian-Ching Wu
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan; LabTurbo Biotech Corporation, Taipei, Taiwan
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yung-Kuo Lee
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Ming-Hong Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan.
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Lugarà R, Renner S, Wolf E, Liesegang A, Bruckmaier R, Giller K. Crossbred Sows Fed a Western Diet during Pre-Gestation, Gestation, Lactation, and Post-Lactation Periods Develop Signs of Lean Metabolic Syndrome That Are Partially Attenuated by Spirulina Supplementation. Nutrients 2022; 14:nu14173574. [PMID: 36079836 PMCID: PMC9460909 DOI: 10.3390/nu14173574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/16/2022] Open
Abstract
Excessive dietary intake of fats and sugars (“Western diet”, WD) is one of the leading causes of obesity. The consumption of the microalga Arthrospira platensis (spirulina, Sp) is increasing due to its presumed health benefits. Both WD and Sp are also consumed by pregnant and breastfeeding women. This study investigated if gestating and lactating domestic pigs are an appropriate model for WD-induced metabolic disturbances similar to those observed in humans and if Sp supplementation may attenuate any of these adverse effects. Pigs were fed a WD high in fat, sugars, and cholesterol or a control diet. Half of the animals per diet group were supplemented with 20 g Sp per day. The WD did not increase body weight or adipose tissue accumulation but led to metabolic impairments such as higher cholesterol concentration in plasma, lower IGF1 plasma levels, and signs of hepatic damage compared to the control group. Spirulina supplementation could not reduce all the metabolic impairments observed in WD-fed animals. These findings indicate limited suitability of gestating and lactating domestic pigs as a model for WD but a certain potential of low-dose Sp supplementation to partially attenuate negative WD effects.
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Affiliation(s)
- Rosamaria Lugarà
- Animal Nutrition, ETH Zurich, Eschikon 27, 8315 Lindau, Switzerland
| | - Simone Renner
- German Center for Diabetes Research (DZD), Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany
- Molecular Animal Breeding and Biotechnology, Department of Veterinary Sciences, Ludwig-Maximilian University Munich, Gene Center, Feodor-Lynen-Strasse 25, 81377 Munich, Germany
| | - Eckhard Wolf
- German Center for Diabetes Research (DZD), Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany
- Molecular Animal Breeding and Biotechnology, Department of Veterinary Sciences, Ludwig-Maximilian University Munich, Gene Center, Feodor-Lynen-Strasse 25, 81377 Munich, Germany
| | - Annette Liesegang
- Animal Nutrition, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 270, 8057 Zurich, Switzerland
| | - Rupert Bruckmaier
- Veterinary Physiology, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, 3001 Bern, Switzerland
| | - Katrin Giller
- Animal Nutrition, ETH Zurich, Eschikon 27, 8315 Lindau, Switzerland
- Correspondence: ; Tel.: +41-52-3549209
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Wang D, Wu M, Zhang X, Li L, Lin M, Shi X, Zhao Y, Huang C, Li X. Hepatokine Fetuin B expression is regulated by leptin-STAT3 signalling and associated with leptin in obesity. Sci Rep 2022; 12:12869. [PMID: 35896788 PMCID: PMC9329397 DOI: 10.1038/s41598-022-17000-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 07/19/2022] [Indexed: 11/09/2022] Open
Abstract
Obesity is an expanding global public health problem and a leading cause of metabolic disorders. The hepatokine Fetuin B participates in regulating insulin resistance, glucose metabolism and liver steatosis. However, the mechanism underlying Fetuin B activation remains unclear. Our previous population-based study demonstrated a significant association between serum Fetuin B and body fat mass in an obese population, which indicates its potential in mediating obesity-related metabolic disorders. In the present study, we further revealed a significant correlation between Fetuin B and leptin, the classic adipokine released by expanding adipose tissue, in this obese population. Consistently, elevated Fetuin B and leptin levels were confirmed in diet-induced obese mice. Furthermore, an in vitro study demonstrated that the leptin signalling pathway directly activated the transcription and expression of Fetuin B in primary hepatocytes and AML12 cells in a STAT3-dependent manner. STAT3 binds to the response elements on FetuB promoter to directly activate FetuB transcription. Finally, the mediating effect of Fetuin B in insulin resistance induced by leptin was confirmed according to mediation analysis in this obese population. Therefore, our study identifies leptin-STAT3 as an upstream signalling pathway that activates Fetuin B and provides new insights into the pathogenic mechanisms of obesity-related metabolic disorders.
