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Chu Y, Yang S, Chen X. Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2025; 269:108844. [PMID: 40113178 DOI: 10.1016/j.pharmthera.2025.108844] [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: 01/08/2025] [Revised: 02/08/2025] [Accepted: 02/20/2025] [Indexed: 03/22/2025]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1-4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases.
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Affiliation(s)
- Yi Chu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Su Yang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiaodong Chen
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
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Warda F, Batch J, Graham L, Haas MJ, Mooradian AD. D-allulose enhances lipid oxidation in HepG2 cells via peroxisome proliferator-activated receptor α (PPARα). Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159599. [PMID: 39884381 DOI: 10.1016/j.bbalip.2025.159599] [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: 03/28/2024] [Revised: 12/31/2024] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Lipid accumulation in hepatocytes in non-alcoholic steatohepatitis (NASH) is attributed partly to loss of insulin-responsiveness and/or an increased pro-inflammatory state. Since the rare sugar D-allulose has insulin mimetic and anti-inflammatory properties, its effects on lipid accumulation in liver-derived cells was tested. In HepG2 cells exposed to 200 μM oleic acid for 72 h, D-allulose treatment decreased intracellular lipid accumulation with an IC50 = 0.45 ± 0.07 mM. A similar effect was observed in cells treated with 10 μM gemfibrozil. D-allulose and gemfibrozil treatment increased oleic acid β-oxidation. Both D-allulose and gemfibrozil increased peroxisome proliferator-activated receptor α (PPARα) expression (two-fold) relative to control cells, while retinoid X receptor was unchanged. D-allulose and gemfibrozil increased PPARα-dependent genes including those involved in fatty acid β-oxidation (acyl-coenzyme A oxidase 1, long-chain-fatty-acid-coenzyme A ligase 5, and carnitine palmitoyltransferase 1 A). D-allulose and gemfibrozil also increased PPARα reporter gene expression and phosphorylation (Serine 12) which were both inhibited by the mitogen-activated protein (MAP) kinase inhibitor PD098059. Other MAP kinase inhibitors, including SB203580, SP600125, and BIX10289 had no effect on reporter gene expression. Oleic acid treatment, but not D-allulose or gemfibrozil, decreased sterol response element binding protein 1 and sterol response element binding protein 2 expression relative to cells not exposed to oleic acid, while peroxisome proliferator-activated receptor γ expression did not change. These results indicate that D-alluose mimics gemfibrozil effects on lipid content in HepG2 cells by promoting fatty acid β-oxidation via PPARα.
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Affiliation(s)
- Firas Warda
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America
| | - Jennifer Batch
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America
| | - Lauren Graham
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America
| | - Michael J Haas
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America.
| | - Arshag D Mooradian
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America
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Ueda H, Honda A, Miyazaki T, Morishita Y, Hirayama T, Iwamoto J, Ikegami T. High-fat/high-sucrose diet results in a high rate of MASH with HCC in a mouse model of human-like bile acid composition. Hepatol Commun 2025; 9:e0606. [PMID: 39670881 PMCID: PMC11637755 DOI: 10.1097/hc9.0000000000000606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/21/2024] [Indexed: 12/14/2024] Open
Abstract
BACKGROUND Wild-type (WT) mice fed a conventional high-fat/high-sucrose diet (HFHSD) rarely develop metabolic dysfunction-associated steatohepatitis (MASH) with HCC. Because mouse bile acid (BA) is highly hydrophilic, we hypothesized that making it hydrophobic would lead to MASH with HCC. METHODS Eleven-week-old WT and Cyp2a12/Cyp2c70 double knockout (DKO) mice were divided into two groups, including one which was fed a normal chow diet, and one which was fed an HFHSD. Samples were collected after 15, 30, 47, and 58 weeks for histological, biochemical, and immunological analyses. RESULTS In the HFHSD group, body weight gain did not differ in WT versus DKO mice, although HFHSD-fed DKO mice exhibited markedly accelerated liver inflammation, fibrosis, and carcinogenesis. HFHSD upregulated lipogenesis and downregulated fatty acid oxidation in both WT and DKO mice, which increased liver lipid accumulation and lipotoxicity. However, the increase in reactive oxygen species production and carcinogenesis observed in DKO mice could not be explained by abnormal lipid metabolism alone. Regarding BA metabolism, DKO mice had a higher hydrophobicity index. They exhibited an age-associated increase in chenodeoxycholic acid (CDCA) levels because of CYP8B1 activity inhibition due to the farnesoid X receptor activation. HFHSD further downregulated CYP8B1, presumably by activating the Liver X receptor. Liver CDCA accumulation was associated with increased inflammation, reactive oxygen species production, and hepatocyte FGF15 induction. Moreover, in noncancerous liver tissues, HFHSD appeared to activate STAT3, an oncogenic transcription factor, which was enhanced by a CDCA-rich environment. CONCLUSIONS Here, we developed a new model of MASH with HCC using mice with human-like BA composition and found that HFHSD and elevated hepatic CDCA synergistically increased the risk of MASH with HCC.
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Affiliation(s)
- Hajime Ueda
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Akira Honda
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Yukio Morishita
- Diagnostic Pathology Division, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Takeshi Hirayama
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Junichi Iwamoto
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Tadashi Ikegami
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
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Edirisinghe O, Ternier G, Alraawi Z, Suresh Kumar TK. Decoding FGF/FGFR Signaling: Insights into Biological Functions and Disease Relevance. Biomolecules 2024; 14:1622. [PMID: 39766329 PMCID: PMC11726770 DOI: 10.3390/biom14121622] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/06/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Fibroblast Growth Factors (FGFs) and their cognate receptors, FGFRs, play pivotal roles in a plethora of biological processes, including cell proliferation, differentiation, tissue repair, and metabolic homeostasis. This review provides a comprehensive overview of FGF-FGFR signaling pathways while highlighting their complex regulatory mechanisms and interconnections with other signaling networks. Further, we briefly discuss the FGFs involvement in developmental, metabolic, and housekeeping functions. By complementing current knowledge and emerging research, this review aims to enhance the understanding of FGF-FGFR-mediated signaling and its implications for health and disease, which will be crucial for therapeutic development against FGF-related pathological conditions.
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Affiliation(s)
- Oshadi Edirisinghe
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR 72701, USA;
| | - Gaëtane Ternier
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA; (G.T.); (Z.A.)
| | - Zeina Alraawi
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA; (G.T.); (Z.A.)
| | - Thallapuranam Krishnaswamy Suresh Kumar
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR 72701, USA;
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA; (G.T.); (Z.A.)
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Balbo SL, Soares GM, Morari J, Felisberto AM, Vettorazzi JF, Bronczek GA, Bonfleur ML, Carneiro EM, Boschero AC, Velloso LA. Impact of Sleeve Gastrectomy on Body Weight and Food Intake Regulation in Diet-Induced Obese Mice. Curr Issues Mol Biol 2024; 46:12633-12640. [PMID: 39590343 PMCID: PMC11592983 DOI: 10.3390/cimb46110749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/31/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
The epidemic of obesity has increased worldwide and is associated with comorbidities such as diabetes and cardiovascular disease. In this context, strategies that modulate body weight and improve glycemic metabolism have increased, and bariatric surgeries such as Sleeve Gastrectomy (SG) have been highlighted in obesity treatment. However, the mechanism by which SG reduces body weight and improves glycemic control remains unknown. Thus, in this study, we aimed to evaluate food intake and the expression of hypothalamic genes involved with the regulation of this process in diet-induced obese mice submitted to SG. For this, we used C57BL/6 mice submitted to a 10-week high-fat diet protocol and submitted to SG. Food intake, fed and fasted glycemia, as well as hypothalamic anorexigenic and orexigenic gene expression were evaluated 4 weeks after the surgical procedure. First, we observed that SG reduces body weight (44.19 ± 0.47 HFD, 43.51 ± 0.71 HFD-SHAM, and 38.22 ± 1.31 HFD-SG), fasting glycemia (115.0 ± 4.60 HFD, 122.4 ± 3.48 HFD-SHAM, and 93.43 ± 4.67 HFD-SG), insulinemia (1.77 ± 0.15 HFD, 1.92 ± 0.27 HFD-SHAM, and 0.93 ± 0.05 HFD-SG), and leptinemia (5.86 ± 1.38 HFD, 6.44 ± 1.51 HFD-SHAM, and 1.43 ± 0.35 HFD-SG) in obese mice. Additionally, SG reduces food (5.15 ± 0.18 HFD, 5.49 ± 0.32, HFD-SHAM, and 3.28 ± 0.26 HFD-SG) and total (16.88 ± 0.88 HFD, 17.05 ± 0.42, HFD-SHAM, and 14.30 ± 0.73 HFD-SG) calorie intake without alterations in anorexigenic and orexigenic gene expression. In conclusion, these data indicate that SG improves obesity-associated alterations at least in part by a reduction in food intake. This effect is not associated with the canonical food intake pathway in the hypothalamus, indicating the involvement of non-canonical pathways in this process.
