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Budkowska M, Ostrycharz-Jasek E, Cecerska-Heryć E, Dołęgowska K, Siennicka A, Nazarewski Ł, Rykowski P, Dołęgowska B. The Impact of Human Liver Transplantation on the Concentration of Fibroblast Growth Factors: FGF19 and FGF21. Int J Mol Sci 2025; 26:1299. [PMID: 39941067 PMCID: PMC11818808 DOI: 10.3390/ijms26031299] [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: 09/23/2024] [Revised: 01/24/2025] [Accepted: 01/31/2025] [Indexed: 02/16/2025] Open
Abstract
The multitude of processes in which the liver participates makes it vulnerable to many serious diseases, which can lead to chronic organ failure. Modern medicine bases the treatment of end-stage liver failure on liver transplantation. To ensure the proper functioning of the transplanted liver, a balance of cellular and immunological processes and appropriate concentrations of many different factors are necessary, including, among others, fibroblast growth factors (FGFs). Over the last several years, studies have focused on some FGF growth factors, i.e., FGF19 and FGF21. These two growth factors belong to the FGF19 subfamily, and we concentrate on these two factors in our work. These factors diffuse away from the site of secretion into the blood, acting as hormones. FGF19 is a growth factor with a high therapeutic potential, involved in the homeostasis of bile acids necessary to maintain the proper function of the transplanted liver. FGF21, in turn, plays an important role in regulating lipid and glucose homeostasis. This study aimed to evaluate changes in the concentration of growth factors FGF19 and FGF21 in the plasma of 84 patients before, 24 h, and 2 weeks after liver transplantation (ELISA test was used). Additionally, the correlations of the basic laboratory parameters-alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), alkaline phosphatase (ALP), total bilirubin, C-reactive protein (CRP), albumin and hemoglobin (Hb)-with FGF19 and FGF21 were determined. Our studies noted statistically significant changes in FGF19 and FGF21 concentrations before, 24 h, and 2 weeks after liver transplantation. The highest values for FGF19 before liver transplantation and the lowest values 24 h after this surgery were observed for FGF21; the highest concentrations were observed the day after liver transplantation, and the lowest were observed immediately before surgery. Observations of increases and decreases in the concentration of the examined factors at individual time points (before and after transplantation) allow us to suspect that FGF19 has an adaptive and protective function toward the transplanted liver. At the same time, FGF21 may affect the regenerative mechanisms of the damaged organ.
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Affiliation(s)
- Marta Budkowska
- Department of Medical Analytics, Pomeranian Medical University, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Ewa Ostrycharz-Jasek
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland;
- Doctoral School, University of Szczecin, 70-383 Szczecin, Poland
- Molecular Biology and Biotechnology Center, University of Szczecin, 71-412 Szczecin, Poland
| | - Elżbieta Cecerska-Heryć
- Department of Laboratory Medicine, Pomeranian Medical University, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (E.C.-H.); (B.D.)
| | - Katarzyna Dołęgowska
- Department of Immunology Diagnostics, Pomeranian Medical University, Al. Powstanców Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Aldona Siennicka
- Department of Medical Analytics, Pomeranian Medical University, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Łukasz Nazarewski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, ul Banacha 1a, 02-097 Warsaw, Poland; (Ł.N.); (P.R.)
| | - Paweł Rykowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, ul Banacha 1a, 02-097 Warsaw, Poland; (Ł.N.); (P.R.)
| | - Barbara Dołęgowska
- Department of Laboratory Medicine, Pomeranian Medical University, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (E.C.-H.); (B.D.)
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Bouju A, Nusse R, Wu PV. A primer on the pleiotropic endocrine fibroblast growth factor FGF19/FGF15. Differentiation 2024; 140:100816. [PMID: 39500656 DOI: 10.1016/j.diff.2024.100816] [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: 06/18/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 12/14/2024]
Abstract
Fibroblast Growth Factor 19 (FGF19) is a member of the Fibroblast Growth Factor (FGF) family, known for its role in various cellular processes including embryonic development and metabolic regulation. FGF19 functions as an endocrine factor, influencing energy balance, bile acid synthesis, glucose and lipid metabolism, as well as cell proliferation. FGF19 has a conserved structure typical of FGFs but exhibits unique features. Unlike most FGFs, which act locally, FGF19 travels through the bloodstream to distant targets including the liver. Its interaction with the β-Klotho (KLB) co-receptor and FGF Receptor 4 (FGFR4) in hepatocytes or FGFR1c in extrahepatic tissues initiates signaling cascades crucial for its biological functions. Although the mouse ortholog, FGF15, diverges significantly from human FGF19 in protein sequence and receptor binding, studies of FGF15-deficient mice have led to a better understanding of the proteins' role in bile acid regulation, metabolism, and embryonic development. Overexpression studies in transgenic mice have further revealed roles in not only ameliorating metabolic diseases but also in promoting hepatocyte proliferation and tumorigenesis. This review summarizes the gene and protein structure of FGF19/15, its expression patterns, phenotypes in mutant models, and implication in human diseases, providing insights into potential therapeutic strategies targeting the FGF19 signaling pathway.
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Affiliation(s)
- Agathe Bouju
- Department of Developmental Biology, Howard Hughes Medical Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA; Sorbonne University, Paris, France
| | - Roel Nusse
- Department of Developmental Biology, Howard Hughes Medical Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Peng V Wu
- Department of Developmental Biology, Howard Hughes Medical Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA.
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Shi X, Zheng Q, Wang X, Guo W, Lin Z, Gao Y, Shore E, Martin RC, Lv G, Li Y. Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice. SCIENCE ADVANCES 2024; 10:eado9311. [PMID: 39441934 PMCID: PMC11498219 DOI: 10.1126/sciadv.ado9311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 09/17/2024] [Indexed: 10/25/2024]
Abstract
Metabolic dysfunction-associated steatohepatitis is well accepted as a potential precursor of hepatocellular carcinoma. Previously, we reported that fibroblast growth factor 21 (FGF21) revealed a novel anti-inflammatory activity via inhibiting the TLR4-IL-17A signaling, which could be a potential anticarcinogenetic mechanism to prevent to MASH-HCC transition. Here, we set out to determine whether FGF21 has a major impact on Kupffer cells' (KCs) ability during MASH-HCC transition. We found aberrant hepatic FGF21 and KC pool in human MASH-HCC. Lack of FGF21 up-regulated ALOX15, which converted the oxidized fatty acids to induce excessive KC death and mobilization of monocyte-derived macrophages (MoMFs) for KC replacement. Lack of FGF21 oversupplied free fatty acids for sphingosine-1-phosphate (S1P) cascade synthesis to mediate MASH-HCC transition via S1P-YAP signaling and cross-talk between tumor cells and macrophages. In conclusion, lack of FGF21 accelerated MASH-HCC transition via the S1P-AP signaling. Compromised MoMFs could present as tumor-associated macrophage phenotype rendering tumor immune microenvironment for MASH-HCC transition.
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Affiliation(s)
- Xiaoju Shi
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China
| | - Qianqian Zheng
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang 110122, China
| | - Xingtong Wang
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Guo
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ziqi Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Yonglin Gao
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Emily Shore
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Robert C. Martin
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China
| | - Yan Li
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
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Bai Y, Zhang J, Li J, Liao M, Zhang Y, Xia Y, Wei Z, Dai Y. Silibinin, a commonly used therapeutic agent for non-alcohol fatty liver disease, functions through upregulating intestinal expression of fibroblast growth factor 15/19. Br J Pharmacol 2024; 181:3663-3684. [PMID: 38839561 DOI: 10.1111/bph.16431] [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: 02/22/2023] [Revised: 09/15/2023] [Accepted: 10/16/2023] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND AND PURPOSE Silibinin is used to treat non-alcohol fatty liver disease (NAFLD) despite having rapid liver metabolism. Therefore, we investigated the role of the intestine in silibinin mechanism of action. EXPERIMENTAL APPROACH NAFLD mice model was established by feeding them with a high-fat diet (HFD). Liver pathological were examined using H&E and oil red O staining. Tissue distribution of silibinin was detected by LC-MS/MS. SiRNA was employed for gene silencing and plasmid was used for gene overexpression. ChIP-qPCR assay was performed to detect the levels of histone acetylation. Recombinant adeno-associated virus 9-short hairpin-fibroblast growth factor (FGF)-15 and -farnesoid X receptor (FXR; NR1H4) were used to knockdown expression of FGF-15 and FXR. KEY RESULTS Oral silibinin significantly reversed NAFLD in mice, although liver concentration was insufficient for reduction of lipid accumulation in hepatocytes. Among endogenous factors capable of reversing NAFLD, the expression of Fgf-15 was selectively up-regulated by silibinin in ileum and colon of mice. When intestinal expression of Fgf-15 was knocked down, protection of silibinin against lipid accumulation and injury of livers nearly disappeared. Silibinin could reduce activity of histone deacetylase 2 (HDAC2), enhance histone acetylation in the promoter region of FXR and consequently increase intestinal expression of FGF-15/19. CONCLUSION AND IMPLICATIONS Oral silibinin selectively promotes expression of FGF-15/19 in ileum by enhancing transcription of FXR via reduction of HDAC2 activity, and FGF-15/19 enters into circulation to exert anti-NAFLD action. As the site of action is the intestine this would explain the discrepancy between pharmacodynamics and pharmacokinetics of silibinin.
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Affiliation(s)
- Yujie Bai
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jing Zhang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jialin Li
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Minghui Liao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yajing Zhang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yufeng Xia
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zhifeng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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Aydin Ö, Meijnikman AS, de Jonge PA, van Stralen K, Börger H, Okur K, Iqbal Z, Warmbrunn MV, Acherman YIZ, Bruin S, Winkelmeijer M, Schimmel AWM, Holst JJ, Poulsen SS, Bäckhed F, Nieuwdorp M, Groen AK, Gerdes VEA. Post-Bariatric Hypoglycemia: an Impaired Metabolic Response to a Meal. Obes Surg 2024; 34:3796-3806. [PMID: 39153140 PMCID: PMC11481667 DOI: 10.1007/s11695-024-07309-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: 02/12/2024] [Revised: 05/09/2024] [Accepted: 05/23/2024] [Indexed: 08/19/2024]
Abstract
AIMS/HYPOTHESIS Post-bariatric hypoglycemia (PBH) is caused by postprandial hyperinsulinemia, due to anatomical alterations and changes in post-prandial metabolism after bariatric surgery. The mechanisms underlying the failing regulatory and compensatory systems are unclear. In this study, we investigated the differences in post-prandial hormones and metabolic profiles between patients with and without PBH. METHODS We performed a mixed meal test (MMT) in 63 subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery. Blood was withdrawn at 0, 10, 20, 30, 60, and 120 min after ingestion of a standardized meal. Glucose, insulin, GLP-1, FGF-19, and FGF-21 were measured and untargeted metabolomics analysis was performed on blood plasma to analyze which hormonal and metabolic systems were altered between patients with and without PBH. RESULTS Out of 63, a total of 21 subjects (33%) subjects developed PBH (glucose < 3.1 mmol/L) after surgery. Decreased glucose and increased insulin excursions during MMT were seen in PBH (p < 0.05). GLP-1, FGF-19, and FGF-21 were elevated after surgery (p < 0.001), but did not differ between PBH and non-PBH groups. We identified 20 metabolites possibly involved in carbohydrate metabolism which differed between the two groups, including increased carnitine and acylcholines in PBH. CONCLUSION Overall, 33% of the subjects developed PBH 1 year after RYGB surgery. While GLP-1, FGF-19, and FGF-21 were similar in PBH and non-PBH patients, metabolomics analysis revealed changes in carnitine and acyclcholines that are possibly involved in energy metabolism, which may play a role in the occurrence of PBH.
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Affiliation(s)
- Ömrüm Aydin
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Abraham S Meijnikman
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Patrick A de Jonge
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Karlijn van Stralen
- Department of Scientific Research, Spaarne Gasthuis, Hoofddorp, the Netherlands
| | - Hanneke Börger
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Kadriye Okur
- Department of Bariatric Surgery, Spaarne Gasthuis, Hoofddorp, the Netherlands
| | - Zainab Iqbal
- Cardiometabolic Research, Vrije Universiteit, Amsterdam, the Netherlands
| | - Moritz V Warmbrunn
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Yair I Z Acherman
- Department of Bariatric Surgery, Spaarne Gasthuis, Hoofddorp, the Netherlands
| | - Sjoerd Bruin
- Department of Bariatric Surgery, Spaarne Gasthuis, Hoofddorp, the Netherlands
| | - Maaike Winkelmeijer
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Alinda W M Schimmel
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | - Steen S Poulsen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Fredrik Bäckhed
- Department of Cardiovascular and Metabolic Research, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Max Nieuwdorp
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Albert K Groen
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Victor E A Gerdes
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands.