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Affiliation(s)
- Dongmei Wang
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.,Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen, 361023, China
| | - Menghua Wu
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Xiaofang Zhang
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Long Li
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.,Institute of Drug Discovery Technology, Ningbo University, Ningbo, 315211, China
| | - Mingzhu Lin
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Xiulin Shi
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Yan Zhao
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Caoxin Huang
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
| | - Xuejun Li
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
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Xu H, Jia Y, Wang X, Wang H, Yu J, Hao W. Renal amyloidogenic leukocyte chemotactic factor 2 combined with IgA nephropathy: A case report. Medicine (Baltimore) 2022; 101:e29638. [PMID: 35866785 PMCID: PMC9302286 DOI: 10.1097/md.0000000000029638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
RATIONALE Amyloidogenic leukocyte chemotactic factor 2 (ALECT2) was recently considered as a new clinicopathologic type of amyloid, which frequently affects kidney in adults and results in different degrees of renal insufficiency and failure with or without proteinuria. Here, we present a case of combining LECT2-associated renal amyloidosis with immunoglobulin (Ig)A nephropathy. PATIENT CONCERNS A 71-year-old Chinese man presented with edema of both lower extremities. DIAGNOSES There was pale eosinophilic material strongly positive for the Congo red stain in interstitium with demonstrated apple green birefringence under polarized light. Immunofluorescent stain was positive for IgA deposits (4+), IgG deposits (2+), C3 deposits (3+) within the mesangium and capillary wall. Immunohistochemistry was positive for κ (+), λ (2+) in mesangial area, and LECT2 (2+) in the interstitium. On electron microscopy, there were electron-dense deposits within mesangial area and subendothelial and randomly orientated and nonbranching fibrils 10 nm in size found in the interstitium areas. Liquid chromatography tandem mass spectrometry was performed on peptides extracted from Congo red-positive, microdissected areas of the paraffin-embedded kidney specimen. LECT 2-associated renal amyloidosis with IgA nephropathy was pathologically confirmed by renal biopsy. INTERVENTIONS Steroids (60 mg/d) were used to treat IgA nephropathy daily. Antihypertensive treatment was switched to an angiotensin-converting enzyme inhibitor. OUTCOMES One year after diagnosis, creatine remained stable in the normal range, and 24-hour proteinuria decreased to 2.9 g. LESSONS To date, ALECT2 has still not been comprehensively investigated. The findings of this research provide insights for concurrent IgA nephropathy with ALECT2.