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Affiliation(s)
- Sandra Lucinei Balbo
- Laboratory of Endocrine Physiology and Metabolism, Biological Sciences and Health Center, Western Parana State University, Cascavel 85819210, PR, Brazil; (A.M.F.J.); (M.L.B.)
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083864, SP, Brazil; (G.M.S.); (J.M.); (G.A.B.); (E.M.C.); (A.C.B.); (L.A.V.)
| | - Gabriela Moreira Soares
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083864, SP, Brazil; (G.M.S.); (J.M.); (G.A.B.); (E.M.C.); (A.C.B.); (L.A.V.)
| | - Joseane Morari
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083864, SP, Brazil; (G.M.S.); (J.M.); (G.A.B.); (E.M.C.); (A.C.B.); (L.A.V.)
| | - Antonio Machado Felisberto
- Laboratory of Endocrine Physiology and Metabolism, Biological Sciences and Health Center, Western Parana State University, Cascavel 85819210, PR, Brazil; (A.M.F.J.); (M.L.B.)
- Laboratory of Medical Sciences, Latin-American Institute of Life and Natural Sciences, Federal University of Latin-American Integration (UNILA), Foz do Iguassu 85867970, PR, Brazil
| | - Jean Franciesco Vettorazzi
- Laboratory of Medical Sciences, Latin-American Institute of Life and Natural Sciences, Federal University of Latin-American Integration (UNILA), Foz do Iguassu 85867970, PR, Brazil
| | - Gabriela Alves Bronczek
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083864, SP, Brazil; (G.M.S.); (J.M.); (G.A.B.); (E.M.C.); (A.C.B.); (L.A.V.)
| | - Maria Lúcia Bonfleur
- Laboratory of Endocrine Physiology and Metabolism, Biological Sciences and Health Center, Western Parana State University, Cascavel 85819210, PR, Brazil; (A.M.F.J.); (M.L.B.)
| | - Everardo Magalhães Carneiro
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083864, SP, Brazil; (G.M.S.); (J.M.); (G.A.B.); (E.M.C.); (A.C.B.); (L.A.V.)
| | - Antonio Carlos Boschero
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083864, SP, Brazil; (G.M.S.); (J.M.); (G.A.B.); (E.M.C.); (A.C.B.); (L.A.V.)
| | - Lício Augusto Velloso
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083864, SP, Brazil; (G.M.S.); (J.M.); (G.A.B.); (E.M.C.); (A.C.B.); (L.A.V.)
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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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7
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Lopez-Pascual A, Russo-Cabrera JS, Ardaiz N, Palmer T, Graham AR, Uriarte I, Gomar C, Ruiz-Guillamon D, Latasa MU, Arechederra M, Fontanellas A, Monte MJ, Marin JJG, Berasain C, Del Rio CL, Fernandez-Barrena MG, Martini PGV, Schultz JR, Berraondo P, Avila MA. Non-mitogenic FGF19 mRNA-based therapy for the treatment of experimental metabolic dysfunction-associated steatotic liver disease (MASLD). Clin Sci (Lond) 2024; 138:1265-1284. [PMID: 39301694 DOI: 10.1042/cs20241137] [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: 06/17/2024] [Revised: 09/16/2024] [Accepted: 09/18/2024] [Indexed: 09/22/2024]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) represents a global health threat. MASH pathophysiology involves hepatic lipid accumulation and progression to severe conditions like cirrhosis and, eventually, hepatocellular carcinoma. Fibroblast growth factor (FGF)-19 has emerged as a key regulator of metabolism, offering potential therapeutic avenues for MASH and associated disorders. We evaluated the therapeutic potential of non-mitogenic (NM)-FGF19 mRNA formulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) in C57BL/6NTac male mice with diet-induced obesity and MASH (DIO-MASH: 40% kcal fat, 20% kcal fructose, 2% cholesterol). After feeding this diet for 21 weeks, NM-FGF19-mRNAs-LNPs or control (C-mRNA-LNPs) were administered (0.5 mg/kg, i.v.) weekly for another six weeks, in which diet feeding continued. NM-FGF19-mRNAs-LNPs treatment in DIO-MASH mice resulted in reduced body weight, adipose tissue depots, and serum transaminases, along with improved insulin sensitivity. Histological analyses confirmed the reversal of MASH features, including steatosis reduction without worsening fibrosis. NM-FGF19-mRNAs-LNPs reduced total hepatic bile acids (BAs) and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the down-regulation of metabolic dysfunction-associated genes in adipose tissue. This study highlights the potential of NM-FGF19-mRNA-LNPs therapy for MASH, addressing both hepatic and systemic metabolic dysregulation. NM-FGF19-mRNA demonstrates efficacy in reducing liver steatosis, improving metabolic parameters, and modulating BA levels and composition. Given the central role played by BA in dietary fat absorption, this effect of NM-FGF19-mRNA may be mechanistically relevant. Our study underscores the high translational potential of mRNA-based therapies in addressing the multifaceted landscape of MASH and associated metabolic perturbations.
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Affiliation(s)
- Amaya Lopez-Pascual
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Joan S Russo-Cabrera
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Nuria Ardaiz
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | | | | | - Iker Uriarte
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | - Celia Gomar
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - David Ruiz-Guillamon
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Maria U Latasa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | - Maria Arechederra
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | - Antonio Fontanellas
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | - Maria J Monte
- CIBERehd, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Jose J G Marin
- CIBERehd, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Carmen Berasain
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | | | - Maite G Fernandez-Barrena
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | | | | | - Pedro Berraondo
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERonc, Madrid, Spain
| | - Matias A Avila
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
- CIBERehd, Madrid, Spain
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Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [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: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
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Gędaj A, Gregorczyk P, Żukowska D, Chorążewska A, Ciura K, Kalka M, Porębska N, Opaliński Ł. Glycosylation of FGF/FGFR: An underrated sweet code regulating cellular signaling programs. Cytokine Growth Factor Rev 2024; 77:39-55. [PMID: 38719671 DOI: 10.1016/j.cytogfr.2024.04.001] [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: 03/21/2024] [Revised: 04/23/2024] [Accepted: 04/23/2024] [Indexed: 06/22/2024]
Abstract
Fibroblast growth factors (FGFs) and their receptors (FGFRs) constitute plasma-membrane localized signaling hubs that transmit signals from the extracellular environment to the cell interior, governing pivotal cellular processes like motility, metabolism, differentiation, division and death. FGF/FGFR signaling is critical for human body development and homeostasis; dysregulation of FGF/FGFR units is observed in numerous developmental diseases and in about 10% of human cancers. Glycosylation is a highly abundant posttranslational modification that is critical for physiological and pathological functions of the cell. Glycosylation is also very common within FGF/FGFR signaling hubs. Vast majority of FGFs (15 out of 22 members) are N-glycosylated and few FGFs are O-glycosylated. Glycosylation is even more abundant within FGFRs; all FGFRs are heavily N-glycosylated in numerous positions within their extracellular domains. A growing number of studies points on the multiple roles of glycosylation in fine-tuning FGF/FGFR signaling. Glycosylation modifies secretion of FGFs, determines their stability and affects interaction with FGFRs and co-receptors. Glycosylation of FGFRs determines their intracellular sorting, constitutes autoinhibitory mechanism within FGFRs and adjusts FGF and co-receptor recognition. Sugar chains attached to FGFs and FGFRs constitute also a form of code that is differentially decrypted by extracellular lectins, galectins, which transform FGF/FGFR signaling at multiple levels. This review focuses on the identified functions of glycosylation within FGFs and FGFRs and discusses their relevance for the cell physiology in health and disease.