- Department of Bariatric Surgery, Spaarne Gasthuis, Hoofddorp, the Netherlands.
- Department of Internal Medicine, Spaarne Gasthuis, Hoofddorp, the Netherlands.
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Phan P, Ternier G, Edirisinghe O, Kumar TKS. Exploring endocrine FGFs - structures, functions and biomedical applications. INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY 2024; 15:68-99. [PMID: 39309613 PMCID: PMC11411148 DOI: 10.62347/palk2137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/17/2024] [Indexed: 09/25/2024]
Abstract
The family of fibroblast growth factors (FGFs) consists of 22 members with diverse biological functions in cells, from cellular development to metabolism. The family can be further categorized into three subgroups based on their three modes of action. FGF19, FGF21, and FGF23 are endocrine FGFs that act in a hormone-like/endocrine manner to regulate various metabolic activities. However, all three members of the endocrine family require both FGF receptors (FGFRs) and klotho co-receptors to elicit their functions. α-klotho and β-klotho act as scaffolds to bring endocrine FGFs closer to their receptors (FGFRs) to form active complexes. Numerous novel studies about metabolic FGFs' structures, mechanisms, and physiological insights have been published to further understand the complex molecular interactions and physiological activities of endocrine FGFs. Herein, we aim to review the structures, physiological functions, binding mechanisms to cognate receptors, and novel biomedical applications of endocrine FGFs in recent years.
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Affiliation(s)
- Phuc Phan
- Department of Chemistry and Biochemistry, Fulbright College of Art and Sciences, University of ArkansasFayetteville, AR 72701, USA
| | - Gaёtane Ternier
- Department of Chemistry and Biochemistry, Fulbright College of Art and Sciences, University of ArkansasFayetteville, AR 72701, USA
| | - Oshadi Edirisinghe
- Cell and Molecular Biology Program, University of ArkansasFayetteville, AR 72701, USA
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Sadowska A, Poniedziałek-Czajkowska E, Mierzyński R. The Role of the FGF19 Family in the Pathogenesis of Gestational Diabetes: A Narrative Review. Int J Mol Sci 2023; 24:17298. [PMID: 38139126 PMCID: PMC10743406 DOI: 10.3390/ijms242417298] [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: 10/27/2023] [Revised: 12/02/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. Understanding the pathogenesis and appropriate diagnosis of GDM enables the implementation of early interventions during pregnancy that reduce the risk of maternal and fetal complications. At the same time, it provides opportunities to prevent diabetes, metabolic syndrome, and cardiovascular diseases in women with GDM and their offspring in the future. Fibroblast growth factors (FGFs) represent a heterogeneous family of signaling proteins which play a vital role in cell proliferation and differentiation, repair of damaged tissues, wound healing, angiogenesis, and mitogenesis and also affect the regulation of carbohydrate, lipid, and hormone metabolism. Abnormalities in the signaling function of FGFs may lead to numerous pathological conditions, including metabolic diseases. The FGF19 subfamily, also known as atypical FGFs, which includes FGF19, FGF21, and FGF23, is essential in regulating metabolic homeostasis and acts as a hormone while entering the systemic circulation. Many studies have pointed to the involvement of the FGF19 subfamily in the pathogenesis of metabolic diseases, including GDM, although the results are inconclusive. FGF19 and FGF21 are thought to be associated with insulin resistance, an essential element in the pathogenesis of GDM. FGF21 may influence placental metabolism and thus contribute to fetal growth and metabolism regulation. The observed relationship between FGF21 and increased birth weight could suggest a potential role for FGF21 in predicting future metabolic abnormalities in children born to women with GDM. In this group of patients, different mechanisms may contribute to an increased risk of cardiovascular diseases in women in later life, and FGF23 appears to be their promising early predictor. This study aims to present a comprehensive review of the FGF19 subfamily, emphasizing its role in GDM and predicting its long-term metabolic consequences for mothers and their offspring.
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Affiliation(s)
| | - Elżbieta Poniedziałek-Czajkowska
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland; (A.S.); (R.M.)
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Wang R, Wang J, Zhang Z, Ma B, Sun S, Gao L, Gao G. FGF21 alleviates endothelial mitochondrial damage and prevents BBB from disruption after intracranial hemorrhage through a mechanism involving SIRT6. Mol Med 2023; 29:165. [PMID: 38049769 PMCID: PMC10696847 DOI: 10.1186/s10020-023-00755-x] [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: 06/04/2023] [Accepted: 11/09/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Disruption of the BBB is a harmful event after intracranial hemorrhage (ICH), and this disruption contributes to a series of secondary injuries. We hypothesized that FGF21 may have protective effects after intracranial hemorrhage (ICH) and investigated possible underlying molecular mechanisms. METHODS Blood samples of ICH patients were collected to determine the relationship between the serum level of FGF21 and the [Formula: see text]GCS%. Wild-type mice, SIRT6flox/flox mice, endothelial-specific SIRT6-homozygous-knockout mice (eSIRT6-/- mice) and cultured human brain microvascular endothelial cells (HCMECs) were used to determine the protective effects of FGF21 on the BBB. RESULTS We obtained original clinical evidence from patient data identifying a positive correlation between the serum level of FGF21 and [Formula: see text]GCS%. In mice, we found that FGF21 treatment is capable of alleviating BBB damage, mitigating brain edema, reducing lesion volume and improving neurofunction after ICH. In vitro, after oxyhemoglobin injury, we further explored the protective effects of FGF21 on endothelial cells (ECs), which are a significant component of the BBB. Mitochondria play crucial roles during various types of stress reactions. FGF21 significantly improved mitochondrial biology and function in ECs, as evidenced by alleviated mitochondrial morphology damage, reduced ROS accumulation, and restored ATP production. Moreover, we found that the crucial regulatory mitochondrial factor deacylase sirtuin 6 (SIRT6) played an irreplaceable role in the effects of FGF21. Using endothelial-specific SIRT6-knockout mice, we found that SIRT6 deficiency largely diminished these neuroprotective effects of FGF21. Then, we revealed that FGF21 might promote the expression of SIRT6 via the AMPK-Foxo3a pathway. CONCLUSIONS We provide the first evidence that FGF21 is capable of protecting the BBB after ICH by improving SIRT6-mediated mitochondrial homeostasis.
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Affiliation(s)
- Runfeng Wang
- Department of Neurosurgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Jin Wang
- Department of Neurosurgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Zhiguo Zhang
- Department of Neurosurgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Bo Ma
- Department of Neurosurgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Shukai Sun
- Department of Neurosurgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Li Gao
- Department of Neurosurgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Guodong Gao
- Department of Neurosurgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, 710038, Shaanxi, China.
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Malick WA, Do R, Rosenson RS. Severe hypertriglyceridemia: Existing and emerging therapies. Pharmacol Ther 2023; 251:108544. [PMID: 37848164 DOI: 10.1016/j.pharmthera.2023.108544] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 09/19/2023] [Accepted: 09/28/2023] [Indexed: 10/19/2023]
Abstract
Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events.
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Affiliation(s)
- Waqas A Malick
- Metabolism and Lipids Program, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ron Do
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Robert S Rosenson
- Metabolism and Lipids Program, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Wang J, Luo LZ, Liang DM, Guo C, Huang ZH, Jian XH, Wen J. Recent progress in understanding mitokines as diagnostic and therapeutic targets in hepatocellular carcinoma. World J Clin Cases 2023; 11:5416-5429. [PMID: 37637689 PMCID: PMC10450380 DOI: 10.12998/wjcc.v11.i23.5416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 07/14/2023] [Accepted: 08/03/2023] [Indexed: 08/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide and the leading contributor to cancer-related deaths. The progression and metastasis of HCC are closely associated with altered mitochondrial metabolism, including mitochondrial stress response. Mitokines, soluble proteins produced and secreted in response to mitochondrial stress, play an essential immunomodulatory role. Immunotherapy has emerged as a crucial treatment option for HCC. However, a positive response to therapy is typically dependent on the interaction of tumor cells with immune regulation within the tumor microenvironment. Therefore, exploring the specific immunomodulatory mechanisms of mitokines in HCC is essential for improving the efficacy of immunotherapy. This study provides a comprehensive overview of the association between HCC and the immune microenvironment and highlights recent progress in understanding the involvement of mitochondrial function in preserving liver function. In addition, a systematic review of mitokines-mediated immunomodulation in HCC is presented. Finally, the potential diagnostic and therapeutic roles of mitokines in HCC are prospected and summarized. Recent progress in mitokine research represents a new prospect for mitochondrial therapy. Considering the potential of mitokines to regulate immune function, investigating them as a relevant molecular target holds great promise for the diagnosis and treatment of HCC.
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Affiliation(s)
- Jiang Wang
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Lan-Zhu Luo
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Dao-Miao Liang
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Chao Guo
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zhi-Hong Huang
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Xiao-Hong Jian
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410013, Hunan Province, China
| | - Jie Wen
- Department of Pediatric Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
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11
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Smirnova OV, Kasparova IE. The role of adipocytokines in the development of non-alcoholic fatty liver disease in children and adolescents. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2023:254-262. [DOI: 10.21518/ms2022-061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Over the past 20 years, the proportion of overweight and obese children and adolescents has increased significantly in most countries. Obesity represents a major cardiometabolic risk and is closely associated with comorbidities such as hypertension, hyperlipidemia, hyperinsulinemia, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). There is a lot of uncertainty regarding the diagnosis of metabolic syndrome in children, mainly due to the various and conflicting definitions that have been proposed. The prevalence of metabolic syndrome varied significantly in children (from 6 to 39%) depending on the applied definition criteria. According to these definitions, only 2% of children met all the criteria for metabolic syndrome. Over the past decade, studies have shown that, in parallel with the increase in the prevalence of obesity in the pediatric population, NAFLD has become the most common form of liver disease in childhood. In NAFLD, inflammatory cytokines/adipokines and other factors lead to steatohepatitis and/or fibrosis. Recently, several adipocytokines and inflammatory cytokines have been identified with significant positive (leptin, chemerin, vaspin, TNF-α, IL-6 and IL-8) or negative (adiponectin) associations with metabolic risk factors. Some of them can be considered as pathophysiological factors linking obesity and its complications such as insulin resistance and NAFLD. However, data on other adipocytokines and their role in metabolism remain controversial and partially unknown, especially with regard to their role in childhood (resistin, NAMPT, FGF-21, A-FABP, RBP4, lipocalin-2, omentin-1, hsCRP). Adipocytokines are a novel and powerful tool not only for the diagnosis and stratification of NAFLD and the metabolic syndrome, but also as a potential therapeutic target. Adipocytokine therapy requires further study in all patients with metabolic syndrome and NAFLD, especially in children and adolescents.
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Affiliation(s)
- O. V. Smirnova
- Federal Research Center “Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences, Separate Subdivision “Scientific Research Institute of medical problems of the North”
| | - I. E. Kasparova
- Federal Research Center “Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences, Separate Subdivision “Scientific Research Institute of medical problems of the North”
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12
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Gill EL, Wang J, Viaene AN, Master SR, Ganetzky RD. Methodologies in Mitochondrial Testing: Diagnosing a Primary Mitochondrial Respiratory Chain Disorder. Clin Chem 2023:7143230. [PMID: 37099687 DOI: 10.1093/clinchem/hvad037] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 03/03/2023] [Indexed: 04/28/2023]
Abstract
BACKGROUND Mitochondria are cytosolic organelles within most eukaryotic cells. Mitochondria generate the majority of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OxPhos). Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) lead to defects in OxPhos and physiological malfunctions (Nat Rev Dis Primer 2016;2:16080.). Patients with primary mitochondrial disorders (PMD) experience heterogeneous symptoms, typically in multiple organ systems, depending on the tissues affected by mitochondrial dysfunction. Because of this heterogeneity, clinical diagnosis is challenging (Annu Rev Genomics Hum Genet 2017;18:257-75.). Laboratory diagnosis of mitochondrial disease depends on a multipronged analysis that can include biochemical, histopathologic, and genetic testing. Each of these modalities has complementary strengths and limitations in diagnostic utility. CONTENT The primary focus of this review is on diagnosis and testing strategies for primary mitochondrial diseases. We review tissue samples utilized for testing, metabolic signatures, histologic findings, and molecular testing approaches. We conclude with future perspectives on mitochondrial testing. SUMMARY This review offers an overview of the current biochemical, histologic, and genetic approaches available for mitochondrial testing. For each we review their diagnostic utility including complementary strengths and weaknesses. We identify gaps in current testing and possible future avenues for test development.