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Affiliation(s)
- Hongzhao Xu
- Department of Nephrology, the first affiliated hospital of Jilin University, Changchun 130021, China
| | - Ye Jia
- Department of Nephrology, the first affiliated hospital of Jilin University, Changchun 130021, China
| | - Xueyao Wang
- Department of Nephrology, the first affiliated hospital of Jilin University, Changchun 130021, China
| | - Hui Wang
- Laboratory of Electron Microscopy, Peking University First Hospital, Beijing 100034, P.R. China
| | - Jinyu Yu
- Department of Pathology, the first affiliated hospital of Jilin University, Changchun 130021, China
| | - Wu Hao
- Department of Nephrology, the first affiliated hospital of Jilin University, Changchun 130021, China
- *Correspondence: Wu Hao, Department of Nephrology, the first affiliated hospital of Jilin University, Changchun 130021, China (e-mail: )
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Kim J, Lee SK, Kim D, Lee E, Park CY, Choe H, Kang MJ, Kim HJ, Kim JH, Hong JP, Lee YJ, Park HS, Heo Y, Jang YJ. Adipose tissue LECT2 expression is associated with obesity and insulin resistance in Korean women. Obesity (Silver Spring) 2022; 30:1430-1441. [PMID: 35722819 DOI: 10.1002/oby.23445] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/14/2022] [Accepted: 03/17/2022] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Leukocyte cell-derived chemotaxin 2 (LECT2) is an obesity-upregulated hepatokine inducing skeletal muscle insulin resistance. The study's aim was to explore whether LECT2 is expressed in human adipose tissue and whether the expression is dysregulated during obesity and associated with obesity-related metabolic disorders. METHODS This study measured metabolic parameters, serum LECT2, and expression of LECT2 and CD209, a gene encoding a putative receptor for LECT2, in abdominal subcutaneous and visceral adipose tissues in women with obesity (with or without type 2 diabetes) and women with normal weight. The expression/secretion of LECT2 and its putative effects were assessed in human adipocytes. RESULTS Adipose tissue LECT2 mRNA and serum LECT2 were higher in women with obesity and were significantly correlated with parameters related to insulin resistance. LECT2 was mainly expressed by adipocytes. Both LECT2 and CD209 expression was higher in adipocytes from women with obesity. Incubating adipocytes with substances mimicking the microenvironment of obesity adipose tissue increased LECT2 expression/secretion. LECT2 treatment of adipocytes suppressed insulin-stimulated Akt phosphorylation; it reduced adiponectin (ADIPOQ) and increased leptin (LEP) expression in a CD209-dependent manner. CONCLUSIONS This study demonstrates that LECT2 expression in adipose tissue is high in patients with obesity and associated with insulin resistance and suggests that adipocyte-derived LECT2 may contribute to adipose tissue dysfunction.
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Affiliation(s)
- Jimin Kim
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
- Brexogen Research Center, Brexogen Inc., Seoul, South Korea
| | - Seul Ki Lee
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
- Brexogen Research Center, Brexogen Inc., Seoul, South Korea
| | - Donguk Kim
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eunyoung Lee
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chan Yoon Park
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
- Department of Food and Nutrition, College of Health Science, The University of Suwon, Hwaseong-si, South Korea
| | - Han Choe
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Min-Ji Kang
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hwa Jung Kim
- Department of Preventive Medicine, University of Ulsan College of Medicine, Seoul, South Korea
- Department of Clinical Epidemiology and Biostatistics, ASAN Medical Center, Seoul, South Korea
| | - Jong-Hyeok Kim
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Joon Pio Hong
- Department of Plastic Surgery, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yeon Ji Lee
- Department of Family Medicine, Inha University School of Medicine, Incheon, South Korea
| | - Hye Soon Park
- Department of Family Medicine, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yoonseok Heo
- Department of General Surgery, Inha University School of Medicine, Incheon, South Korea
| | - Yeon Jin Jang
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
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Xie Y, Fan K, Guan S, Hu Y, Gao Y, Zhou W. LECT2: A pleiotropic and promising hepatokine, from bench to bedside. J Cell Mol Med 2022; 26:3598-3607. [PMID: 35656863 PMCID: PMC9258709 DOI: 10.1111/jcmm.17407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 03/12/2022] [Accepted: 05/02/2022] [Indexed: 11/28/2022] Open
Abstract
LECT2 (leucocyte cell-derived chemotaxin 2) is a 16-kDa protein mainly produced by hepatocytes. It was first isolated in PHA-activated human T-cell leukaemia SKW-3 cells and originally identified as a novel neutrophil chemotactic factor. However, many lines of studies suggested that LECT2 was a pleiotropic protein, it not only functioned as a cytokine to exhibit chemotactic property, but also played multifunctional roles in some physiological conditions and pathological abnormalities, involving liver regeneration, neuronal development, HSC(haematopoietic stem cells) homeostasis, liver injury, liver fibrosis, hepatocellular carcinoma, metabolic disorders, inflammatory arthritides, systemic sepsis and systemic amyloidosis. Among the above studies, it was discovered that LECT2 could be a promising molecular biomarker and therapeutic target. This review summarizes LECT2-related receptors and pathways, basic and clinical researches, primarily in mice and human, for a better comprehension and management of these diseases in the future.