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Affiliation(s)
- Aleksandra Gędaj
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw 50-383, Poland
| | - Paulina Gregorczyk
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw 50-383, Poland
| | - Dominika Żukowska
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw 50-383, Poland
| | - Aleksandra Chorążewska
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw 50-383, Poland
| | - Krzysztof Ciura
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw 50-383, Poland
| | - Marta Kalka
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw 50-383, Poland
| | - Natalia Porębska
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw 50-383, Poland
| | - Łukasz Opaliński
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw 50-383, Poland.
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10
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Li X, Lu W, Kharitonenkov A, Luo Y. Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases. J Intern Med 2024; 295:292-312. [PMID: 38212977 DOI: 10.1111/joim.13767] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2024]
Abstract
Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19-FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials.
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Affiliation(s)
- Xiaokun Li
- School of Pharmacological Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weiqin Lu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA
| | | | - Yongde Luo
- School of Pharmacological Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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11
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Ferrell JM, Dilts M, Pokhrel S, Stahl Z, Boehme S, Wang X, Chiang JYL. Fibroblast Growth Factor 19 Alters Bile Acids to Induce Dysbiosis in Mice With Alcohol-Induced Liver Disease. Cell Mol Gastroenterol Hepatol 2024; 18:71-87. [PMID: 38417701 PMCID: PMC11127034 DOI: 10.1016/j.jcmgh.2024.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/01/2024]
Abstract
BACKGROUND & AIMS Excessive alcohol consumption can lead to alcohol-associated liver disease, a spectrum of conditions ranging from steatosis to fibrosis and cirrhosis. Bile acids regulate metabolic pathways by binding to cellular and nuclear receptors, and they also interact with the gut microbiome to control microbial overgrowth. Fibroblast growth factor 19 (FGF-19) is an ileum-derived hormone induced and released in response to bile acid activation of the nuclear receptor farnesoid X receptor. FGF-19 signaling is dysregulated with ethanol consumption and is increased in patients with alcoholic hepatitis. Here, we examined the effects of FGF-19 in a mouse model of chronic + binge ethanol feeding. METHODS After injection of adeno-associated virus-green fluorescent protein or AAV-FGF-19, female C57BL/6J mice were pair-fed a Lieber DeCarli liquid diet (5% v/v) or control diet for 10 days and were given a bolus gavage of 5% ethanol or maltose control to represent a binge drinking episode. Tissues were collected for analysis 9 hours after the binge. RESULTS Chronic + binge ethanol feeding induced steatosis regardless of FGF-19 expression. Interestingly, FGF-19 and ethanol resulted in significantly increased liver inflammation, as measured by Il6, Tgfβ, and Tnfα, compared with ethanol alone. Both ethanol and FGF-19 decreased bile acid synthesis, and FGF-19 significantly reduced secondary bile acids, leading to overgrowth of specific pathogenic bacteria including Enterococcus faecalis, Escherichia coli, and Clostridium perfringens. CONCLUSIONS Dysregulation of FGF-19 and consequent changes in bile acid synthesis and composition during alcohol consumption may be a contributing factor to alcohol-induced liver disease and dysbiosis.
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Affiliation(s)
- Jessica M Ferrell
- Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio.
| | - Matthew Dilts
- Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
| | - Sabita Pokhrel
- Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
| | - Zachary Stahl
- Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
| | - Shannon Boehme
- Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
| | - Xinwen Wang
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown Ohio
| | - John Y L Chiang
- Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
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12
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Soares GM, Balbo SL, Bronczek GA, Vettorazzi JF, Marmentini C, Zangerolamo L, Velloso LA, Carneiro EM. Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing β-cell function and survival via FGF15/19. Am J Physiol Endocrinol Metab 2024; 326:E134-E147. [PMID: 38117265 DOI: 10.1152/ajpendo.00218.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 12/21/2023]
Abstract
Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, β-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E β-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor β-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor β-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E β-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.
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Affiliation(s)
- Gabriela M Soares
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Sandra L Balbo
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Laboratory of Endocrine Physiology and Metabolism, Biological Sciences and Health Center, Western Paraná State University (UNIOESTE), Cascavel, Brazil
| | - Gabriela A Bronczek
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Jean F Vettorazzi
- Latin-American Institute of Life and Nature Sciences, Federal University of Latin-American Integration (UNILA), Foz do Iguacu, Brazil
| | - Carine Marmentini
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Lucas Zangerolamo
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Lício A Velloso
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Everardo M Carneiro
- Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
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13
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Ursic-Bedoya J, Desandré G, Chavey C, Marie P, Polizzi A, Rivière B, Guillou H, Assenat E, Hibner U, Gregoire D. FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis. EMBO Mol Med 2024; 16:238-250. [PMID: 38228803 PMCID: PMC10897482 DOI: 10.1038/s44321-023-00021-x] [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: 09/15/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/18/2024] Open
Abstract
FGF19 hormone has pleiotropic metabolic functions, including the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone's metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormone's oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver.
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Affiliation(s)
- José Ursic-Bedoya
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
- Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, CHU Montpellier, University of Montpellier, Montpellier, France
| | - Guillaume Desandré
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Carine Chavey
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Pauline Marie
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Arnaud Polizzi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Benjamin Rivière
- Department of Pathology, Gui de Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Eric Assenat
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
- Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, CHU Montpellier, University of Montpellier, Montpellier, France
| | - Urszula Hibner
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Damien Gregoire
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
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14
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Wang Y, Bi X, Zhao H, Li Z, Zhao J, Zhou J, Huang Z, Zhang Y, Chen X, Zhang C, Cai J, Ren Y. Prognostic significance of the preoperative alkaline phosphatase‑to‑albumin ratio in patients with hepatocellular carcinoma after hepatic resection. Oncol Lett 2023; 25:147. [PMID: 36936019 PMCID: PMC10018275 DOI: 10.3892/ol.2023.13733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
This study aimed to investigate the prognostic value of the preoperative alkaline phosphatase-to-albumin ratio (APAR) in patients with hepatocellular carcinoma (HCC) who underwent radical hepatectomy. The clinicopathological data from 330 patients was retrospectively analyzed. Receiver operating characteristic curves of APAR for diagnostic tumor recurrence were plotted with a cut-off value of 1.74. A high preoperative APAR value was significantly associated with hepatitis B surface antigen level, tumor diameter, and tumor-node-metastasis stage. The disease-free survival (DFS) and overall survival (OS) of patients with a high preoperative APAR were shorter than those with a low APAR. The independent risk factors for DFS were an APAR ≥1.74, and macrovascular invasion or tumor thrombus. The independent risk factors for OS were an APAR ≥1.74, existing clinical symptoms, α-fetoprotein level ≥20 ng/ml, macrovascular invasion or tumor thrombus, and family history of cancer. In conclusion, a preoperative APAR (≥1.74) is an independent risk factor influencing the poor prognosis of patients with HCC after curative hepatectomy, and patients with such a result should be closely monitored.
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Affiliation(s)
- Yikai Wang
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Zhiyu Li
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Yefan Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Xiao Chen
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Chongda Zhang
- New York University Medical Center, New York University, New York, NY 10016, USA
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Yijun Ren
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
- Correspondence to: Dr Yijun Ren, Department of Orthopedics, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei 430060, P.R. China, E-mail:
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15
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Ruze R, Song J, Yin X, Chen Y, Xu R, Wang C, Zhao Y. Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review. Signal Transduct Target Ther 2023; 8:139. [PMID: 36964133 PMCID: PMC10039087 DOI: 10.1038/s41392-023-01376-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 01/31/2023] [Accepted: 02/15/2023] [Indexed: 03/26/2023] Open
Abstract
Research on obesity- and diabetes mellitus (DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers. The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence, which is partially responsible for the slight but constant increase in pancreatic cancer (PC) occurrence. PC is a highly lethal malignancy characterized by its insidious symptoms, delayed diagnosis, and devastating prognosis. The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent whole-body systemic changes that are suitable for cancer initiation. The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways. Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment (TME) for carcinogenesis, which can be exacerbated by several crucial pathophysiological processes and TME components, such as autophagy, endoplasmic reticulum stress, oxidative stress, epithelial-mesenchymal transition, and exosome secretion. This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity- and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.
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Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
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16
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Tian H, Zhang S, Liu Y, Wu Y, Zhang D. Fibroblast Growth Factors for Nonalcoholic Fatty Liver Disease: Opportunities and Challenges. Int J Mol Sci 2023; 24:ijms24054583. [PMID: 36902015 PMCID: PMC10003526 DOI: 10.3390/ijms24054583] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/24/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD.