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Affiliation(s)
- Emily L Gill
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Jing Wang
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Angela N Viaene
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Stephen R Master
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Rebecca D Ganetzky
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States
- Division of Human Genetics, Children's Hospital of Philadelphia, Mitochondrial Medicine Frontier Program, Philadelphia, PA, United States
- Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, United States
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13
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Malick WA, Waksman O, Do R, Koenig W, Pradhan AD, Stroes ESG, Rosenson RS. Clinical Trial Design for Triglyceride-Rich Lipoprotein-Lowering Therapies: JACC Focus Seminar 3/3. J Am Coll Cardiol 2023; 81:1646-1658. [PMID: 37076219 DOI: 10.1016/j.jacc.2023.02.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 04/21/2023]
Abstract
Triglyceride-rich lipoproteins (TRLs) are a source of residual risk in patients with atherosclerotic cardiovascular disease, and are indirectly correlated with triglyceride (TG) levels. Previous clinical trials studying TG-lowering therapies have either failed to reduce major adverse cardiovascular events or shown no linkage of TG reduction with event reduction, particularly when these agents were tested on a background of statin therapy. Limitations in trial design may explain this lack of efficacy. With the advent of new RNA-silencing therapies in the TG metabolism pathway, there is renewed focus on reducing TRLs for major adverse cardiovascular event reduction. In this context, the pathophysiology of TRLs, pharmacological effects of TRL-lowering therapies, and optimal design of cardiovascular outcomes trials are major considerations.
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Affiliation(s)
- Waqas A Malick
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ori Waksman
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ron Do
- Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Wolfgang Koenig
- Deutsches Herzzentrum Munchen, Technische Universitat Munchen, Munich, DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
| | - Aruna D Pradhan
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Division of Cardiovascular Medicine, VA Boston Medical Center, Boston, Massachusetts, USA
| | - Erik S G Stroes
- Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Robert S Rosenson
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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14
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Drexler S, Cai C, Hartmann AL, Moch D, Gaitantzi H, Ney T, Kraemer M, Chu Y, Zheng Y, Rahbari M, Treffs A, Reiser A, Lenoir B, Valous NA, Jäger D, Birgin E, Sawant TA, Li Q, Xu K, Dong L, Otto M, Itzel T, Teufel A, Gretz N, Hawinkels LJAC, Sánchez A, Herrera B, Schubert R, Moshage H, Reissfelder C, Ebert MPA, Rahbari N, Breitkopf-Heinlein K. Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes. Mol Cell Endocrinol 2023; 570:111934. [PMID: 37085108 DOI: 10.1016/j.mce.2023.111934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 04/06/2023] [Accepted: 04/16/2023] [Indexed: 04/23/2023]
Abstract
Bone morphogenetic protein (BMP)-9, a member of the TGFβ-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients' samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis.
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Affiliation(s)
- Stephan Drexler
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Chen Cai
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Anna-Lena Hartmann
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Denise Moch
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Haristi Gaitantzi
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Theresa Ney
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Malin Kraemer
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Yuan Chu
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Yuwei Zheng
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Mohammad Rahbari
- German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, 69120, Heidelberg, Germany
| | - Annalena Treffs
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Alena Reiser
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Bénédicte Lenoir
- Clinical Cooperation Unit "Applied Tumor Immunity", German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Nektarios A Valous
- Clinical Cooperation Unit "Applied Tumor Immunity", German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Dirk Jäger
- Clinical Cooperation Unit "Applied Tumor Immunity", German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases and Heidelberg University Hospital, 69120, Heidelberg, Germany
| | - Emrullah Birgin
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Tejas A Sawant
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Qi Li
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Fengtai District, Beijing, China
| | - Keshu Xu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Av., Wuhan, Hubei, China
| | - Lingyue Dong
- Department of Cell Biology, Capital Medical University, Beijing, Fengtai, 100054, China
| | - Mirko Otto
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Timo Itzel
- Division of Hepatology, Division of Clinical Bioinformatics, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany; Clinical Cooperation Unit "Healthy Metabolism", Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, 69120, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Division of Hepatology, Division of Clinical Bioinformatics, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany; Clinical Cooperation Unit "Healthy Metabolism", Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, 69120, Heidelberg University, Mannheim, Germany
| | - Norbert Gretz
- Medical Faculty Mannheim, Medical Research Center, Heidelberg University, 68167, Mannheim, Germany
| | - Lukas J A C Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands
| | - Aránzazu Sánchez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute Hospital Clínico San Carlos (IdISSC), E-28040, Madrid, Spain
| | - Blanca Herrera
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute Hospital Clínico San Carlos (IdISSC), E-28040, Madrid, Spain
| | - Rudolf Schubert
- Physiology, Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, 86159, Augsburg, Germany
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9712 CP, Groningen, the Netherlands
| | - Christoph Reissfelder
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany; Clinical Cooperation Unit "Healthy Metabolism", Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, 69120, Heidelberg University, Mannheim, Germany
| | - Matthias P A Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany; Clinical Cooperation Unit "Healthy Metabolism", Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, 69120, Heidelberg University, Mannheim, Germany
| | - Nuh Rahbari
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Katja Breitkopf-Heinlein
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
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15
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Garay Guerrero J, Ishida E, Shibusawa N, Lei X, Yamada S, Horiguchi K, Yamada M. Role of Thyrotropin-Releasing Hormone in Regulating Fibroblast Growth Factor 21 in Mouse Pancreatic β Cells. Thyroid 2023; 33:251-260. [PMID: 36333931 DOI: 10.1089/thy.2022.0144] [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] [Indexed: 11/06/2022]
Abstract
Background: Thyrotropin-releasing hormone (TRH) is primarily produced in the hypothalamus and regulates the thyrotropin secretion from the pituitary. TRH is distributed ubiquitously in the extrahypothalamic region, especially in pancreatic islets, while its physiological role remains nebulous. We have previously established a TRH-deficient mouse model, and showed impaired glucose tolerance and downregulated expression of fibroblast growth factor 21 (FGF21) in islets. Recent studies have demonstrated the physiological roles of pancreatic FGF21. Therefore, in this study, we elucidate the direct functions of TRH in pancreatic islets via the regulation of FGF21. Methods: To explore the functions of TRH in pancreatic islets, a microarray analysis using isolated islets from TRH-knockout mice was conducted. The regulatory mechanism of TRH in pancreatic FGF21 was investigated using islet cell lines; reverse transcription-quantitative polymerase chain reaction and Western blotting were used to determine the mRNA and protein expression levels of FGF21 in pancreatic islets and islet cell lines. Induction of FGF21 expression by TRH treatment was examined in vitro. To identify the transcription factors binding to the region responsible for TRH-induced stimulation of the FGF21 promoter, electromobility shift assays were conducted. Results: Among the detected and considerably changed genes in microarray, FGF21 was the most consistently downregulated in TRH-deficient mice islets. FGF21 was strongly co-expressed with insulin in mouse islets, and TRH stimulated endogenous Fgf21 mRNA expression in the islet cell line βHC9. The E-box site in the FGF21 promoter was responsible for TRH-induced stimulation via the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. The transcription factor upstream stimulatory factor 1 (USF1) could specifically bind to the E-box site. Overexpression of USF1 increased FGF21 promoter activity. Conclusion: FGF21 was transcriptionally upregulated by TRH through the ERK1/2 and USF1 pathways in pancreatic β cells.
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Affiliation(s)
- Jennifer Garay Guerrero
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Emi Ishida
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Nobuyuki Shibusawa
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Xiao Lei
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Sayaka Yamada
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Kazuhiko Horiguchi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Masanobu Yamada
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
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16
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Tian C, Zhao J, Liu D, Sun J, Ji C, Jiang Q, Li H, Wang X, Sun Y. Identification of metabolism-related genes for predicting peritoneal metastasis in patients with gastric cancer. BMC Genom Data 2022; 23:84. [PMID: 36503378 PMCID: PMC9743729 DOI: 10.1186/s12863-022-01096-0] [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: 03/25/2022] [Accepted: 10/25/2022] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE The reprogramming of metabolism is an important factor in the metastatic process of cancer. In our study, we intended to investigate the predictive value of metabolism-related genes (MRGs) in recurrent gastric cancer (GC) patients with peritoneal metastasis. METHODS The sequencing data of mRNA of GC patients were obtained from Asian Cancer Research Group (ACRG) and the GEO databases (GSE53276). The differentially expressed MRGs (DE-MRGs) between a cell line without peritoneal metastasis (HSC60) and one with peritoneal metastasis (60As6) were analyzed with the Limma package. According to the LASSO regression, eight MRGs were identified as crucially related to peritoneal seeding recurrence in patients. Then, disease free survival related genes were screened using Cox regression, and a promising prognostic model was constructed based on 8 MRGs. We trained and verified it in two independent cohort. RESULTS We confirmed 713 DE-MRGs and the enriched pathways. Pathway analysis found that the MRG-related pathways were related to tumor metabolism development. With the help of Kaplan-Meier analysis, we found that the group with higher risk scores had worse rates of peritoneal seeding recurrence than the group with lower scores in the cohorts. CONCLUSIONS This study developed an eight-gene signature correlated with metabolism that could predict peritoneal seeding recurrence for GC patients. This signature could be a promising prognostic model, providing better strategy in treatment.
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Affiliation(s)
- Chenyu Tian
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Junjie Zhao
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dan Liu
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Sun
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chengbo Ji
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Quan Jiang
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Haojie Li
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xuefei Wang
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yihong Sun
- grid.413087.90000 0004 1755 3939Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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17
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Ziomber-Lisiak A, Piana K, Ostachowicz B, Wróbel P, Kasprzyk P, Kaszuba-Zwoińska J, Baranowska-Chowaniec A, Juszczak K, Szczerbowska-Boruchowska M. The New Markers of Early Obesity-Related Organ and Metabolic Abnormalities. Int J Mol Sci 2022; 23:13437. [PMID: 36362225 PMCID: PMC9658002 DOI: 10.3390/ijms232113437] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/19/2022] [Accepted: 10/28/2022] [Indexed: 12/25/2023] Open
Abstract
The objective of our study was to identify new markers related to excessive body adiposity and its early consequences. For this purpose we determined serum FGF-19 and FGF-21 concentrations in obese rats, whose role in the pathogenesis of obesity is not yet established. In addition, a total reflection X-ray fluorescence technique was applied to determine the elemental chemistry of certain tissues affected by obesity. Next, the new biochemical and molecular parameters were correlated with well-known obesity-related markers of metabolic abnormalities. Our obese rats were characterized by increased calorie consumption and body adiposity, hypercholesterolemia, elevated levels of liver enzymes and FGF-21, while the level of FGF-19 was reduced. Strong relationships between new hormones and established metabolic parameters were observed. Furthermore, we demonstrated that obesity had the greatest effect on elemental composition in the adipose tissue and liver and that rubidium (Rb) had the highest importance in distinguishing the studied groups of animals. Tissue Rb strongly correlated with both well-known and new markers of obesity. In conclusion, we confirmed serum FGF-19 and FGF-21 as useful new markers of obesity-related metabolic alternations and we robustly propose Rb as a novel indicator of excessive body adiposity and its early consequences. However, further investigations are encouraged to address this clinical issue.