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Affiliation(s)
- Yuan Xie
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
- Department of General Surgery IIThe First People's Hospital of ZhaoqingZhaoqingChina
| | - Kai‐Wei Fan
- Department of Cerebrovascular DiseaseThe First People's Hospital of ZhaoqingZhaoqingChina
| | - Shi‐Xing Guan
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yang Hu
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yi Gao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
| | - Wei‐Jie Zhou
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina
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Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET. Nat Commun 2022; 13:3176. [PMID: 35676290 PMCID: PMC9177837 DOI: 10.1038/s41467-022-30879-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
Retinoic acid-inducible gene (RIG)-I is an essential innate immune sensor that recognises pathogen RNAs and induces interferon (IFN) production. However, little is known about how host proteins regulate RIG-I activation. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2), a hepatokine and ligand of the MET receptor tyrosine kinase is an antiviral regulator that promotes the RIG-I-mediated innate immune response. Upon binding to MET, LECT2 induces the recruitment of the phosphatase PTP4A1 to MET and facilitates the dissociation and dephosphorylation of phosphorylated SHP2 from MET, thereby protecting RIG-I from SHP2/c-Cbl-mediated degradation. In vivo, LECT2 overexpression enhances RIG-I-dependent IFN production and inhibits lymphocytic choriomeningitis virus (LCMV) replication in the liver, whereas these changes are reversed in LECT2 knockout mice. Forced suppression of MET abolishes IFN production and antiviral activity in vitro and in vivo. Interestingly, hepatocyte growth factor (HGF), an original MET ligand, inhibits LECT2-mediated anti-viral signalling; conversely, LECT2-MET signalling competes with HGF-MET signalling. Our findings reveal previously unrecognized crosstalk between MET-mediated proliferation and innate immunity and suggest that targeting LECT2 may have therapeutic value in infectious diseases and cancer. The innate antiviral immune response is an important defense against infection. Here, the authors show that leukocyte cell-derived chemotaxin 2 (LECT2) promotes RIG-I-mediated innate immune responses by preventing its degradation, and inhibits lymphocytic choriomeningitis virus replication in the liver.
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Berthou F, Sobolewski C, Abegg D, Fournier M, Maeder C, Dolicka D, Correia de Sousa M, Adibekian A, Foti M. Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk. Int J Mol Sci 2022; 23:ijms23073959. [PMID: 35409319 PMCID: PMC8999584 DOI: 10.3390/ijms23073959] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/25/2022] [Accepted: 03/31/2022] [Indexed: 11/16/2022] Open
Abstract
Liver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secreted hepatic factors improving metabolic homeostasis. Our results indicated that protein factors, rather than specific metabolites, released by PTEN-deficient hepatocytes trigger an improved muscle insulin sensitivity and a decreased adiposity in LPTENKO. In this regard, a proteomic analysis of conditioned media from PTEN-deficient primary hepatocytes identified seven hepatokines whose expression/secretion was deregulated. Distinct expression patterns of these hepatokines were observed in hepatic tissues from human/mouse with NAFLD. The expression of specific factors was regulated by the PTEN/PI3K, PPAR or AMPK signaling pathways and/or modulated by classical antidiabetic drugs. Finally, loss-of-function studies identified FGF21 and the triad AHSG, ANGPTL4 and LECT2 as key regulators of insulin sensitivity in muscle cells and in adipocytes biogenesis, respectively. These data indicate that hepatic PTEN deficiency and steatosis alter the expression/secretion of hepatokines regulating insulin sensitivity in muscles and the lipid metabolism in adipose tissue. These hepatokines could represent potential therapeutic targets to treat obesity and insulin resistance.