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Affiliation(s)
- Haoyu Tian
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Shuairan Zhang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Ying Liu
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Yifan Wu
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Dianbao Zhang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
- Correspondence: or
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17
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Fu K, Chen X, Shou N, Wang Z, Yuan X, Wu D, Wang Q, Cheng Y, Ling N, Shi Z. Swainsonine Induces Liver Inflammation in Mice via Disturbance of Gut Microbiota and Bile Acid Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:1758-1767. [PMID: 36638362 DOI: 10.1021/acs.jafc.2c08519] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Swainsonine induced liver inflammation in livestock; however, the underlying mechanisms, especially the role of bile acids (BAs), in the pathogenesis remained elusive. Here, our results showed that swainsonine induced hepatic inflammation via changing BA metabolism and gut microbiota in mice. Swainsonine significantly upregulated the levels of deoxycholic acid (DCA) and taurine-β-muricholic acid (T-β-MCA) in the serum and liver of mice due to the markedly increased genus Clostridium and the decreased genus Lactobacillus in the gut. As antagonists of the farnesoid X receptor (FXR), elevated DCA and T-β-MCA inhibited hepatic Fxr gene expression and thus suppressed FXR-SHP signaling and activated hepatic Cyp7a1 gene expression, which induced a significant upregulation of the total BA level in serum, contributing to liver inflammation. These findings offer new insights into the underlying mechanisms in which swainsonine induced liver inflammation in mice via the gut-liver axis and suggest that gut microbiota and its metabolite BAs may be underlying triggering factors.
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Affiliation(s)
- Keyi Fu
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Xi Chen
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Na Shou
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Zilong Wang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Xuefeng Yuan
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Dandan Wu
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Qi Wang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Yanfen Cheng
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Ning Ling
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Zunji Shi
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Center for Grassland Microbiome, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China
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Abstract
Striving to optimize surgical outcomes, the Enhanced Recovery After Surgery (ERAS) pathway mitigates patients' stress through the implementation of evidence-based practices during the pre-, intra-, and postoperative periods. Intestinal flora is a sophisticated ecosystem integrating with the host and the external environment, which serves as a mediator in diverse interventions of ERAS to regulate human metabolism and inflammation. This review linked gut microbes and their metabolites with ERAS interventions, offering novel high-quality investigative proponents for ERAS. ERAS could alter the composition and function of intestinal flora in patients by alleviating various perioperative stress responses. Modifying gut flora through multiple modalities, such as diet and nutrition, to accelerate recovery might be a complementary approach when exploring novel ERAS initiatives. Meanwhile, the pandemic of COVID-19 and the availability of promising qualitative evidence created both challenges and opportunities for the establishment of ERAS mode.
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FGFR Inhibitors in Cholangiocarcinoma-A Novel Yet Primary Approach: Where Do We Stand Now and Where to Head Next in Targeting This Axis? Cells 2022; 11:cells11233929. [PMID: 36497187 PMCID: PMC9737583 DOI: 10.3390/cells11233929] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/20/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinomas (CCAs) are rare but aggressive tumours with poor diagnosis and limited treatment options. Molecular targeted therapies became a promising proposal for patients after progression under first-line chemical treatment. In light of an escalating prevalence of CCA, it is crucial to fully comprehend its pathophysiology, aetiology, and possible targets in therapy. Such knowledge would play a pivotal role in searching for new therapeutic approaches concerning diseases' symptoms and their underlying causes. Growing evidence showed that fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) pathway dysregulation is involved in a variety of processes during embryonic development and homeostasis as well as tumorigenesis. CCA is known for its close correlation with the FGF/FGFR pathway and targeting this axis has been proposed in treatment guidelines. Bearing in mind the significance of molecular targeted therapies in different neoplasms, it seems most reasonable to move towards intensive research and testing on these in the case of CCA. However, there is still a need for more data covering this topic. Although positive results of many pre-clinical and clinical studies are discussed in this review, many difficulties lie ahead. Furthermore, this review presents up-to-date literature regarding the outcomes of the latest clinical data and discussion over future directions of FGFR-directed therapies in patients with CCA.
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Matye DJ, Qin X, Hasan MN, Gu L, Clayton YD, Li F, Li T. Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis. LIVER RESEARCH 2022; 6:276-283. [PMID: 36819659 PMCID: PMC9933918 DOI: 10.1016/j.livres.2022.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/07/2022] [Accepted: 11/07/2022] [Indexed: 11/15/2022]
Abstract
Background and aims Several bile acids-based monotherapies have been developed for non-alcoholic steatohepatitis (NASH) treatment but clinical trial findings suggest that they do not satisfactorily improve NASH and liver fibrosis in many patients. Recently, we have shown that combining a gut-restricted apical sodium-bile acid transporter (ASBT) inhibitor GSK2330672 (GSK) with adeno-associated virus (AAV)-mediated liver fibroblast growth factor 15 (FGF15) overexpression provides significantly improved efficacy than either single treatment against NASH and liver fibrosis in a high fat, cholesterol, and fructose (HFCFr) diet-induced NASH mouse model. The beneficial effects of the combined treatment can be attributed to the markedly reduced bile acid pool that reduces liver bile acid burden and intestinal lipid absorption. The aim of this study is to further investigate if combining GSK treatment with the orally bioavailable obeticholic acid (OCA), which induces endogenous FGF15 and inhibits hepatic bile acid synthesis, can achieve similar anti-NASH effect as the GSK+AAV-FGF15 co-treatment in HFCFr-diet-fed mice. Materials and methods Male C57BL/6J mice were fed HFCFr diet to induce NASH and liver fibrosis. The effect of GSK, OCA, and GSK+OCA treatments on NASH development was compared and contrasted among all groups. Results Findings from this study showed that the GSK+OCA co-treatment did not cause persistent reduction of obesity over a 12-week treatment period. Neither single treatment nor the GSK+OCA co-treatment reduce hepatic steatosis, but all three treatments reduced hepatic inflammatory cytokines and fibrosis by a similar magnitude. The GSK+OCA co-treatment caused a higher degree of total bile acid pool reduction (~55%) than either GSK or OCA treatment alone. However, such bile acid pool reduction was insufficient to cause increased fecal lipid loss. The GSK+OCA co-treatment prevented GSK-mediated induction of hepatic cholesterol 7alpha-hydroxylase but failed to induce ileal FGF15 expression. GSK did not reduce gallbladder OCA amount in the GSK+OCA group compared to the OCA group, suggesting that ASBT inhibition does not reduce hepatic OCA distribution. Conclusions Unlike the GSK+AAV-FGF15 co-treatment, the GSK+OCA co-treatment does not provide improved efficacy against NASH and liver fibrosis than either single treatment in mice. The lack of synergistic effect may be partly attributed to the moderate reduction of total bile acid pool and the lack of high level of FGF15 exposure as seen in the GSK+AAV-FGF15 co-treatment.