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Affiliation(s)
- Agata Ziomber-Lisiak
- Chair of Pathophysiology, Faculty of Medicine, Jagiellonian University Medical College, ul. Czysta 18, 31-121 Krakow, Poland
| | - Kaja Piana
- Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Al. Mickiewicza 30, 30-059 Krakow, Poland
| | - Beata Ostachowicz
- Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Al. Mickiewicza 30, 30-059 Krakow, Poland
| | - Paweł Wróbel
- Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Al. Mickiewicza 30, 30-059 Krakow, Poland
| | - Paula Kasprzyk
- Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Al. Mickiewicza 30, 30-059 Krakow, Poland
| | - Jolanta Kaszuba-Zwoińska
- Chair of Pathophysiology, Faculty of Medicine, Jagiellonian University Medical College, ul. Czysta 18, 31-121 Krakow, Poland
| | - Agnieszka Baranowska-Chowaniec
- Chair of Pathophysiology, Faculty of Medicine, Jagiellonian University Medical College, ul. Czysta 18, 31-121 Krakow, Poland
| | - Kajetan Juszczak
- Department of Urology and Andrology, Collegium Medicum, Nicolaus Copernicus University, ul. M. Curie Skłodowskiej 9, 85-094 Bydgoszcz, Poland
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Bzdega K, Karolak JA. Phenotypic spectrum of FGF10-related disorders: a systematic review. PeerJ 2022; 10:e14003. [PMID: 36124135 PMCID: PMC9482362 DOI: 10.7717/peerj.14003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/13/2022] [Indexed: 01/19/2023] Open
Abstract
FGF10, as an FGFR2b-specific ligand, plays a crucial role during cell proliferation, multi-organ development, and tissue injury repair. The developmental importance of FGF10 has been emphasized by the identification of FGF10 abnormalities in human congenital disorders affecting different organs and systems. Single-nucleotide variants in FGF10 or FGF10-involving copy-number variant deletions have been reported in families with lacrimo-auriculo-dento-digital syndrome, aplasia of the lacrimal and salivary glands, or lethal lung developmental disorders. Abnormalities involving FGF10 have also been implicated in cleft lip and palate, myopia, or congenital heart disease. However, the exact developmental role of FGF10 and large phenotypic heterogeneity associated with FGF10 disruption remain incompletely understood. Here, we review human and animal studies and summarize the data on FGF10 mechanism of action, expression, multi-organ function, as well as its variants and their usefulness for clinicians and researchers.
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19
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Chrysavgis L, Giannakodimos I, Chatzigeorgiou A, Tziomalos K, Papatheodoridis G, Cholongitas E. The role of fibroblast growth factor 19 in the pathogenesis of nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2022; 16:835-849. [PMID: 36124827 DOI: 10.1080/17474124.2022.2127408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) has emerged as the predominant cause of chronic liver injury worldwide. Bile acids and their receptors are profoundly implicated in the pathogenesis of NAFLD and its progression to nonalcoholic steatohepatitis and cirrhosis. AREAS COVERED We conducted extensive literature search using PubMed database, and we summarized the relevant literature. We provided an overview of the fibroblast growth factor 19 (FGF-19)-farnesoid X receptor (FXR) axis and summarized the latest findings derived from animal and human studies concerning the impact of FGF-19 on NAFLD. EXPERT OPINION FGF-19, a nutritionally regulated endocrine post-prandial hormone, governs bile acid metabolism, lipid oxidation, lipogenesis, and energy homeostasis. As no approved medication for NAFLD exists, FGF-19 seems to be a propitious therapeutic opportunity for NAFLD, since its administration was associated with ameliorated results in hepatic steatosis, liver inflammation and fibrosis. Furthermore, promising results have been derived from clinical trials concerning the beneficial efficacy of FGF-19 on histological findings and laboratory parameters of NAFLD. However, we should bear in mind the pleiotropic effects of FGF-19 on various metabolically active tissues along with its potential tumorigenic reservoir. Further clinical research is required to determine the clinical application of FGF-19-based therapies on NAFLD.
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Affiliation(s)
- Lampros Chrysavgis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Ilias Giannakodimos
- First Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Athens, Greece
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20
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 150] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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21
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Research Progress of Fibroblast Growth Factor 21 in Fibrotic Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5042762. [PMID: 35677107 PMCID: PMC9168133 DOI: 10.1155/2022/5042762] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 05/04/2022] [Accepted: 05/10/2022] [Indexed: 11/24/2022]
Abstract
Fibrosis is a common pathological outcome of chronic injuries, characterized by excessive deposition of extracellular matrix components in organs, as seen in most chronic inflammatory diseases. At present, there is an increasing tendency of the morbidity and mortality of diseases caused by fibrosis, but the treatment measures for fibrosis are still limited. Fibroblast growth factor 21 (FGF21) belongs to the FGF19 subfamily, which also has the name endocrine FGFs because of their endocrine manner. In recent years, it has been found that plasma FGF21 level is significantly correlated with fibrosis progression. Furthermore, there is evidence that FGF21 has a pronounced antifibrotic effect in a variety of fibrotic diseases. This review summarizes the biological effects of FGF21 and discusses what is currently known about this factor and fibrosis disease, highlighting emerging insights that warrant further research.
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22
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Physiological and pathophysiological role of endocrine fibroblast growth factors. POSTEP HIG MED DOSW 2022. [DOI: 10.2478/ahem-2022-0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
The endocrine subfamily of fibroblast growth factors (FGF) includes three factors: FGF19, FGF21, FGF23. They act on distal tissues through FGF receptors (FGFRs). The FGFR activation requires two cofactors: α- and β-Klotho, which are structurally related single-pass transmembrane proteins. The endocrine FGFs regulate various metabolic processes involved in the regulation of glucose and lipid metabolism as well as bile acid circulation, vitamin D modulation, and phosphate homeostasis. The FGF-FGFR dysregulation is widely implicated in the pathogenesis of various disorders. Significant alterations in plasma FGF concentration are associated with the most prevalent chronic diseases, including dyslipidemia, type 2 diabetes, cardiovascular diseases, obesity, non-alcoholic fatty liver disease, diseases of the biliary tract, chronic kidney disease, inflammatory bowel disease, osteomalacia, various malignancies, and depression. Therefore, the endocrine FGFs may serve as disease predictors or biomarkers, as well as potential therapeutic targets. Currently, numerous analogues and inhibitors of endocrine FGFs are under development for treatment of various disorders, and recently, a human monoclonal antibody against FGF23 has been approved for treatment of X-linked hypophosphatemia. The aim of this review is to summarize the current data on physiological and pathophysiological actions of the endocrine FGF subfamily and recent research concerning the therapeutic potential of the endocrine FGF pathways.
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23
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Fiorucci S, Distrutti E. Linking liver metabolic and vascular disease via bile acid signaling. Trends Mol Med 2021; 28:51-66. [PMID: 34815180 DOI: 10.1016/j.molmed.2021.10.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 10/22/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder affecting over one quarter of the global population. Liver fat accumulation in NAFLD is promoted by increased de novo lipogenesis leading to the development of a proatherosclerotic lipid profile and atherosclerotic cardiovascular disease (CVD). The CVD component of NAFLD is the main determinant of patient outcome. The farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) are bile acid-activated receptors that modulate inflammation and lipid and glucose metabolism in the liver and CV system, and are thus potential therapeutic targets. We review bile acid signaling in liver, metabolic tissues, and the CV system, and we propose the development of dual FXR/GPBAR1 ligands, intestine-restricted FXR ligands, or statin combinations to limit side effects and effectively manage the liver and CV components of NAFLD.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Eleonora Distrutti
- Struttura Complessa di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
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24
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Dâmaso AR, Machado PP, Rhein SO, Masquio DCL, Oyama LM, Boldarine VT, de Oliveira GI, Tock L, Thivel D, da Silveira Campos RM. Effects of an interdisciplinary weight loss program on fibroblast growth factor 21 and inflammatory biomarkers in women with overweight and obesity. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:821-831. [PMID: 34762789 PMCID: PMC10065393 DOI: 10.20945/2359-3997000000419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Objective To investigate the effects of an interdisciplinary intervention on biomarkers of inflammation and their relationship with fibroblast growth factor 21 (FGF21) concentrations in women with overweight and obesity. Methods Thirty-one women were enrolled in a 12-week interdisciplinary weight loss program delivered by a team comprising an endocrinologist, nutritionist and exercise physiologist. Body composition; anthropometric measures; metabolic and inflammatory markers including adiponectin, leptin, and atrial natriuretic peptide (ANP) were assessed at baseline and post-therapy. The homeostasis model assessment of insulin resistance (HOMA-IR) and the homeostasis model assessment of adiponectin (HOMA-AD) were calculated. The participants were divided into two groups: those with increased FGF21, and those with decreased FGF21. Results The sample comprised women aged 32 ± 5 years with a body mass index of 33.64 ± 3.49 kg/m2. Body weight, waist circumference and leptin concentration were decreased in the whole sample after therapy. However, only the group with an increase in FGF21 concentration presented significant improvements in adiponectin concentration and adiponectin/leptin ratio. Moreover, although there was a reduction of leptin in both groups, it was greater in the increased FGF21 groups. There was a reduction in ANP in the decreased FGF21 group. Conclusion Changes in FGF21 concentrations were different among the women participating in the weight loss program, with some having increased levels and some reduced levels. Furthermore, improvements in adiponectin and the adiponectin/leptin ratio were found only in the group with increased FGF21 concentration.
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Affiliation(s)
- Ana Raimunda Dâmaso
- Programa de Pós-graduação em Nutrição, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil,
| | - Paola Próspero Machado
- Programa de Pós-graduação em Nutrição, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
| | - Samantha Ottani Rhein
- Programa de Pós-graduação em Nutrição, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
| | | | - Lila Missae Oyama
- Programa de Pós-graduação em Nutrição, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.,Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
| | - Valter Tadeu Boldarine
- Programa de Pós-graduação em Nutrição, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.,Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
| | | | - Lian Tock
- Grupo de Estudos da Obesidade (GEO/UNIFESP), Escola Paulista de Medicina, São Paulo, SP, Brasil
| | - David Thivel
- Clermont Auvergne University, EA 3533, Laboratory of the Metabolic Adaptations to Exercise under Physiological and Pathological Conditions (AME2P), Clermont-Ferrand, France; CRNH-Auvergne, Clermont-Ferrand, France
| | - Raquel Munhoz da Silveira Campos
- Departamento de Biociências, Universidade Federal de São Paulo, Campus Baixada Santista, Santos, SP, Brasil, .,Programa de Pós-Graduação Interdisciplinar em Ciências da Saúde, Universidade Federal de São Paulo, Campus Baixada Santista, Santos, SP, Brasil
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25
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Durnwald C, Mele L, Landon MB, Varner MW, Casey BM, Reddy UM, Wapner RJ, Rouse DJ, Tita ATN, Thorp JM, Chien EK, Saade GR, Peaceman AM, Blackwell SC. Fibroblast Growth Factor 21 and Metabolic Dysfunction in Women with a Prior Glucose-Intolerant Pregnancy. Am J Perinatol 2021; 38:1380-1385. [PMID: 32575141 PMCID: PMC7755696 DOI: 10.1055/s-0040-1712966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE We sought to determine if there is an association between fibroblast growth factor 21 (FGF21) levels and a history of gestational diabetes mellitus (GDM) in women with and without metabolic dysfunction, defined as a diagnosis of metabolic syndrome or type 2 diabetes (T2DM), 5 to 10 years following participation in a multiple cohort GDM study. STUDY DESIGN At 5 to 10 years after index pregnancy, women underwent a follow-up visit and were categorized as having no metabolic syndrome, metabolic syndrome, or T2DM. FGF21 levels were compared between women who did and did not have a history of GDM using multivariable linear regression. RESULTS Among 1,889 women, 950 underwent follow-up and 796 had plasma samples analyzed (413 GDM and 383 non-GDM). Total 30.7% of women had been diagnosed with T2DM or metabolic syndrome. Overall, there was no difference in median FGF21 levels in pg/mL between the prior GDM and non-GDM groups (p = 0.12), and the lack of association was observed across all three metabolic categories at follow-up (p for interaction = 0.70). CONCLUSION There was no association between FGF21 levels and prior history of mild GDM in women with and without metabolic dysfunction 5 to 10 years after the index pregnancy (ClinicalTrials.gov number, NCT00069576, original trial).
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Affiliation(s)
- Celeste Durnwald
- Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lisa Mele
- George Washington University Biostatistics Center, Washington, District of Columbia
| | - Mark B. Landon
- Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio
| | - Michael W. Varner
- Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah
| | - Brian M. Casey
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Uma M. Reddy
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.M.R.), Bethesda, MD
| | - Ronald J. Wapner
- Department of Obstetrics and Gynecology, Columbia University, New York, New York
| | - Dwight J. Rouse
- Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island
| | - Alan T. N. Tita
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama
| | - John M. Thorp
- Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina
| | - Edward K. Chien
- Department of Obstetrics and Gynecology, MetroHealth Medical Center – Case Western Reserve University, Cleveland, Ohio
| | - George R. Saade
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
| | - Alan M. Peaceman
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
| | - Sean C. Blackwell
- Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston-Children’s Memorial Hermann Hospital, Houston, Texas
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26
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Moos WH, Faller DV, Glavas IP, Harpp DN, Kamperi N, Kanara I, Kodukula K, Mavrakis AN, Pernokas J, Pernokas M, Pinkert CA, Powers WR, Steliou K, Tamvakopoulos C, Vavvas DG, Zamboni RJ, Sampani K. Pathogenic mitochondrial dysfunction and metabolic abnormalities. Biochem Pharmacol 2021; 193:114809. [PMID: 34673016 DOI: 10.1016/j.bcp.2021.114809] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/10/2021] [Accepted: 10/12/2021] [Indexed: 02/07/2023]
Abstract
Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.