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Affiliation(s)
- Flavien Berthou
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Cyril Sobolewski
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Daniel Abegg
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA; (D.A.); (A.A.)
| | - Margot Fournier
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Christine Maeder
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Dobrochna Dolicka
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Marta Correia de Sousa
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Alexander Adibekian
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA; (D.A.); (A.A.)
| | - Michelangelo Foti
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
- Diabetes Center, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
- Correspondence: ; Tel.: +41-(22)-379-52-04
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Qin YJ, Xiao K, Zhong Z, Zhao Y, Yu T, Sun XF. LECT2 Ameliorates Blood-Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway. Invest Ophthalmol Vis Sci 2022; 63:7. [PMID: 35262733 PMCID: PMC8934553 DOI: 10.1167/iovs.63.3.7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Current treatments for diabetic retinopathy (DR) have considerable limitations, emphasizing the need for new therapeutic options. The effect of leukocyte cell-derived chemotaxin 2 (LECT2) on diabetes-induced blood–retinal barrier impairment and the possible underlying mechanism were investigated both in vivo and in vitro. Methods Twenty diabetic and 22 nondiabetic eyes were included in this study. Additionally, we established a streptozotocin-induced diabetic mouse model and observed vascular leakage in mice treated with or without recombinant LECT2 (rLECT2) intravitreal injection (40 µg/mL, 1 µL). The levels of LECT2 and interendothelial junction proteins (ZO1, VE-cadherin, and occludin) were analyzed by western blot and/or immunofluorescence. Endothelial junctions in mouse retinas were observed by transmission electron microscopy (TEM). Moreover, confluent human retinal microvascular endothelial cells (HRMECs) and human umbilical vein endothelial cells (HUVECs) were treated (0–72 hours) with glucose (0 or 30 mM) in the presence or absence of rLECT2 (40–360 ng/mL). After treatment, intact cell monolayers were monitored for permeability to 40-kD FITC-dextran. Interendothelial junction targets and Tie2/Akt/mTOR signaling pathway components were investigated by western blot. Results In diabetic human and mouse retinas and high-glucose (30 mM)–treated HRMECs and HUVECs, the levels of LECT2 and interendothelial junction proteins were decreased. rLECT2 treatment (80 ng/mL) significantly attenuated the hyperglycemia-induced reduction in endothelial cell barrier function and inhibited the migration and tube formation of HRMECs and HUVECs. In addition, rLECT2 increased the levels of interendothelial junction proteins via activation of the Tie2/Akt/mTOR signaling pathway. Furthermore, intravitreal rLECT2 injections increased the levels of interendothelial junction proteins and reversed diabetes-induced junction disruption. Conclusions rLECT2 can increase the levels of interendothelial tight junction proteins through activation of the Tie2/Akt/mTOR signaling pathway and can ameliorate inner blood–retinal barrier impairment secondary to diabetes. LECT2 might be a potential target to prevent the progression of DR.