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Affiliation(s)
- David J. Matye
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Xuan Qin
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Mohammad Nazmul Hasan
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Lijie Gu
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Yung Dai Clayton
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Feng Li
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
- NMR and Drug Metabolism Core, Baylor College of Medicine, Houston, TX, USA
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Zhang X, Soutto M, Chen Z, Bhat N, Zhu S, Eissmann MF, Ernst M, Lu H, Peng D, Xu Z, El-Rifai W. Induction of Fibroblast Growth Factor Receptor 4 by Helicobacter pylori via Signal Transducer and Activator of Transcription 3 With a Feedforward Activation Loop Involving SRC Signaling in Gastric Cancer. Gastroenterology 2022; 163:620-636.e9. [PMID: 35588797 PMCID: PMC9629135 DOI: 10.1053/j.gastro.2022.05.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 04/07/2022] [Accepted: 05/09/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Helicobacter pylori (H pylori) infection is the main risk factor for gastric cancer. The role of fibroblast growth factor receptors (FGRFs) in H pylori-mediated gastric tumorigenesis remains largely unknown. This study investigated the molecular and mechanistic links between H pylori, inflammation, and FGFR4 in gastric cancer. METHODS Cell lines, human and mouse gastric tissue samples, and gastric organoids models were implemented. Infection with H pylori was performed using in vitro and in vivo models. Western blot, real-time quantitative reverse-transcription polymerase chain reaction, flow cytometry, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation, and luciferase reporter assays were used for molecular, mechanistic, and functional studies. RESULTS Analysis of FGFR family members using The Cancer Genome Atlas data, followed by validation, indicated that FGFR4 messenger (m)RNA was the most significantly overexpressed member in human gastric cancer tissue samples (P < .001). We also detected high levels of Fgfr4 mRNA and protein in gastric dysplasia and adenocarcinoma lesions in mouse models. Infection with J166, 7.13, and PMSS1 cytotoxin-associated gene A (CagA)+ H pylori strains induced FGFR4 mRNA and protein expression in in vitro and in vivo models. This was associated with a concordant activation of signal transducer and activator of transcription 3 (STAT3). Analysis of the FGFR4 promoter suggested several putative binding sites for STAT3. Using chromatin immunoprecipitation assay and an FGFR-promoter luciferase reporter containing putative STAT3 binding sites and their mutants, we confirmed a direct functional binding of STAT3 on the FGFR4 promoter. Mechanistically, we also discovered a feedforward activation loop between FGFR4 and STAT3 where the fibroblast growth factor 19–FGFR4 axis played an essential role in activating STAT3 in a SRC proto-oncogene non-receptor tyrosine kinase dependent manner. Functionally, we found that FGFR4 protected against H pylori-induced DNA damage and cell death. CONCLUSIONS Our findings demonstrated a link between infection, inflammation, and FGFR4 activation, where a feedforward activation loop between FGFR4 and STAT3 is established via SRC proto-oncogene non-receptor tyrosine kinase in response to H pylori infection. Given the relevance of FGFR4 to the etiology and biology of gastric cancer, we propose FGFR4 as a druggable molecular vulnerability that can be tested in patients with gastric cancer.
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Affiliation(s)
- Xing Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida; Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Mohammed Soutto
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Zheng Chen
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Nadeem Bhat
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Shoumin Zhu
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Moritz F Eissmann
- Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
| | - Matthias Ernst
- Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
| | - Heng Lu
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Dunfa Peng
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Wael El-Rifai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
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22
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Liu S, Liu M, Zhang ML, Wang CZ, Zhang YL, Zhang YJ, Du CY, Sheng SF, Wang W, Fan YT, Song JN, Huang JC, Feng YY, Qiao W, Huang JL, Li YH, Zhou L, Zhang J, Chang YS. Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression. Acta Pharmacol Sin 2022; 43:2362-2372. [PMID: 35105957 PMCID: PMC9433408 DOI: 10.1038/s41401-021-00850-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 12/21/2021] [Indexed: 11/09/2022]
Abstract
Bile acid (BA) homeostasis is regulated by the extensive cross-talk between liver and intestine. Many bile-acid-activated signaling pathways have become attractive therapeutic targets for the treatment of metabolic disorders. In this study we investigated the regulatory mechanisms of BA in the intestine. We showed that the BA levels in the gallbladder and faeces were significantly increased, whereas serum BA levels decreased in systemic Krüppel-like factor 9 (Klf9) deficiency (Klf9-/-) mice. These phenotypes were also observed in the intestine-specific Klf9-deleted (Klf9vil-/-) mice. In contrast, BA levels in the gallbladder and faeces were reduced, whereas BA levels in the serum were increased in intestinal Klf9 transgenic (Klf9Rosa26+/+) mice. By using a combination of biochemical, molecular and functional assays, we revealed that Klf9 promoted the expression of apical sodium-dependent bile acid transporter (Asbt) in the terminal ileum to enhance BA absorption in the intestine. Reabsorbed BA affected liver BA synthetic enzymes by regulating Fgf15 expression. This study has identified a previously neglected transcriptional pathway that regulates BA homeostasis.
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Affiliation(s)
- Shuang Liu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Man Liu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Meng-Lin Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Cui-Zhe Wang
- Department of Basic Medicine, Shihezi University School of Medicine, Shihezi, 832000, China
| | - Yin-Liang Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Yu-Jie Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Chun-Yuan Du
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Su-Fang Sheng
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Wei Wang
- Key Laboratory of Biotechnology of Hubei Province, Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, 430062, China
| | - Ya-Tong Fan
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Jia-Ni Song
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Jin-Can Huang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Yue-Yao Feng
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Wei Qiao
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Jin-Long Huang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Yu-Hui Li
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Jun Zhang
- Department of Basic Medicine, Shihezi University School of Medicine, Shihezi, 832000, China.
| | - Yong-Sheng Chang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300052, China.
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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] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/19/2022] [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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24
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Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 2022; 19:432-450. [PMID: 35165436 DOI: 10.1038/s41575-021-00566-7] [Citation(s) in RCA: 226] [Impact Index Per Article: 75.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2021] [Indexed: 02/06/2023]
Abstract
Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.
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25
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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Guthrie G, Vonderohe C, Burrin D. Fibroblast growth factor 15/19 expression, regulation, and function: An overview. Mol Cell Endocrinol 2022; 548:111617. [PMID: 35301051 PMCID: PMC9038700 DOI: 10.1016/j.mce.2022.111617] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 12/12/2022]
Abstract
Since the discovery of fibroblast growth factor (FGF)-19 over 20 years ago, our understanding of the peptide and its role in human biology has moved forward significantly. A member of a superfamily of paracrine growth factors regulating embryonic development, FGF19 is unique in that it is a dietary-responsive endocrine hormone linked with bile acid homeostasis, glucose and lipid metabolism, energy expenditure, and protein synthesis during the fed to fasted state. FGF19 achieves this through targeting multiple tissues and signaling pathways within those tissues. The diverse functional capabilities of FGF19 is due to the unique structural characteristics of the protein and its receptor binding in various cell types. This review will cover the current literature on the protein FGF19, its target receptors, and the biological pathways they target through unique signaling cascades.
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Affiliation(s)
- Greg Guthrie
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Caitlin Vonderohe
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Douglas Burrin
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States.
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Huang X, Fan M, Huang W. Pleiotropic roles of FXR in liver and colorectal cancers. Mol Cell Endocrinol 2022; 543:111543. [PMID: 34995680 PMCID: PMC8818033 DOI: 10.1016/j.mce.2021.111543] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 12/01/2022]
Abstract
Nuclear receptor farnesoid X receptor (FXR) is generally considered a cell protector of enterohepatic tissues and a suppressor of liver cancer and colorectal carcinoma (CRC). Loss or reduction of FXR expression occurs during carcinogenesis, and the FXR level is inversely associated with the aggressive behaviors of the malignancy. Global deletion of FXR and tissue-specific deletion of FXR display distinct effects on tumorigenesis. Epigenetic silencing and inflammatory context are two main contributors to impaired FXR expression and activity. FXR exerts its antitumorigenic function via the following mechanisms: 1) FXR regulates multiple metabolic processes, notably bile acid homeostasis; 2) FXR antagonizes hepatic and enteric inflammation; 3) FXR impedes aberrant activation of some cancer-related pathways; and 4) FXR downregulates a number of oncogenes while upregulating some tumor suppressor genes. Restoring FXR functions via its agonists provides a therapeutic approach for patients with liver cancer and CRC. However, an in-depth understanding of the species-specific pharmacological effects is a prerequisite for assessing the clinical safety and efficacy of FXR agonists in human cancer treatment.