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Affiliation(s)
- Walter H Moos
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA.
| | - Douglas V Faller
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Cancer Research Center, Boston University School of Medicine, Boston, MA, USA
| | - Ioannis P Glavas
- Department of Ophthalmology, New York University School of Medicine, New York, NY, USA
| | - David N Harpp
- Department of Chemistry, McGill University, Montreal, QC, Canada
| | - Natalia Kamperi
- Center for Clinical, Experimental Surgery and Translational Research Pharmacology-Pharmacotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | | | | | - Anastasios N Mavrakis
- Department of Medicine, Tufts University School of Medicine, St. Elizabeth's Medical Center, Boston, MA, USA
| | - Julie Pernokas
- Advanced Dental Associates of New England, Woburn, MA, USA
| | - Mark Pernokas
- Advanced Dental Associates of New England, Woburn, MA, USA
| | - Carl A Pinkert
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA
| | - Whitney R Powers
- Department of Health Sciences, Boston University, Boston, MA, USA; Department of Anatomy, Boston University School of Medicine, Boston, MA, USA
| | - Kosta Steliou
- Cancer Research Center, Boston University School of Medicine, Boston, MA, USA; PhenoMatriX, Inc., Natick, MA, USA
| | - Constantin Tamvakopoulos
- Center for Clinical, Experimental Surgery and Translational Research Pharmacology-Pharmacotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | - Demetrios G Vavvas
- Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA, USA
| | - Robert J Zamboni
- Department of Chemistry, McGill University, Montreal, QC, Canada
| | - Konstantina Sampani
- Beetham Eye Institute, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
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27
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Wong YK, Tse HF. Circulating Biomarkers for Cardiovascular Disease Risk Prediction in Patients With Cardiovascular Disease. Front Cardiovasc Med 2021; 8:713191. [PMID: 34660715 PMCID: PMC8517145 DOI: 10.3389/fcvm.2021.713191] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 09/08/2021] [Indexed: 12/23/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death globally. Risk assessment is crucial for identifying at-risk individuals who require immediate attention as well as to guide the intensity of medical therapy to reduce subsequent risk of CVD. In the past decade, many risk prediction models have been proposed to estimate the risk of developing CVD. However, in patients with a history of CVD, the current models that based on traditional risk factors provide limited power in predicting recurrent cardiovascular events. Several biomarkers from different pathophysiological pathways have been identified to predict cardiovascular events, and the incorporation of biomarkers into risk assessment may contribute to enhance risk stratification in secondary prevention. This review focuses on biomarkers related to cardiovascular and metabolic diseases, including B-type natriuretic peptide, high-sensitivity cardiac troponin I, adiponectin, adipocyte fatty acid-binding protein, heart-type fatty acid-binding protein, lipocalin-2, fibroblast growth factor 19 and 21, retinol-binding protein 4, plasminogen activator inhibitor-1, 25-hydroxyvitamin D, and proprotein convertase subtilisin/kexin type 9, and discusses the potential utility of these biomarkers in cardiovascular risk prediction among patients with CVD. Many of these biomarkers have shown promise in improving risk prediction of CVD. Further research is needed to assess the validity of biomarker and whether the strategy for incorporating biomarker into clinical practice may help to optimize decision-making and therapeutic management.
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Affiliation(s)
- Yuen-Kwun Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Hung-Fat Tse
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.,Department of Medicine, Shenzhen Hong Kong University Hospital, Shenzhen, China.,Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, The University of Hong Kong, Hong Kong, China.,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Hong Kong, China
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28
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Zhou X, Zhang Y, Wang N. Regulation and Potential Biological Role of Fibroblast Growth Factor 21 in Chronic Kidney Disease. Front Physiol 2021; 12:764503. [PMID: 34675822 PMCID: PMC8525706 DOI: 10.3389/fphys.2021.764503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/15/2021] [Indexed: 12/23/2022] Open
Abstract
Chronic kidney disease (CKD) is an incurable progressive disease with the progressive impairment of kidney function, which can accelerate the progression of cardiovascular disease, increase the risk of infection, and lead to related complications such as anemia and bone disease. CKD is to a great extent preventable and treatable, and it is particularly important to improve the early diagnosis, strengthen the research underlying the mechanism of disease occurrence and development, and innovate new intervention measures. Fibroblast growth factor 21 (FGF21) belongs to one of members of endocrine FGF subfamily with evolutionarily conserved functions and performs a vital role in the regulation of energy balance and adipose metabolism. FGF21 needs to rely on β-Klotho protein to specifically bind to FGF receptor (FGFR), which activates the FGF21 signaling exerting the biological function. FGF21 is deemed as an important regulatory factor extensively modulating many cellular functions under physiologic and pathologic conditions. Although the metabolic effect of FGF21 has been extensively studied, its potential biological role in the kidney has not been generally investigated. In this review, we summarize the biological characteristics, regulation and biological function of FGF21 based on the current studies, and briefly discuss the potential relationship with chronic kidney disease.
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Affiliation(s)
- Xue Zhou
- Department of Nephrology, Tianjin Haihe Hospital, Tianjin, China
| | - Yuefeng Zhang
- Department of Nephrology, Tianjin Haihe Hospital, Tianjin, China
| | - Ning Wang
- Tianjin Third Central Hospital, Tianjin, China
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29
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Biagioli M, Fiorucci S. Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease. LIVER RESEARCH 2021; 5:119-141. [PMID: 39957845 PMCID: PMC11791866 DOI: 10.1016/j.livres.2021.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/29/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023]
Abstract
Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors. The two best characterized receptors of this family are the nuclear receptor, farnesoid X receptor (FXR) and the G protein-coupled receptor, G protein-coupled bile acid receptor 1 (GPBAR1). FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism, energy balance, autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders. Clinical trials in non-alcoholic fatty liver disease (NAFLD), however, have shown that selective FXR agonists cause side effects while their efficacy is partial. Because FXR and GPBAR1 exert additive effects, dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials. Here, we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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30
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Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma. Cells 2021; 10:cells10081901. [PMID: 34440674 PMCID: PMC8391498 DOI: 10.3390/cells10081901] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/18/2021] [Accepted: 07/22/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. HCC progression and metastasis are closely related to altered mitochondrial metabolism, including mitochondrial stress responses, metabolic reprogramming, and mitoribosomal defects. Mitochondrial oxidative phosphorylation (OXPHOS) defects and reactive oxygen species (ROS) production are attributed to mitochondrial dysfunction. In response to oxidative stress caused by increased ROS production, misfolded or unfolded proteins can accumulate in the mitochondrial matrix, leading to initiation of the mitochondrial unfolded protein response (UPRmt). The mitokines FGF21 and GDF15 are upregulated during UPRmt and their levels are positively correlated with liver cancer development, progression, and metastasis. In addition, mitoribosome biogenesis is important for the regulation of mitochondrial respiration, cell viability, and differentiation. Mitoribosomal defects cause OXPHOS impairment, mitochondrial dysfunction, and increased production of ROS, which are associated with HCC progression in mouse models and human HCC patients. In this paper, we focus on the role of mitochondrial metabolic signatures in the development and progression of HCC. Furthermore, we provide a comprehensive review of cell autonomous and cell non-autonomous mitochondrial stress responses during HCC progression and metastasis.
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Fiorucci S, Biagioli M, Baldoni M, Ricci P, Sepe V, Zampella A, Distrutti E. The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease. Expert Opin Drug Discov 2021; 16:1193-1208. [PMID: 33849361 DOI: 10.1080/17460441.2021.1916465] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The farnesoid-x-receptor (FXR) is a ubiquitously expressed nuclear receptor selectively activated by primary bile acids. AREA COVERED FXR is a validated pharmacological target. Herein, the authors review preclinical and clinical data supporting the development of FXR agonists in the treatment of nonalcoholic fatty liver disease. EXPERT OPINION Development of systemic FXR agonists to treat the metabolic liver disease has been proven challenging because the side effects associated with these agents including increased levels of cholesterol and LDL-c and reduced HDL-c raising concerns over their long-term cardiovascular safety. Additionally, pruritus has emerged as a common, although poorly explained, dose-related side effect with all FXR ligands, but is especially common with OCA. FXR agonists that are currently undergoing phase 2/3 trials are cilofexor, tropifexor, nidufexor and MET409. Some of these agents are currently being developed as combination therapies with other agents including cenicriviroc, a CCR2/CCR5 inhibitor, or firsocostat an acetyl CoA carboxylase inhibitor. Additional investigations are needed to evaluate the beneficial effects of combination of these agents with statins. It is expected that in the coming years, FXR agonists will be developed as a combination therapy to minimize side effects and increase likelihood of success by targeting different metabolic pathways.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento Di Medicina E Chirurgia, Università Di Perugia, Perugia, Italy
| | - Michele Biagioli
- Dipartimento Di Medicina E Chirurgia, Università Di Perugia, Perugia, Italy
| | - Monia Baldoni
- Dipartimento Di Medicina E Chirurgia, Università Di Perugia, Perugia, Italy
| | - Patrizia Ricci
- Dipartimento Di Medicina E Chirurgia, Università Di Perugia, Perugia, Italy
| | - Valentina Sepe
- Department of Pharmacy University of Napoli, Federico II, Napoli, Italy
| | - Angela Zampella
- Department of Pharmacy University of Napoli, Federico II, Napoli, Italy
| | - Eleonora Distrutti
- SC Di Gastroenterologia Ed Epatologia, Azienda Ospedaliera Di Perugia, Perugia, Italy
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Salgado JV, Goes MA, Salgado Filho N. FGF21 and Chronic Kidney Disease. Metabolism 2021; 118:154738. [PMID: 33617873 DOI: 10.1016/j.metabol.2021.154738] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/27/2021] [Accepted: 02/16/2021] [Indexed: 02/05/2023]
Abstract
The global nephrology community recognizes the increasing burden of kidney disease and its poor health outcomes in the general population. Given this, strategies to establish early diagnosis, improve understanding of the natural course and develop novel therapeutic interventions to slow progression and reduce complications are encouraged. Fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, has emerged as a master homeostasis regulator of local and systemic lipid, glucose and energy metabolism. In addition, FGF21 should be considered an autonomic and endocrine regulator of stress responses in general. Promising results has been shown in both dysmetabolic animal models and metabolic disease patients after pharmacological administration of FGF21 analogs. The association of FGF21 with renal function has been studied for more than ten years. However, the functional role of FGF21 in the kidney is still poorly understood. This review summarizes the biological effects of FGF21 and discusses what is currently known about this hormone and chronic kidney disease, highlighting important gaps that warrant further research.
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Affiliation(s)
- João Victor Salgado
- Division of Nephrology, Federal University of São Paulo, Brazil; Department of Physiological Sciences, Federal University of Maranhão, Brazil.
| | | | - Natalino Salgado Filho
- Kidney Disease Prevention Centre, University Hospital, Federal University of Maranhão, Brazil; Department of Medicine I, Federal University of Maranhão, Brazil
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Lamos EM, Kristan M, Siamashvili M, Davis SN. Effects of anti-diabetic treatments in type 2 diabetes and fatty liver disease. Expert Rev Clin Pharmacol 2021; 14:837-852. [PMID: 33882758 DOI: 10.1080/17512433.2021.1917374] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are significant non-communicable diseases that often affect individuals concurrently. In individuals with both T2DM and NAFLD, there is evidence that anti-diabetic therapies may demonstrate potential combined beneficial metabolic and reduced hepatic inflammatory effects.Areas covered: A PubMed and Google Scholar search was performed to find relevant literature. Included studies focused on individuals with T2DM and NAFLD receiving anti-diabetic treatments including bariatric surgery, insulin sensitizers, incretin mimetics, and SGLT2 inhibitors. Additional articles highlight investigational treatments.Expert opinion: In individuals with T2DM and NAFLD, 5-10% weight loss or bariatric surgery if unable to lose weight or maintain weight loss are appropriate. GLP-1 receptor agonists and SGLT2 inhibitors result in weight loss, appear safe and may provide beneficial hepatic outcomes. Whether their effects are related to favorable weight changes or intrinsic hepatic effects is unclear. Thiazolidinediones have advantageous anti-hyperglycemic and hepatic effects but individuals must be monitored for weight gain and edema. Metformin and DPP-4 inhibitor beneficial hepatic effects remain debated. There are opportunities to standardize markers and imaging of NAFLD. Studies powered to evaluate the possible cardiovascular benefits of anti-diabetic therapies in individuals with T2DM and NAFLD are needed.