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Affiliation(s)
- Yuan-Jun Qin
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Ke Xiao
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Zheng Zhong
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Yin Zhao
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Tian Yu
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Xu-Fang Sun
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
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Friend or foe for obesity: how hepatokines remodel adipose tissues and translational perspective. Genes Dis 2022. [DOI: 10.1016/j.gendis.2021.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Zambon Azevedo V, Silaghi CA, Maurel T, Silaghi H, Ratziu V, Pais R. Impact of Sarcopenia on the Severity of the Liver Damage in Patients With Non-alcoholic Fatty Liver Disease. Front Nutr 2022; 8:774030. [PMID: 35111794 PMCID: PMC8802760 DOI: 10.3389/fnut.2021.774030] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
An extensive body of the literature shows a strong interrelationship between the pathogenic pathways of non-alcoholic fatty liver disease (NAFLD) and sarcopenia through the muscle-liver-adipose tissue axis. NAFLD is one of the leading causes of chronic liver diseases (CLD) affecting more than one-quarter of the general population worldwide. The disease severity spectrum ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and its complications: end-stage chronic liver disease and hepatocellular carcinoma. Sarcopenia, defined as a progressive loss of the skeletal muscle mass, reduces physical performances, is associated with metabolic dysfunction and, possibly, has a causative role in NAFLD pathogenesis. Muscle mass is a key determinant of the whole-body insulin-mediated glucose metabolism and impacts fatty liver oxidation and energy homeostasis. These mechanisms drive the accumulation of ectopic fat both in the liver (steatosis, fatty liver) and in the muscle (myosteatosis). Myosteatosis rather than the muscle mass per se, seems to be closely associated with the severity of the liver injury. Sarcopenic obesity is a recently described entity which associates both sarcopenia and obesity and may trigger worse clinical outcomes including hepatic fibrosis progression and musculoskeletal disabilities. Furthermore, the muscle-liver-adipose tissue axis has a pivotal role in changes of the body composition, resulting in a distinct clinical phenotype that enables the identification of the "sarcopenic NAFLD phenotype." This review aims to bring some light into the complex relationship between sarcopenia and NAFLD and critically discuss the key mechanisms linking NAFLD to sarcopenia, as well as some of the clinical consequences associated with the coexistence of these two entities: the impact of body composition phenotypes on muscle morphology, the concept of sarcopenic obesity, the relationship between sarcopenia and the severity of the liver damage and finally, the future directions and the existing gaps in the knowledge.
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Affiliation(s)
- Vittoria Zambon Azevedo
- Doctoral School Physiology, Physiopathology and Therapeutics 394, Sorbonne Université, Paris, France
- Centre de Recherche de Cordeliers, INSERM UMRS 1138, Paris, France
| | - Cristina Alina Silaghi
- Department of Endocrinology, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Thomas Maurel
- Institute of Cardiometabolism and Nutrition, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France
| | - Horatiu Silaghi
- Department of Surgery V, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Vlad Ratziu
- Centre de Recherche de Cordeliers, INSERM UMRS 1138, Paris, France
- Institute of Cardiometabolism and Nutrition, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France
- Sorbonne Université, Paris, France
| | - Raluca Pais
- Institute of Cardiometabolism and Nutrition, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France
- Sorbonne Université, Paris, France
- Centre de Recherche Saint Antoine, INSERM UMRS 938, Paris, France
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Park CY, Lee SK, Kim J, Kim D, Choe H, Jeong JH, Choi KC, Park HS, Han SN, Jang YJ. Endoplasmic reticulum stress increases LECT2 expression via ATF4. Biochem Biophys Res Commun 2021; 585:169-176. [PMID: 34808500 DOI: 10.1016/j.bbrc.2021.11.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/11/2021] [Indexed: 12/23/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity, insulin resistance, and endoplasmic reticulum (ER) stress. Elevated circulating levels of the hepatokine leukocyte cell-derived chemotaxin-2 (LECT2) have also been noted in NAFLD; however, the mechanism underlying this association is unclear. To investigate a possible link between ER stress/unfolded protein response (UPR) signaling and LECT2 secretion, HepG2 cells were incubated with ER stress inducers with or without an ER stress-reducing chemical chaperone. Additionally, UPR pathway genes were knocked down and overexpressed, and a ChIP assay was performed. In diet-induced obese mice, hepatic expression of LECT2 and activating transcription factor 4 (ATF4) was measured. In HepG2 cells, LECT2 expression was increased by ER stressors, an effect blocked by the chemical chaperone. Among UPR pathway proteins, only knockdown of ATF4 suppressed ER stress-induced LECT2 expression, while overexpression of ATF4 enhanced LECT2 expression. The ChIP assay revealed that ATF4 binds to three putative binding sites on the LECT2 promoter and binding is promoted by an ER stress inducer. In steatotic livers of obese mice, LECT2 and ATF4 expression was concomitantly elevated. Our data indicate that activation of ER stress/UPR signaling induces LECT2 expression in steatotic liver; specifically, ATF4 appears to mediate upregulation of LECT2 transcription.