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Affiliation(s)
- Xiongfei Huang
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350004, PR China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, 350108, PR China.
| | - Mingjie Fan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
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Ursic-Bedoya J, Chavey C, Desandré G, Meunier L, Dupuy AM, Gonzalez-Dopeso Reyes I, Tordjmann T, Assénat E, Hibner U, Gregoire D. Fibroblast Growth Factor 19 stimulates water intake. Mol Metab 2022; 60:101483. [PMID: 35367668 PMCID: PMC9019402 DOI: 10.1016/j.molmet.2022.101483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/18/2022] [Accepted: 03/27/2022] [Indexed: 11/30/2022] Open
Affiliation(s)
- José Ursic-Bedoya
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, University of Montpellier, France
| | - Carine Chavey
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Guillaume Desandré
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Lucy Meunier
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, University of Montpellier, France
| | - Anne-Marie Dupuy
- Biochemistry and Hormonology Department, Lapeyronie Hospital, University of Montpellier, Montpellier, France
| | | | - Thierry Tordjmann
- Université Paris Saclay, Faculté des Sciences d'Orsay, INSERM U.1193, Bât. 443, 91405, Orsay, France
| | - Eric Assénat
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, University of Montpellier, France
| | - Urszula Hibner
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Damien Gregoire
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
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Wang Y, Zheng L, Zhou Z, Yao D, Huang Y, Liu B, Duan Y, Li Y. Review article: insights into the bile acid-gut microbiota axis in intestinal failure-associated liver disease-redefining the treatment approach. Aliment Pharmacol Ther 2022; 55:49-63. [PMID: 34713470 DOI: 10.1111/apt.16676] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/04/2021] [Accepted: 10/15/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Intestinal failure-associated liver disease (IFALD) increases mortality of patients with intestinal failure (IF), but lacks effective prevention or treatment approaches. Bile acids, gut microbiota and the host have close and complex interactions, which play a central role in modulating host immune and metabolic homeostasis. Increasing evidence suggests that derangement of the bile acid-gut microbiota (BA-GM) axis contributes to the development of IFALD. AIMS To review the BA-GM axis in the pathogenesis and clinical applications of IFALD, and to explore future directions for effective disease management. METHODS We conducted a literature search on bile acid and gut microbiota in IF and liver diseases. RESULTS The BA-GM axis demonstrates a unique IF signature manifesting as an increase in primary-to-secondary bile acids ratio, disturbed enterohepatic circulation, blunted bile acid signalling pathways, gut microbial dysbiosis, and altered microbial metabolic outputs. Bile acids and gut microbiota shape the compositional and functional alterations of each other in IF; collaboratively, they promote immune dysfunction and metabolic aberration in the liver. Diagnostic markers and treatments targeting the BA-GM axis showed promising potential in the management of IFALD. CONCLUSIONS Bile acids and gut microbiota play a central role in the development of IFALD and make attractive biomarkers as well as therapeutic targets. A multitarget, individualised therapy aiming at different parts of the BA-GM axis may provide optimal clinical benefits and requires future investigation.
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Affiliation(s)
- Yaoxuan Wang
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Lei Zheng
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Zhiyuan Zhou
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Danhua Yao
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Yuhua Huang
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Bin Liu
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Yantao Duan
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Yousheng Li
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
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Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver. J Hepatol 2021; 75:1440-1451. [PMID: 34364916 DOI: 10.1016/j.jhep.2021.07.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/09/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Fibroblast growth factor (FGF) receptor 4 (FGFR4) and its cognate ligand, FGF19, are implicated in a range of cellular processes, including differentiation, metabolism and proliferation. Indeed, their aberrant activation has been associated with the development of hepatic tumours. Despite great advances in early diagnosis and the development of new therapies, liver cancer is still associated with a high mortality rate, owing primarily to high molecular heterogeneity and unclear molecular targeting. The development of FGFR4 inhibitors is a promising tool in patients with concomitant supraphysiological levels of FGF19 and several clinical trials are testing these treatments for patients with advanced hepatocellular carcinoma (HCC). Conversely, using FGF19 analogues to activate FGFR4-KLOTHO β represents a novel therapeutic strategy in patients presenting with cholestatic liver disorders and non-alcoholic steatohepatitis, which could potentially prevent the development of metabolic HCC. Herein, we provide an overview of the currently available therapeutic options for targeting FGFR4 in HCC and other liver diseases, highlighting the need to carefully stratify patients and personalise therapeutic strategies.
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Tomonari T, Sato Y, Tanaka H, Mitsuhashi T, Hirao A, Tanaka T, Taniguchi T, Okamoto K, Sogabe M, Miyamoto H, Muguruma N, Takayama T. Therapeutic efficacy of lenvatinib in nonviral unresectable hepatocellular carcinoma. JGH Open 2021; 5:1275-1283. [PMID: 34816013 PMCID: PMC8593789 DOI: 10.1002/jgh3.12663] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 08/31/2021] [Accepted: 09/19/2021] [Indexed: 12/30/2022]
Abstract
AIM To investigate the therapeutic effect of lenvatinib (LEN) in liver disease etiology, especially nonviral hepatocellular carcinoma (HCC). METHODS AND RESULTS Sixty-seven patients with unresectable advanced HCC (u-HCC) treated with LEN and consisting of 26 hepatitis C virus (HCV), 19 hepatitis B virus (HBV), 11 alcohol, and 11 nonalcoholic steatohepatitis (NASH) cases were retrospectively recruited. Univariate and multivariate Cox proportional hazard models were used to determine predictive factors for survival. The objective response rate in the nonviral (alcohol and NASH) group was higher than that in the viral group (59.1% [13/22] vs. 46.7% [21/45]). Progression-free survival was significantly longer in the nonviral group than in the viral group (13.7 vs. 6.6 months; hazard ratio [HR] 0.324; 95% confidence interval [CI] 0.174-0.602; P < 0.01). Similarly, median overall survival (OS) was significantly longer in the nonviral group than in the viral group (not evaluable vs. 15.9 months; HR = 0.277; 95% CI = 0.116-0.662; P < 0.01). Multivariate analysis revealed that portal vein invasion (HR = 5.327, P = 0.0025), treatment line (HR = 0.455, P = 0.023), and etiology (HR = 0.180, P = 0.00055) were significant independent factors associated with OS in u-HCC patients treated with LEN. CONCLUSION Our results suggest that LEN is more effective against nonviral u-HCC than against viral u-HCC.
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Affiliation(s)
- Tetsu Tomonari
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Hironori Tanaka
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Takeshi Mitsuhashi
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Akihiro Hirao
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Takahiro Tanaka
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Tatsuya Taniguchi
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
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Nita A, Abraham SP, Krejci P, Bosakova M. Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling. Cells 2021; 10:1445. [PMID: 34207779 PMCID: PMC8227969 DOI: 10.3390/cells10061445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/27/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.
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Affiliation(s)
- Alexandru Nita
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; (A.N.); (S.P.A.); (P.K.)
| | - Sara P. Abraham
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; (A.N.); (S.P.A.); (P.K.)
| | - Pavel Krejci
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; (A.N.); (S.P.A.); (P.K.)
- Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
| | - Michaela Bosakova
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; (A.N.); (S.P.A.); (P.K.)
- Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
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The Role of Fibroblast Growth Factor 19 in Hepatocellular Carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1180-1192. [PMID: 34000282 DOI: 10.1016/j.ajpath.2021.04.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 04/09/2021] [Accepted: 04/22/2021] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the third leading cause of cancer-related deaths worldwide. Liver resection or liver transplantation is the most effective therapy for HCC because drugs approved by the US Food and Drug Administration to treat patients with unresectable HCC have an unfavorable overall survival rate. Therefore, the development of biomarkers for early diagnosis and effective therapy strategies are still necessary to improve patient outcomes. Fibroblast growth factor (FGF) 19 was amplified in patients with HCC from various studies, including patients from The Cancer Genome Atlas. FGF19 plays a syngeneic function with other signaling pathways in primary liver cancer development, such as epidermal growth factor receptor, Wnt/β-catenin, the endoplasmic reticulum-related signaling pathway, STAT3/IL-6, RAS, and extracellular signal-regulated protein kinase, among others. The current review presents a comprehensive description of the FGF19 signaling pathway involved in liver cancer development. The use of big data and bioinformatic analysis can provide useful clues for further studies of the FGF19 pathway in HCC, including its application as a biomarker, targeted therapy, and combination therapy strategies.