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Affiliation(s)
- Elizabeth M Lamos
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Megan Kristan
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Maka Siamashvili
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Influence of ursodeoxycholic acid therapy on levels of fibroblast growth factor 21, adiponectin and biochemical parameters in intrahepatic cholestasis of pregnancy. Clin Exp Hepatol 2021; 7:13-24. [PMID: 34027111 PMCID: PMC8122093 DOI: 10.5114/ceh.2021.104419] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 10/15/2020] [Indexed: 12/11/2022] Open
Abstract
The aim was to assess whether fibroblast growth factor 21 (FGF-21) and adiponectin influence intrahepatic cholestasis of pregnancy (ICP) pathogenesis and whether ursodeoxycholic acid (UDCA) has an impact on their levels. 50 pregnant women with ICP (ICP PW), 50 with uncomplicated pregnancy (HPW) and 50 healthy nonpregnant women (HW) were included. In ICP PW the first blood sample was drawn at the time of diagnosis, while in HPW it was drawn in the 28th week of pregnancy. The next blood samples were drawn in the 32nd and 36th week of pregnancy and one day after delivery. UDCA was administered when ICP was diagnosed. In ICP PW serum FGF-21 concentration was the lowest at the time of diagnosis with an evident increase after UDCA administration. Serum FGF-21 levels were significantly higher in ICP PW than in HPW from the first to the last measurement. There was a negative association between adiponectin and bile acids (BAs) levels in the later stage of pregnancy in ICP PW. Up-regulated FGF-21 serum levels in ICP patients compared to HPW persisted after delivery, suggesting its role in disease pathophysiology. The negative association between serum adiponectin and BAs of the later stage of pregnancy may suggest its role in regulation of BAs concentration. UDCA exerts a beneficial effect on insulin sensitivity and up-regulates FGF-21 in ICP.
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Kanzaki H, Chiba T, Ao J, Koroki K, Kanayama K, Maruta S, Maeda T, Kusakabe Y, Kobayashi K, Kanogawa N, Kiyono S, Nakamura M, Kondo T, Saito T, Nakagawa R, Ogasawara S, Suzuki E, Ooka Y, Muroyama R, Nakamoto S, Yasui S, Tawada A, Arai M, Kanda T, Maruyama H, Mimura N, Kato J, Zen Y, Ohtsuka M, Iwama A, Kato N. The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma. Sci Rep 2021; 11:5303. [PMID: 33674622 PMCID: PMC7935880 DOI: 10.1038/s41598-021-84117-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/12/2021] [Indexed: 12/24/2022] Open
Abstract
FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.
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Affiliation(s)
- Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
| | - Junjie Ao
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Kengo Kanayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Susumu Maruta
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takahiro Maeda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Yuko Kusakabe
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Yoshihiko Ooka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Ryosuke Muroyama
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Akinobu Tawada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Naoya Mimura
- Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Atsushi Iwama
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
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Panera N, Meroni M, Longo M, Crudele A, Valenti L, Bellacchio E, Miele L, D'Oria V, Paolini E, Maggioni M, Fracanzani AL, Alisi A, Dongiovanni P. The KLB rs17618244 gene variant is associated with fibrosing MAFLD by promoting hepatic stellate cell activation. EBioMedicine 2021; 65:103249. [PMID: 33640795 PMCID: PMC7921469 DOI: 10.1016/j.ebiom.2021.103249] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 01/20/2021] [Accepted: 02/03/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The rs17618244 G>A β-Klotho (KLB) variant has been associated with increased risk of ballooning and inflammation in pediatric patients with metabolic associated fatty liver disease (MAFLD), by reducing KLB expression. In hepatocytes, KLB downregulation induced fat accumulation and the expression of inflammatory and lipotoxic genes. We aimed to examine firstly the impact of the KLB rs17618244 variation on liver damage in adult patients with MAFLD and secondly its effect on hepatic stellate cells (HSCs) activation. METHODS The impact of the KLB rs17618244 variant on histological liver damage was surveyed in a retrospective cohort of 1111 adult patients with MAFLD. Subgroup analysis was performed according to the presence of obesity (BMI>35; n = 708). Immortalized HSCs (LX-2) were transfected with the KLB wild type (LX-2_KLBwt), or with the mutant one carrying the rs17618244 (LX-2_KLBmut). FINDINGS At ordinal regression analysis the KLB rs17618244 variant was associated with hepatic fibrosis (OR 1.23, 95% C.I.1.004-1.51; p = 0.04), but not with steatosis, inflammation and ballooning. By stratifying patients according to the presence of obesity, the KLB A allele was further associated with lobular inflammation (OR 1.32, 95% C.I.1.02-1.72; p = 0.03) and cirrhosis (OR 2.51, 95% C.I.1.23-5.05; p = 0.01) Moreover, hepatic KLB expression correlated with that of fibrogenic genes. LX-2_KLBmut cells showed reduced KLB protein levels paralleled by an induction of pro-fibrogenic genes and enhanced proliferative rate. INTERPRETATION The KLB rs17618244 variant is associated with hepatic fibrosis, inflammation and cirrhosis mainly in obese patients with MAFLD and HSCs which carry this mutation are highly proliferative and acquire a myofibroblast-like phenotype. FUNDING Ricerca Finalizzata Ministero della Salute GR-2019-12,370,172 (NP), Ricerca Corrente Fondazione IRCCS Cà Granda (PD and ALF), Ricerca Finalizzata Ministero della Salute RF-2013-02,358,319 (ALF), and Ricerca Corrente and 5 × 1000 Ministero della Salute (AA).
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Affiliation(s)
- Nadia Panera
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, 4, Piazza Sant'Onofrio, Rome 00165, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, Milan 20122, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, Milan 20122, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano 20122, Italy
| | - Annalisa Crudele
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, 4, Piazza Sant'Onofrio, Rome 00165, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy; Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Emanuele Bellacchio
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Luca Miele
- Area Medicina Interna, Gastroenterologia e Oncologia Medica, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy
| | - Valentina D'Oria
- Microscopy Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, Milan 20122, Italy; Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano 20133, Italy
| | - Marco Maggioni
- Deparment of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35 Milan 20122, Italy
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, Milan 20122, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, 4, Piazza Sant'Onofrio, Rome 00165, Italy.
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, Milan 20122, Italy.
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Fiorucci S, Distrutti E, Carino A, Zampella A, Biagioli M. Bile acids and their receptors in metabolic disorders. Prog Lipid Res 2021; 82:101094. [PMID: 33636214 DOI: 10.1016/j.plipres.2021.101094] [Citation(s) in RCA: 140] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/03/2021] [Accepted: 02/12/2021] [Indexed: 02/08/2023]
Abstract
Bile acids are a large family of atypical steroids which exert their functions by binding to a family of ubiquitous cell membrane and nuclear receptors. There are two main bile acid activated receptors, FXR and GPBAR1, that are exclusively activated by bile acids, while other receptors CAR, LXRs, PXR, RORγT, S1PR2and VDR are activated by bile acids in addition to other more selective endogenous ligands. In the intestine, activation of FXR and GPBAR1 promotes the release of FGF15/19 and GLP1 which integrate their signaling with direct effects exerted by theother receptors in target tissues. This network is tuned in a time ordered manner by circadian rhythm and is critical for the regulation of metabolic process including autophagy, fast-to-feed transition, lipid and glucose metabolism, energy balance and immune responses. In the last decade FXR ligands have entered clinical trials but development of systemic FXR agonists has been proven challenging because their side effects including increased levels of cholesterol and Low Density Lipoproteins cholesterol (LDL-c) and reduced High-Density Lipoprotein cholesterol (HDL-c). In addition, pruritus has emerged as a common, dose related, side effect of FXR ligands. Intestinal-restricted FXR and GPBAR1 agonists and dual FXR/GPBAR1 agonists have been developed. Here we review the last decade in bile acids physiology and pharmacology.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Adriana Carino
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli, Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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Wang SS, Gu Q, Liu N, Li J, Liu X. Aerobic exercise attenuates ectopic renal sinus adipose tissue accumulation-related renal hypoxia injury in obese mice. Life Sci 2021; 279:119106. [PMID: 33497740 DOI: 10.1016/j.lfs.2021.119106] [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: 12/14/2020] [Revised: 01/02/2021] [Accepted: 01/03/2021] [Indexed: 12/20/2022]
Abstract
AIMS We explored the effect of aerobic exercise on renal sinus adipose (RSA) accumulation and RSA accumulation-related renal injury in obese mice. MAIN METHODS C57BL/6J male mice (n = 30) were evenly divided into three groups: control group (CON, n = 10), obese group (OB, n = 10; given high-fat diet) and obese + aerobic exercise group (OB + E, n = 10; given HFD and 8 weeks of moderate-intensity exercise training). The body weight and kidney weight were measured after sacrificing. Morphological alterations of adipose and renal tissues were measured on hematoxylin-eosin (HE) stained slides. The macrophages surface markers (F4/80, CD68, CD206, CD163), monocyte chemotactic protein 1 (MCP-1) and hypoxia inducible factor-1α (HIF-1α) were examined by immunohistochemistry assay. Inflammation-related factors (FGF-21, KIM-1, IL-6) were analyzed via serum enzyme-linked immunosorbent assay. KEY FINDINGS We found that aerobic exercise significantly reduced body weight, kidney weight, serum FGF-21 and KIM-1 levels, and ameliorated glomerular hypertrophy and RSA size accumulation in OB + E group compared with OB group. Furthermore, HIF-1α in the RSA and renal tissues was significantly increased in the OB group (P < 0.05), but exercise effectively reduced the expression of HIF-1α and ameliorated renal inflammation by reducing MCP-1 and CD68 expression (both P < 0.05), improving the conversion from M1 (CD68) to M2 (CD206, CD163) macrophages (P < 0.05), and finally alleviating the level of IL-6 (P < 0.01). SIGNIFICANCE Aerobic exercise could reduce RSA accumulation-related adipose hypoxia and macrophage infiltration, and subsequently attenuate the progress of renal injury.
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Affiliation(s)
- Sha-Sha Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Qing Gu
- Department of Endocrinology, Shidong Hospital, Shanghai, China
| | - Nian Liu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Jingyuan Li
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Xiangyun Liu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China.
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Yang MN, Huang R, Liu X, Xu YJ, Wang WJ, He H, Zhang GH, Zheng T, Fang F, Fan JG, Li F, Zhang J, Li J, Ouyang F, Luo ZC. Fibroblast Growth Factor 19 in Gestational Diabetes Mellitus and Fetal Growth. Front Endocrinol (Lausanne) 2021; 12:805722. [PMID: 35145481 PMCID: PMC8821646 DOI: 10.3389/fendo.2021.805722] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/27/2021] [Indexed: 12/15/2022] Open
Abstract
Fibroblast growth factor 19 (FGF19) has been implicated in glucose homeostasis. Gestational diabetes mellitus (GDM) enhances fetal insulin secretion and fetal growth. Girls weigh less and are more insulin resistant than boys at birth. We sought to assess whether FGF19 is associated with GDM and fetal growth and explore potential sex dimorphic associations. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns of GDM versus euglycemic mothers matched by infant's sex and gestational age at birth. Cord plasma FGF19, insulin, C-peptide, proinsulin, IGF-I and IGF-II concentrations were measured. Cord plasma FGF19 concentrations were similar in GDM versus euglycemic pregnancies (mean ± SD: 43.5 ± 28.2 versus 44.5 ± 30.2 pg/mL, P=0.38). FGF19 was not correlated with IGF-I or IGF-II. FGF19 concentrations were positively correlated with birth weight (r=0.23, P=0.01) and length (r=0.21, P=0.02) z scores, C-peptide (r=0.27, P=0.002) and proinsulin (r=0.27, P=0.002) concentrations in females. Each SD increment in cord plasma FGF19 was associated with a 0.25 (0.07-0.43) increase in birth weight z score in females. In contrast, FGF19 was not correlated with birth weight or length in males. These sex dimorphic associations remained after adjusting for maternal and neonatal characteristics. The study is the first to demonstrate that GDM does not matter for cord blood FGF19 concentrations. The female specific positive correlation between FGF19 and birth weight is suggestive of a sex-dimorphic role of FGF19 in fetal growth. The observations call for more studies to validate the novel findings and elucidate the underlying mechanisms.