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Affiliation(s)
- Chan Yoon Park
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea; Department of Food & Nutrition, College of Health Science, The University of Suwon, Hwaseong-si, Gyeonggi-do, South Korea
| | - Seul Ki Lee
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jimin Kim
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Donguk Kim
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Han Choe
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji-Hoon Jeong
- Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kyung-Chul Choi
- Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hye Soon Park
- Department of Family Medicine, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sung Nim Han
- Department of Food and Nutrition & Research Institute of Human Ecology, College of Human Ecology, Seoul National University, Seoul, South Korea
| | - Yeon Jin Jang
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea.
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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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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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Armandi A, Rosso C, Caviglia GP, Ribaldone DG, Bugianesi E. The Impact of Dysmetabolic Sarcopenia Among Insulin Sensitive Tissues: A Narrative Review. Front Endocrinol (Lausanne) 2021; 12:716533. [PMID: 34858322 PMCID: PMC8631324 DOI: 10.3389/fendo.2021.716533] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 10/12/2021] [Indexed: 12/25/2022] Open
Abstract
Sarcopenia is a common muscular affection among elderly individuals. More recently, it has been recognized as the skeletal muscle (SM) expression of the metabolic syndrome. The prevalence of sarcopenia is increasing along with visceral obesity, to which it is tightly associated. Nonetheless, it is a still underreported entity by clinicians, despite the worsening in disease burden and reduced patient quality of life. Recognition of sarcopenia is clinically challenging, and variability in study populations and diagnostic methods across the clinical studies makes it hard to reach a strong evidence. Impaired insulin activity in SM is responsible for the altered molecular pathways and clinical manifestations of sarcopenia, which is morphologically expressed by myosteatosis. Lipotoxicity, oxidative stress and adipose tissue-derived inflammation lead to both alterations in glucose disposal and protein synthesis in SM, with raising insulin resistance (IR) and SM atrophy. In particular, hyperleptinemia and leptin resistance interfere directly with SM activity, but also with the release of Growth Hormone from the hypohysis, leading to a lack in its anabolic effect on SM. Moreover, sarcopenia is independently associated to liver fibrosis in Non-Alcoholic Fatty Liver Disease (NAFLD), which in turn worsens SM functionality through the secretion of proinflammatory heptokines. The cross-talk between the liver and SM in the IR setting is of crucial relevance, given the high prevalence of NAFLD and the reciprocal impact of insulin-sensitive tissues on the overall disease burden. Along with the efforts of non-invasive diagnostic approaches, irisin and myostatin are two myokines currently evaluated as potential biomarkers for diagnosis and prognostication. Decreased irisin levels seem to be potentially associated to sarcopenia, whereas increased myostatin has shown to negatively impact on sarcopenia in pre-clinical studies. Gene variants in irisin have been explored with regard to the impact on the liver disease phenotype, with conflicting results. The gut-muscle axis has gain relevance with the evidence that insulin resistance-derived gut dysbiosis is responsible for increased endotoxemia and reduction in short-chain free fatty acids, directly affecting and predisposing to sarcopenia. Based on the current evidence, more efforts are needed to increase awareness and improve the management of sarcopenic patients.