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Matye DJ, Wang H, Luo W, Sharp RR, Chen C, Gu L, Jones KL, Ding WX, Friedman JE, Li T. Combined ASBT Inhibitor and FGF15 Treatment Improves Therapeutic Efficacy in Experimental Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol 2021; 12:1001-1019. [PMID: 33965587 PMCID: PMC8346663 DOI: 10.1016/j.jcmgh.2021.04.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Pharmacologic agents targeting bile acid signaling show promise for treating nonalcoholic steatohepatitis (NASH). However, clinical findings suggest that new treatment strategies with enhanced therapeutic efficacy and minimized undesired effects are needed. This preclinical study investigates whether combining an apical sodium-bile acid transporter (ASBT) inhibitor GSK233072 (GSK672) and fibroblast growth factor-15 (FGF15) signaling activation improves anti-NASH efficacy. METHODS Mice with high fat, cholesterol, and fructose (HFCFr) diet-induced NASH and stage 2 fibrosis are used as a NASH model. GSK672 or AAV8-TBG-FGF15 interventions are administered alone or in combination to HFCFr diet-fed mice. RESULTS The combined treatment significantly enhances therapeutic efficacy against steatosis, inflammation, ballooning, and fibrosis than either single treatment. Mechanistically, the synergistic actions of GSK672 and FGF15 on inhibiting gut bile acid reuptake and hepatic bile acid synthesis achieve greater magnitude of bile acid pool reduction that not only decreases bile acid burden in NASH livers but also limits intestinal lipid absorption, which, together with FGF15 signaling activation, produces weight loss, reduction of adipose inflammation, and attenuated hepatocellular organelle stress. Furthermore, the combined treatment attenuates increased fecal bile acid excretion and repressed bile acid synthesis, which underlie diarrhea and hypercholesterolemia associated with ASBT inhibition and FGF19 analogue, respectively, in clinical settings. CONCLUSIONS Concomitant ASBT inhibition and FGF15 signaling activation produce metabolic changes that partially mimic the bariatric surgery condition whereby lipid malabsorption and increased FGF15/19 signaling synergistically mediate weight loss and metabolic improvement. Further clinical studies may be warranted to investigate whether combining ASBT inhibitor and FGF19 analogue enhances anti-NASH efficacy and reduced treatment-associated adverse events in humans.
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Affiliation(s)
- David J Matye
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Huaiwen Wang
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Wenyi Luo
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Rachel R Sharp
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Harold Hamm Diabetes Center, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Cheng Chen
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Lijie Gu
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Kenneth L Jones
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Harold Hamm Diabetes Center, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Jacob E Friedman
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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Sciarrillo CM, Keirns BH, Koemel NA, Anderson KL, Emerson SR. Fibroblast Growth Factor 19: Potential modulation of hepatic metabolism for the treatment of non-alcoholic fatty liver disease. Liver Int 2021; 41:894-904. [PMID: 33506572 DOI: 10.1111/liv.14802] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 12/14/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease that is becoming more prevalent in concert with obesity and poor lifestyle habits. Although NAFLD is treatable via lifestyle modification in early stages, more advanced liver pathologies (eg non-alcoholic steatohepatitis [NASH]) are harder to reverse. There is no Food and Drug Administration approved pharmacological treatment for NAFLD, and little research has been done to identify compounds that target key NAFLD mechanisms. Bile acids and bile acid receptors have been implicated in NAFLD pathogenesis and modulating bile acids and bile acid receptors has recently been targeted as a therapeutic treatment option for NAFLD. Fibroblast growth factor 19 (FGF19), a nutritionally regulated post-prandial hormone, is a chief regulator of bile acid metabolism and an important player in lipid and carbohydrate metabolism, including key mechanisms of NAFLD pathogenesis. In this review, we discuss recent findings related to FGF19-regulated processes involved in the pathogenesis of NAFLD. We summarize known and conjectural frameworks and limitations for the clinical application of FGF19-targeted therapies as they relate to NAFLD.
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Affiliation(s)
| | - Bryant H Keirns
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Nicholas A Koemel
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Kendall L Anderson
- Department of Pediatric Gastroenterology and Hepatology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Sam R Emerson
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, USA
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The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 2021; 18:335-347. [PMID: 33568795 DOI: 10.1038/s41575-020-00404-2] [Citation(s) in RCA: 243] [Impact Index Per Article: 60.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2020] [Indexed: 01/31/2023]
Abstract
Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apcmin/+ mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
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Wang J, Zhao H, Zheng L, Zhou Y, Wu L, Xu Y, Zhang X, Yan G, Sheng H, Xin R, Jiang L, Lei J, Zhang J, Chen Y, Peng J, Chen Q, Yang S, Yu K, Li D, Xie Q, Li Y. FGF19/SOCE/NFATc2 signaling circuit facilitates the self-renewal of liver cancer stem cells. Am J Cancer Res 2021; 11:5045-5060. [PMID: 33754043 PMCID: PMC7978301 DOI: 10.7150/thno.56369] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/31/2021] [Indexed: 02/07/2023] Open
Abstract
Background & Aims: Liver cancer stem cells (LCSCs) mediate therapeutic resistance and correlate with poor outcomes in patients with hepatocellular carcinoma (HCC). Fibroblast growth factor (FGF)-19 is a crucial oncogenic driver gene in HCC and correlates with poor prognosis. However, whether FGF19 signaling regulates the self-renewal of LCSCs is unknown. Methods: LCSCs were enriched by serum-free suspension. Self-renewal of LCSCs were characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and tumorigenic potential assays. Ca2+ image was employed to determine the intracellular concentration of Ca2+. Gain- and loss-of function studies were applied to explore the role of FGF19 signaling in the self-renewal of LCSCs. Results: FGF19 was up-regulated in LCSCs, and positively correlated with certain self-renewal related genes in HCC. Silencing FGF19 suppressed self-renewal of LCSCs, whereas overexpressing FGF19 facilitated CSCs-like properties via activation of FGF receptor (FGFR)-4 in none-LCSCs. Mechanistically, FGF19/FGFR4 signaling stimulated store-operated Ca2+ entry (SOCE) through both the PLCγ and ERK1/2 pathways. Subsequently, SOCE-calcineurin signaling promoted the activation and translocation of nuclear factors of activated T cells (NFAT)-c2, which transcriptionally activated the expression of stemness-related genes (e.g., NANOG, OCT4 and SOX2), as well as FGF19. Furthermore, blockade of FGF19/FGFR4-NFATc2 signaling observably suppressed the self-renewal of LCSCs. Conclusions: FGF19/FGFR4 axis promotes the self-renewal of LCSCs via activating SOCE/NFATc2 pathway; in turn, NFATc2 transcriptionally activates FGF19 expression. Targeting this signaling circuit represents a potential strategy for improving the therapeutic efficacy of HCC.
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Razmi H, Tarighat-Esfanjani A, Payahoo L, Mobasseri M, Amirpour M, Mirzaei E, Ghoreishi Z. Relationship between the levels of serum fibroblast growth factor 19 and metabolic factors in obese and normal weight subjects with and without type 2 diabetes mellitus: a case-control study. Horm Mol Biol Clin Investig 2021; 42:11-17. [PMID: 33544512 DOI: 10.1515/hmbci-2020-0075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/14/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Fibroblast growth factor 19 (FGF-19) is a metabolic regulating factor with an anti-diabetic effect. This study aimed to evaluate FGF-19 in patients with type 2 diabetes mellitus (T2DM) and its relationship with some metabolic risk factors. METHODS In this case-control study, 80 diabetic patients and 80 non-diabetic individuals were divided into two subgroups based on body mass index (BMI): obese people (BMI≥30) and participants with normal weight (25>BMI≥18.5). Furthermore, stratified analysis by gender was also performed. The metabolic factors were measured and compared in all groups. The relationship between FGF-19 and the measured items was investigated in each group. RESULTS The FGF-19 levels did not show a significant difference between groups. The serum levels of FGF-19 were negatively associated with some metabolic items, such as BMI, low-density lipoprotein (LDL), total cholesterol (TC) (p<0.01), and LDL/high-density lipoprotein (HDL) ratio (p=0.02) only in the healthy group with normal weight. According to the gender-based classification of individuals, FGF-19 showed a significant inverse relationship with BMI, weight (WT), waist circumference (WC), and hip circumference (HC) (p<0.05) in diabetic men; besides, FGF-19 in non-diabetic women had a significant negative association with TC, LDL, and LDL/HDL ratio (p<0.05). CONCLUSIONS The levels of FGF-19 were negatively correlated to WT, BMI, WC and HC in diabetic males. More studies are needed to warrant these results.