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Affiliation(s)
- Meng-Nan Yang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Department of Obstetrics and Gynecology, Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Mount Sinai Hospital, Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Rong Huang
- Department of Obstetrics and Gynecology, Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Mount Sinai Hospital, Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Xin Liu
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Ya-Jie Xu
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Wen-Juan Wang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Hua He
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Guang-Hui Zhang
- Department of Clinical Assay Laboratory, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Tao Zheng
- Department of Obstetrics and Gynecology, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Fang Fang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Li
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jun Zhang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jiong Li
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Department of Clinical Medicine-Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Fengxiu Ouyang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- *Correspondence: Zhong-Cheng Luo, ; Fengxiu Ouyang,
| | - Zhong-Cheng Luo
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Department of Obstetrics and Gynecology, Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Mount Sinai Hospital, Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- *Correspondence: Zhong-Cheng Luo, ; Fengxiu Ouyang,
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Sjöbom U, Christenson K, Hellström A, Nilsson AK. Inflammatory Markers in Suction Blister Fluid: A Comparative Study Between Interstitial Fluid and Plasma. Front Immunol 2020; 11:597632. [PMID: 33224151 PMCID: PMC7670055 DOI: 10.3389/fimmu.2020.597632] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
Background Biomarker analysis allows for the detection and prediction of disease as well as health monitoring. The use of interstitial fluid (ISF) as a matrix for biomarkers has recently gained interest. This study aimed to compare levels of inflammatory markers in ISF from suction blister fluid (SBF) and plasma. Methods Plasma and SBF were collected from 18 healthy individuals. Samples were analyzed for 92 inflammation-related protein biomarkers by Proximity Extension Assay (PEA). Protein profiles in the two matrices were compared using traditional and multivariate statistics. Results Out of 92 targeted proteins, 70 were successfully quantified in both plasma and SBF. Overall, plasma and SBF displayed distinct protein profiles with up to 40-fold difference in abundance of specific proteins. The levels of 25 proteins were significantly correlated between plasma and SBF and several of these were recognized as potential markers to monitor health using ISF. Conclusions Skin ISF and plasma have unique protein profiles but many inflammatory markers are proportionally related between the matrices at the individual level. ISF is a promising biofluid for the monitoring of biomarkers in clinical studies and routine analyses.
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Affiliation(s)
- Ulrika Sjöbom
- Institute of Health and Care Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Karin Christenson
- Department of Oral Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ann Hellström
- Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders K Nilsson
- Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Sasaki N, Gomi F, Yoshimura H, Yamamoto M, Matsuda Y, Michishita M, Hatakeyama H, Kawano Y, Toyoda M, Korc M, Ishiwata T. FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12102976. [PMID: 33066597 PMCID: PMC7602396 DOI: 10.3390/cancers12102976] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 10/06/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that is projected to become the leading cause of cancer death by 2050. Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane receptor that is overexpressed in half of PDACs. We determined that its expression in PDAC positively correlated with larger tumor size and more advanced tumor stage, and that BLU9931, a selective FGFR4 inhibitor, reduced PDAC cell proliferation and invasion while promoting their senescence. Quercetin, a senolytic drug, induced cell death in BLU9931-treated cells. We propose that targeting FGFR4 in combination with senolysis could provide a novel therapeutic strategy in patients whose PDAC expresses high FGFR4 levels. Abstract Fibroblast growth factor receptor 4 (FGFR4), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/FGFR4 signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/FGFR4 signaling in human pancreatic ductal adenocarcinoma (PDAC). In human PDAC cases, FGFR4 expression positively correlated with larger primary tumors and more advanced stages. Among eight PDAC cell lines, FGFR4 was expressed at the highest levels in PK-1 cells, in which single-nucleotide polymorphism G388R in FGFR4 was detected. For inhibition of autocrine/paracrine FGF19/FGFR4 signaling, we used BLU9931, a highly selective FGFR4 inhibitor. Inhibition of signal transduction through ERK, AKT, and STAT3 pathways by BLU9931 reduced proliferation in FGF19/FGFR4 signaling-activated PDAC cells. By contrast, BLU9931 did not alter stemness features, including stemness marker expression, anticancer drug resistance, and sphere-forming ability. However, BLU9931 inhibited cell invasion, in part, by downregulating membrane-type matrix metalloproteinase-1 in FGF19/FGFR4 signaling-activated PDAC cells. Furthermore, downregulation of SIRT1 and SIRT6 by BLU9931 contributed to senescence induction, priming these cells for quercetin-induced death, a process termed senolysis. Thus, we propose that BLU9931 is a promising therapeutic agent in FGFR4-positive PDAC, especially when combined with senolysis (195/200).
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Affiliation(s)
- Norihiko Sasaki
- Research team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Sakae-cho 35-2, Itabashi-ku, Tokyo 173-0015, Japan; (N.S.); (M.T.)
| | - Fujiya Gomi
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan;
| | - Hisashi Yoshimura
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (H.Y.); (M.Y.)
| | - Masami Yamamoto
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (H.Y.); (M.Y.)
| | - Yoko Matsuda
- Oncology Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa 761-0793, Japan;
| | - Masaki Michishita
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan;
| | - Hitoshi Hatakeyama
- Department of Comprehensive Education in Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan;
| | - Yoichi Kawano
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo 113-8603, Japan;
| | - Masashi Toyoda
- Research team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Sakae-cho 35-2, Itabashi-ku, Tokyo 173-0015, Japan; (N.S.); (M.T.)
| | - Murray Korc
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, CA 92697, USA;
| | - Toshiyuki Ishiwata
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan;
- Correspondence: ; Tel.: +81-3-3964-1141 (ext. 4414)
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Kibble M, Khan SA, Ammad-ud-din M, Bollepalli S, Palviainen T, Kaprio J, Pietiläinen KH, Ollikainen M. An integrative machine learning approach to discovering multi-level molecular mechanisms of obesity using data from monozygotic twin pairs. ROYAL SOCIETY OPEN SCIENCE 2020; 7:200872. [PMID: 33204460 PMCID: PMC7657920 DOI: 10.1098/rsos.200872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/29/2020] [Indexed: 05/19/2023]
Abstract
We combined clinical, cytokine, genomic, methylation and dietary data from 43 young adult monozygotic twin pairs (aged 22-36 years, 53% female), where 25 of the twin pairs were substantially weight discordant (delta body mass index > 3 kg m-2). These measurements were originally taken as part of the TwinFat study, a substudy of The Finnish Twin Cohort study. These five large multivariate datasets (comprising 42, 71, 1587, 1605 and 63 variables, respectively) were jointly analysed using an integrative machine learning method called group factor analysis (GFA) to offer new hypotheses into the multi-molecular-level interactions associated with the development of obesity. New potential links between cytokines and weight gain are identified, as well as associations between dietary, inflammatory and epigenetic factors. This encouraging case study aims to enthuse the research community to boldly attempt new machine learning approaches which have the potential to yield novel and unintuitive hypotheses. The source code of the GFA method is publically available as the R package GFA.
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Affiliation(s)
- Milla Kibble
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK
- Author for correspondence: Milla Kibble e-mail:
| | - Suleiman A. Khan
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Muhammad Ammad-ud-din
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Sailalitha Bollepalli
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Teemu Palviainen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Jaakko Kaprio
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Department of Public Health, University of Helsinki, Helsinki, Finland
| | - Kirsi H. Pietiläinen
- Obesity Research Unit, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
| | - Miina Ollikainen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
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Zheng Q, Martin RC, Shi X, Pandit H, Yu Y, Liu X, Guo W, Tan M, Bai O, Meng X, Li Y. Lack of FGF21 promotes NASH-HCC transition via hepatocyte-TLR4-IL-17A signaling. Theranostics 2020; 10:9923-9936. [PMID: 32929325 PMCID: PMC7481424 DOI: 10.7150/thno.45988] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022] Open
Abstract
Rationale: Hepatocellular carcinoma (HCC) has been increasingly recognized in nonalcoholic steatohepatitis (NASH) patients. Fibroblast growth factor 21 (FGF21) is reported to prevent NASH and delay HCC development. In this study, the effects of FGF21 on NASH progression and NASH-HCC transition and the potential mechanism(s) were investigated. Methods: NASH models and NASH-HCC models were established in FGF21Knockout (KO) mice to evaluate NASH-HCC transition. IL-17A signaling was investigated in the isolated hepatic parenchymal cells, splenocytes, and hepatocyte and HCC cell lines. Results: Lack of FGF21 caused significant up-regulation of the hepatocyte-derived IL-17A via Toll-like receptor 4 (TLR4) and NF-κB signaling. Restoration of FGF21 alleviated the high NAFLD activity score (NAS) and attenuated the TLR4-triggered hepatocyte-IL-17A expression. The HCC nodule number and tumor size were significantly alleviated by treatments of anti-IL-17A antibody. Conclusion: This study revealed a novel anti-inflammatory mechanism of FGF21 via inhibiting the hepatocyte-TLR4-IL-17A signaling in NASH-HCC models. The negative feedback loop on the hepatocyte-TLR4-IL-17A axis could be a potential anti-carcinogenetic mechanism for FGF21 to prevent NASH-HCC transition.
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Affiliation(s)
- Qianqian Zheng
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang 110122, China
| | - Robert C. Martin
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Xiaoju Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China
| | - Harshul Pandit
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Youxi Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China
| | - Xingkai Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China
| | - Wei Guo
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China
| | - Min Tan
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Ou Bai
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China
| | - Xin Meng
- Department of Biochemistry and Molecular Biology, College of Life Science, China Medical University, Shenyang 110122, China
| | - Yan Li
- Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
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Marchelek-Mysliwiec M, Dziedziejko V, Dolegowka K, Pawlik A, Safranow K, Stepniewska J, Wisniewska M, Malyszko J, Ciechanowski K. Association of FGF19, FGF21 and FGF23 with carbohydrate metabolism parameters and insulin resistance in patients with chronic kidney disease. J Appl Biomed 2020; 18:61-69. [PMID: 34907727 DOI: 10.32725/jab.2020.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 02/11/2020] [Indexed: 11/05/2022] Open
Abstract
Insulin resistance (IR) is characterised by increased gluconeogenesis in the liver and the resistance of peripheral receptors to insulin. Several factors, including IR, type 2 diabetes, new-onset diabetes after transplant (NODAT) and secondary parathyroidism, are related to chronic kidney disease (CKD). These factors are associated with higher mortality due to the increased risk of cardiovascular complications. Many factors have been identified as potential markers of IR in CKD. These factors include fibroblast growth factors (FGFs), a subfamily of endocrine polypeptides. In this study, we examined the association of FGF19, FGF21 and FGF23 with selected parameters related to carbohydrate metabolism and insulin resistance in non diabetic patients with predialysis CKD and in non diabetic patients after renal transplantation. The study included 108 non diabetic subjects: 40 patients with predialysis CKD, 45 patients with CKD who had undergone renal transplantation, and 23 healthy subjects (control group). In patients who had undergone renal transplantation, concentrations of FGF23 were increased compared to the control group and patients with predialysis CKD. The highest and lowest FGF19 concentrations were observed in CKD patients and in patients who had undergone kidney transplantation, respectively. This difference was statistically significant. Leptin concentrations were higher in CKD patients compared to the control group and patients who had undergone kidney transplantation. There were no statistically significant differences in adiponectin concentrations, lean body mass or fat tissue mass between the studied groups. HOMA-IR and insulin levels were significantly increased in CKD patients and in patients who had undergone renal transplantation in comparison to the control group. The results of the study suggest the involvement of FGF in carbohydrate metabolism and insulin resistance in patients with predialysis CKD, as well as a correlation with kidney function.