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Affiliation(s)
| | | | | | | | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
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Xu H, Li X, Wu Z, Zhao L, Shen J, Liu J, Qin J, Shen Y, Ke J, Wei Y, Li J, Gao Y. LECT2, A Novel and Direct Biomarker of Liver Fibrosis in Patients With CHB. Front Mol Biosci 2021; 8:749648. [PMID: 34631799 PMCID: PMC8492992 DOI: 10.3389/fmolb.2021.749648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/06/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B (CHB) patients with severe liver fibrosis would be more likely to progress to a poorer prognosis. Treatment is considered once the liver fibrosis reaches significant liver fibrosis (≥S2). Leukocyte cell-derived chemotaxin-2 (LECT2) has been shown to contribute to liver fibrosis progression. No research has focused on the role of LECT2 in liver fibrosis in CHB patients. This study enrolled 227 CHB patients and divided them into the training group (n = 147) and validation group (n = 80), respectively. The expression of LECT2 in serum, protein and mRNA of the human liver tissues was detected to analyze the possible associations between LECT2 and liver fibrosis. A receiver operating characteristic curve (ROC) was used to estimate the efficacy of LECT2 for predicting liver fibrosis. The data showed that there was a positive relationship between LECT2 and the progression of liver fibrosis. In the training group, LECT2 was demonstrated to have better effectiveness than APRI and FIB-4. The AUC was 0.861, 0.698, and 0.734 for significant liver fibrosis, and 0.855, 0.769, and 0.752 for advanced liver fibrosis. Besides, the efficacy of LECT2 in different statuses of patients with CHB was examined and the effectiveness of LECT2 had also been confirmed in the validation group. All the results confirmed that LECT2 could act as a perfect predictor and thus offers a novel and direct biomarker to estimate liver fibrosis more accurately.
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Affiliation(s)
- Honghai Xu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xutong Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zihao Wu
- Department of Pathology, The Forth Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Linyan Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jiapei Shen
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jiaying Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jiangfeng Qin
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuanlong Shen
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jing Ke
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuanyuan Wei
- Department of Hospital Infection Prevention and Control, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yufeng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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50
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Zhu S, Bennett S, Li Y, Liu M, Xu J. The molecular structure and role of LECT2 or CHM-II in arthritis, cancer, and other diseases. J Cell Physiol 2021; 237:480-488. [PMID: 34550600 DOI: 10.1002/jcp.30593] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/31/2021] [Accepted: 09/11/2021] [Indexed: 12/20/2022]
Abstract
Leukocyte cell-derived chemotaxin-2 (LECT2 or LECT-2), also called chondromodulin II (ChM-II or CHM2) plays a versatile role in various tissues. It was first identified as a chemotactic factor to promote the migration of neutrophils. It was also reported as a hepatokine to regulate glucose metabolism, obesity, and nonalcoholic fatty liver disease. As a secreted factor, LECT2 binds to several cell surface receptors CD209a, Tie1, and Met to regulate inflammatory reaction, fibrogenesis, vascular invasion, and tumor metastasis in various cell types. As an intracellular molecule, it is associated with LECT2-mediated amyloidosis, in which LECT2 misfolding results in insoluble fibrils in multiple tissues such as the kidney, liver, and lung. Recently, LECT2 was found to be associated with the development of rheumatoid arthritis and osteoarthritis, involving the dysregulation of osteoclasts, mesenchymal stem cells, osteoblasts, chondrocytes, and endothelial cells in the bone microenvironment. LECT2 is implicated in the development of cancers, such as hepatocellular carcinoma via MET-mediated PTP1B/Raf1/ERK signaling pathways and is proposed as a biomarker. The mechanisms by which LECT2 regulates diverse pathogenic conditions in various tissues remain to be fully elucidated. Further research to understand the role of LECT2 in a tissue tropism-dependent manner would facilitate the development of LECT2 as a biomarker for diagnosis and therapeutic target.
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Affiliation(s)
- Sipin Zhu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Samuel Bennett
- School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Yihe Li
- School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Mei Liu
- School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia.,Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Jiake Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia
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