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Affiliation(s)
- Malgorzata Marchelek-Mysliwiec
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
| | - Violetta Dziedziejko
- Pomeranian Medical University, Department of Biochemistry and Medical Chemistry, Szczecin, Poland
| | - Katarzyna Dolegowka
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
| | - Andrzej Pawlik
- Pomeranian Medical University, Department of Physiology, Szczecin, Poland
| | - Krzysztof Safranow
- Pomeranian Medical University, Department of Biochemistry and Medical Chemistry, Szczecin, Poland
| | - Joanna Stepniewska
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
| | - Magda Wisniewska
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
| | - Jolanta Malyszko
- Warsaw Medical University, Department of Nephrology, Dialysis and Internal Medicine, Warsaw, Poland
| | - Kazimierz Ciechanowski
- Pomeranian Medical University, Clinical Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland
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Klotho and fibroblast growth factors 19 and 21 serum concentrations in children and adolescents with normal body weight and obesity and their associations with metabolic parameters. BMC Pediatr 2020; 20:294. [PMID: 32546231 PMCID: PMC7296965 DOI: 10.1186/s12887-020-02199-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/11/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Fibroblast growth factor 19 (FGF19), fibroblast growth factor 21 (FGF21) and Klotho are regulators of energy homeostasis. However, in the pediatric population, the relationships between obesity, metabolic disorders and the aforementioned factors have not been clearly investigated. We analyzed the role of FGF19, FGF21 and Klotho protein in children with normal body weight as well as in overweight and obese subjects and explored their associations with insulin resistance (IR) and metabolic syndrome (MS) and its components. METHODS This was a cross-sectional study conducted in a group of hospitalized children and adolescents. Laboratory investigations included serum analysis of FGF19, FGF21, and Klotho with ELISA kits as well as the analysis of the lipid profile and ALT serum concentrations. Moreover, each subject underwent an oral glucose tolerance test (OGTT) with fasting insulinemia measurement to detect glucose tolerance abnormalities and calculate the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index. Furthermore, the clinical analysis included blood pressure measurement, body fat percentage estimation and assessment of the prevalence of MS and its components. RESULTS The study was conducted with 174 children/adolescents aged 6-17 years with normal body weight (N = 48), obesity (N = 92) and overweight (N = 34). Klotho concentration was significantly higher in the obese children [median 168.6 pg/ml (90.2 to 375.9)]) than in the overweight [131.3 pg/ml (78.0 to 313.0)] and normal-body-weight subjects [116.6 pg/ml (38.5 to 163.9)] (p = 0.0334) and was also significantly higher in insulin-resistant children than in insulin-sensitive children [185.3 pg/ml (102.1 to 398.2) vs 132.6 pg/ml (63.9 to 275.6), p = 0.0283]. FGF21 was elevated in patients with MS compared to the FGF21 levels in other subjects [136.2 pg/ml (86.5 to 239.9) vs 82.6 pg/ml (41.8 to 152.4), p = 0.0286]. The multivariable model showed that FGF19 was an independent predictor of IR after adjusting for pubertal stage and BMI Z-score. CONCLUSIONS Klotho levels were associated with body weight status in children and adolescents. Moreover, Klotho, FGF19 and FGF21 concentrations correlated with IR status and/or components of MS.
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Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to mitochondrial transfer-RNA mutations and mitochondrial DNA deletions. Neurol Sci 2020; 41:3653-3662. [PMID: 32504279 DOI: 10.1007/s10072-020-04422-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diagnosis of mitochondrial diseases (MDs) is challenging, since they are multisystemic disorders, characterized by a heterogeneous symptomatology. Recently, an increase in serum levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has been found in the majority of patients with MDs compared with healthy controls. On the other hand, the finding of low FGF21 and GDF15 levels in some patients with MDs suggests that different types of respiratory chain defects may lead to different profiles of these two proteins. OBJECTIVE In this study, we aimed to validate the diagnostic reliability of FGF21 and GDF15 assays in MDs and to evaluate a possible correlation between serum levels of the two biomarkers with genotype of MD patients. Serum FGF21 and GDF15 levels were measured by a quantitative ELISA. RESULTS Our results showed increased serum FGF21 and GDF15 levels in MD patients; however, GDF15 measurement seems to be more sensitive and specific for screening tests for MD than FGF21. Moreover, we showed a positive correlation with both FGF21 and GDF15 levels and the number of COX-negative fibers. CONCLUSION Finally, we also demonstrated that the increase of FGF21 and GDF15 was related to MDs caused by mitochondrial translation defects, and multiple and single mtDNA deletions, but not to MDs due to mutations in the respiratory chain subunits.
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Jensterle M, Janez A, Fliers E, DeVries JH, Vrtacnik-Bokal E, Siegelaar SE. The role of glucagon-like peptide-1 in reproduction: from physiology to therapeutic perspective. Hum Reprod Update 2020; 25:504-517. [PMID: 31260047 DOI: 10.1093/humupd/dmz019] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 04/09/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) have become firmly established in the treatment of type 2 diabetes and obesity, disorders frequently associated with diminished reproductive health. Understanding of the role of GLP-1 and GLP-1 RAs in reproduction is currently limited and largely unaddressed in clinical studies. OBJECTIVE AND RATIONALE The purpose of this narrative review is to provide a comprehensive overview of the role of GLP-1 in reproduction and to address a therapeutic perspective that can be derived from these findings. SEARCH METHODS We performed a series of PubMed database systemic searches, last updated on 1 February 2019, supplemented by the authors' knowledge and research experience in the field. A search algorithm was developed incorporating the terms glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor, GLP-1R, or incretins, and this was combined with terms related to reproductive health. The PICO (Population, Intervention, Comparison, Outcome) framework was used to identify interventional studies including GLP-1 RAs and dipeptidyl peptidase-4 (DPP-4) inhibitors, which prevent the degradation of endogenously released GLP-1. We identified 983 potentially relevant references. At the end of the screening process, we included 6 observational (3 preclinical and 3 human) studies, 24 interventional (9 preclinical and 15 human) studies, 4 case reports, and 1 systematic and 2 narrative reviews. OUTCOMES The anatomical distribution of GLP-1 receptor throughout the reproductive system and observed effects of GLP-1 in preclinical models and in a few clinical studies indicate that GLP-1 might be one of the important modulating signals connecting the reproductive and metabolic system. The outcomes show that there is mostly stimulating role of GLP-1 and its mimetics in mammalian reproduction that goes beyond mere weight reduction. In addition, GLP-1 seems to have anti-inflammatory and anti-fibrotic effects in the gonads and the endometrium affected by obesity, diabetes, and polycystic ovary syndrome (PCOS). It also seems that GLP-1 RAs and DPP-4 inhibitors can reverse polycystic ovary morphology in preclinical models and decrease serum concentrations of androgens and their bioavailability in women with PCOS. Preliminary data from interventional clinical studies suggest improved menstrual regularity as well as increased fertility rates in overweight and/or obese women with PCOS treated with GLP-1 RAs in the preconception period. WIDER IMPLICATIONS GLP-1 RAs and DPP-4 inhibitors show promise in the treatment of diabetes and obesity-related subfertility. Larger interventional studies are needed to establish the role of preconception intervention with GLP-1 based therapies, assessing fertility outcomes in obesity, PCOS, and diabetes-related fertility problems. The potential impact of the dose- and exposure time-response of different GLP-1 RAs need further exploration. Future research should also investigate sex-specific variability of GLP-1 on reproductive outcomes, in particular on the gonads where the observations in males are most conflicting.
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Affiliation(s)
- Mojca Jensterle
- Department of Endocrinology, Diabetes and Metabolic Diseases, Division of Internal Medicine, University Medical Centre Ljubljana, Zaloška cesta 7, Ljubljana, Slovenia
| | - Andrej Janez
- Department of Endocrinology, Diabetes and Metabolic Diseases, Division of Internal Medicine, University Medical Centre Ljubljana, Zaloška cesta 7, Ljubljana, Slovenia
| | - Eric Fliers
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - J Hans DeVries
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Eda Vrtacnik-Bokal
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, Slajmerjeva ulica 03, Ljubljana, Slovenia
| | - Sarah E Siegelaar
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
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Panezai J, Ali A, Ghaffar A, Benchimol D, Altamash M, Klinge B, Engström PE, Larsson A. Upregulation of circulating inflammatory biomarkers under the influence of periodontal disease in rheumatoid arthritis patients. Cytokine 2020; 131:155117. [PMID: 32403006 DOI: 10.1016/j.cyto.2020.155117] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/11/2020] [Accepted: 04/28/2020] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Periodontal disease (PD) and rheumatoid arthritis (RA) are chronic immuno-inflammatory conditions with osteolysis being a hallmark feature. The influence of PD on RA's systemic inflammatory status and disease activity remains unclear. The objective of this study was to assess the systemic inflammation and disease activity of RA under the influence of PD. METHODS In this case-control study, 38 RA patients (19 with PD and 19 without PD) were compared to 38 non-RA patients and 12 healthy controls. Periodontal parameters (bleeding on probing (BOP), probing pocket depth (PPD), PPD Total, PPD Disease and marginal bone loss (MBL) were determined. Serological analyses included quantification of 92 inflammatory biomarkers using a multiplex proximity extension assay, anti-citrullinated protein antibodies (ACPA), rheumatoid factor (IgM-RF) and erythrocyte sedimentation rate (ESR). RA disease activity was determined using Disease Activity Score for 28 joints (DAS28). All RA patients were on medication. RESULTS IgM-RF was higher in RA patients with PD. PD conditions were more severe in the non-RA group. Inflammatory biomarkers (IL-10RB, IL-18, CSF-1, NT-3, TRAIL, PD-L1, LIF-R, SLAMF1, FGF-19, TRANCE, CST5, STAMPB, SIRT2, TWEAK, CX3CL1, CXCL5, MCP-1) were significantly higher in RA patients with PD than RA without PD. DAS28 associated with twice as many inflammatory biomarkers in RA patients with PD whereas IgM-RF and ACPA associated more frequently with biomarkers in the RA without PD group. IgM-RF correlated inversely with BOP. CONCLUSION Periodontal disease augments systemic inflammation in RA. A profound influence exists independent of autoimmune status.
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Affiliation(s)
- Jeneen Panezai
- Altamash Institute of Dental Medicine, Department of Periodontology, Karachi, Pakistan; Karolinska Institutet, Department of Dental Medicine, Division of Oral Diseases, Section of Periodontology, Huddinge, Sweden; Balochistan University of Information Technology, Engineering and Management Sciences, Department of Microbiology, Faculty of Life Sciences and Informatics, Quetta, Pakistan.
| | - Azra Ali
- Habib Medical Centre, Rheumatology Clinic, Karachi, Pakistan, Karachi, Pakistan
| | - Ambereen Ghaffar
- Habib Medical Centre, Rheumatology Clinic, Karachi, Pakistan, Karachi, Pakistan
| | - Daniel Benchimol
- Karolinska Institutet, Department of Dental Medicine, Division of Oral Diagnostics and Rehabilitation, Section of Oral Diagnostics and Surgery, Huddinge, Sweden
| | - Mohammad Altamash
- Altamash Institute of Dental Medicine, Department of Periodontology, Karachi, Pakistan
| | - Bjӧrn Klinge
- Karolinska Institutet, Department of Dental Medicine, Division of Oral Diseases, Section of Periodontology, Huddinge, Sweden; Malmö University, Faculty of Odontology, Department of Periodontology, Malmö, Sweden
| | - Per-Erik Engström
- Karolinska Institutet, Department of Dental Medicine, Division of Oral Diseases, Section of Periodontology, Huddinge, Sweden
| | - Anders Larsson
- Uppsala University, Department of Medical Sciences, Uppsala, Sweden
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COBAN M, YİLMAZ U, DOLU S, ASİLTURK E, SOZER Y, EROL B, ELLİDAG HY. Intact Fibroblast Growth Factor 23 and Peripheral Vascular Complications in Patients on Hemodialysis. DICLE MEDICAL JOURNAL 2020. [DOI: 10.5798/dicletip.706013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Lin S, Yu L, Ni Y, He L, Weng X, Lu X, Zhang C. Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT. Diabetes Metab J 2020; 44:158-172. [PMID: 31701691 PMCID: PMC7043973 DOI: 10.4093/dmj.2018.0235] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 04/02/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study. METHODS Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4'-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months. RESULTS DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2). CONCLUSION FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.
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Affiliation(s)
- Sundong Lin
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Lechu Yu
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yongqing Ni
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lulu He
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Xiaolu Weng
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
| | - Xuemian Lu
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Chi Zhang
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
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