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Affiliation(s)
- Hamidreza Razmi
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Tarighat-Esfanjani
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Laleh Payahoo
- Department of Nutrition and Food Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Majid Mobasseri
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Amirpour
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Mirzaei
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohre Ghoreishi
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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39
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Williams CM, Harper Calderon J, E H, Jimenez Y, Barringer K, Carbonaro M, Molina‐Portela MDP, Thurston G, Li Z, Daly C. Monomeric/dimeric forms of Fgf15/FGF19 show differential activity in hepatocyte proliferation and metabolic function. FASEB J 2021; 35:e21286. [DOI: 10.1096/fj.202002203r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/25/2020] [Accepted: 12/03/2020] [Indexed: 12/13/2022]
Affiliation(s)
- Courtney M. Williams
- Oncology and Angiogenesis Department Regeneron Pharmaceuticals, Inc Tarrytown NY USA
| | | | - Hock E
- Oncology and Angiogenesis Department Regeneron Pharmaceuticals, Inc Tarrytown NY USA
| | - Yasalp Jimenez
- Oncology and Angiogenesis Department Regeneron Pharmaceuticals, Inc Tarrytown NY USA
| | - Kevin Barringer
- Oncology and Angiogenesis Department Regeneron Pharmaceuticals, Inc Tarrytown NY USA
| | - Marisa Carbonaro
- Oncology and Angiogenesis Department Regeneron Pharmaceuticals, Inc Tarrytown NY USA
| | | | - Gavin Thurston
- Oncology and Angiogenesis Department Regeneron Pharmaceuticals, Inc Tarrytown NY USA
| | - Zhe Li
- Oncology and Angiogenesis Department Regeneron Pharmaceuticals, Inc Tarrytown NY USA
| | - Christopher Daly
- Oncology and Angiogenesis Department Regeneron Pharmaceuticals, Inc Tarrytown NY USA
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40
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Talukdar S, Kharitonenkov A. FGF19 and FGF21: In NASH we trust. Mol Metab 2020; 46:101152. [PMID: 33383173 PMCID: PMC8085573 DOI: 10.1016/j.molmet.2020.101152] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/04/2020] [Accepted: 12/18/2020] [Indexed: 02/08/2023] Open
Abstract
Objective FGF19 and FGF21 have shown therapeutic promise since their discovery, attested by the fact there are at least 5 assets that activate the FGFR/KLB pathway and one FGF19 analog in clinical development. Methods We performed a detailed analyses of published preclinical and clinical data to offer insights into the mechanism of action, as well as PK/PD and efficacy data of the clinical assets. Results Scouring the literature, we offer mechanistic insights from preclinical data using rodents and non-human primates and pharmacodynamic data from clinical studies. Conclusion The basic and applied science around endocrine FGFs has evolved exponentially over the years with FGF19 and FGF21 analogs are now entering Phase 3 clinical research.
Fibroblast Growth Factors 19 and 21 (FGF19 and FGF21) are novel endocrine messengers that regulate multiple aspects of energy homeostasis. The magnitude and pleiotropic character of their beneficial pharmacology led to coordinated efforts to design novel FGF19/21-based therapeutics. The robust effects of FGF19 and FGF21 on lipid metabolism transformed clinical emphasis for these factors toward their use for NASH. In this review, we communicate an overview of FGF19 and FGF21 biology and the recent clinical developments with FGF21/19-based analogs.
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Affiliation(s)
- Saswata Talukdar
- Merck & Co., Inc., 213 East Grand Avenue, South San Francisco, CA, 94080, United States.
| | - Alexei Kharitonenkov
- AK Biotechnologies, LLC 3812 Verdure Lane, Zionsville, IN, 46077, United States.
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41
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Doward LC, Balp MM, Twiss J, Slota C, Cryer D, Brass CA, Anstee QM, Sanyal AJ. Development of a Patient-Reported Outcome Measure for Non-Alcoholic Steatohepatitis (NASH-CHECK): Results of a Qualitative Study. PATIENT-PATIENT CENTERED OUTCOMES RESEARCH 2020; 14:533-543. [PMID: 33336323 PMCID: PMC8357766 DOI: 10.1007/s40271-020-00485-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 11/18/2020] [Indexed: 12/13/2022]
Abstract
Background Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease characterized by excessive liver fat accumulation, inflammation, cell injury, and fibrosis. It is viewed as largely asymptomatic in its earlier (non-cirrhotic) stages, and information on the patient-perceived impact of NASH is scarce. Objective This study aimed to develop a NASH-specific patient-reported outcome (PRO) measure (NASH-CHECK) for use as a trial endpoint, using methods compliant with regulatory expectations. Methods A NASH conceptual model was developed based on the literature and clinical/patient expert review. The model guided concept elicitation (CE) interviews in patients with non-cirrhotic NASH recruited via a US tertiary care center. NASH-CHECK content was generated via thematic analysis of CE data and review by clinical/patient experts. Cognitive debriefing (CD) interviews with US patients evaluated content validity. Results The literature review confirmed that NASH impacts on functioning and health-related quality of life (HRQoL). Overall, 23 CE and 20 CD interviews were conducted. Key symptoms reported in CE interviews included pain in the upper-right abdomen (n = 14), fatigue (n = 18), poor sleep quality (n = 12), impaired memory (n = 13), and reduced focus (n = 11); key HRQoL impacts included impaired physical functioning, reduced ability to conduct daily living tasks, reduced quality of relationships, low mood, anxiety, and self-consciousness. The 52-item first-draft NASH-CHECK was reduced to 31 items based on patient feedback on item relevance, acceptability, and comprehension. Conclusions The interviews revealed key symptoms and broad HRQoL impacts of NASH. As a disease-specific PRO measure assessing symptoms and HRQoL, the NASH-CHECK is relevant, comprehensive, and acceptable to patients and clinicians.
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Affiliation(s)
- Lynda C Doward
- RTI Health Solutions, The Pavilion, Towers Business Park, Wilmslow Road, Didsbury, Manchester, M20 2LS, UK.
| | | | - James Twiss
- RTI Health Solutions, The Pavilion, Towers Business Park, Wilmslow Road, Didsbury, Manchester, M20 2LS, UK
| | | | | | | | - Quentin M Anstee
- Translational and Clinical Research Institute, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.,Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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42
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Myojin Y, Kodama T, Maesaka K, Motooka D, Sato Y, Tanaka S, Abe Y, Ohkawa K, Mita E, Hayashi Y, Hikita H, Sakamori R, Tatsumi T, Taguchi A, Eguchi H, Takehara T. ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma. Clin Cancer Res 2020; 27:1150-1161. [PMID: 33288659 DOI: 10.1158/1078-0432.ccr-20-3382] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/27/2020] [Accepted: 11/17/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is characterized by high intertumor heterogeneity of genetic drivers. Two multitarget tyrosine kinase inhibitors (TKI), lenvatinib and sorafenib, are used as standard-of-care chemotherapeutics in patients with advanced HCC, but a stratification strategy has not been established because of a lack of efficacious biomarkers. Therefore, we sought biomarkers that indicate lenvatinib-susceptible HCC. EXPERIMENTAL DESIGN We performed genetic screening of HCC driver genes involved in TKI susceptibility using a novel HCC mouse model in which tumor diversity of genetic drivers was recapitulated. A biomarker candidate was evaluated in human HCC cell lines. Secreted proteins from HCC cells were then screened using mass spectrometry. Serum and tumor levels of the biomarker candidates were analyzed for their association and prediction of overall survival in patients with HCC. RESULTS We found that lenvatinib selectively eliminated FGF19-expressing tumors, whereas sorafenib eliminated MET- and NRAS-expressing tumors. FGF19 levels and lenvatinib susceptibility were correlated in HCC cell lines, and FGF19 inhibition eliminated lenvatinib susceptibility. Lenvatinib-resistant HCC cell lines, generated by long-term exposure to lenvatinib, showed FGF19 downregulation but were resensitized to lenvatinib by FGF19 reexpression. Thus, FGF19 is a tumor biomarker of lenvatinib-susceptible HCC. Proteome and secretome analyses identified ST6GAL1 as a tumor-derived secreted protein positively regulated by FGF19 in HCC cells. Serum ST6GAL1 levels were positively correlated with tumor FGF19 expression in patients with surgically resected HCC. Among patients with serum ST6GAL1-high HCC who underwent TKI therapy, lenvatinib therapy showed significantly better survival than sorafenib. CONCLUSIONS Serum ST6GAL may be a novel biomarker that identifies lenvatinib-susceptible FGF19-driven HCC.
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Affiliation(s)
- Yuta Myojin
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuki Maesaka
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Daisuke Motooka
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| | - Yu Sato
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Satoshi Tanaka
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yuichi Abe
- Division of Molecular Diagnostics, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Kazuyoshi Ohkawa
- Department of Gastroenterology and Hepatology, Osaka International Cancer Institute, Osaka, Japan
| | - Eiji Mita
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yoshito Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ayumu Taguchi
- Division of Molecular Diagnostics, Aichi Cancer Center Research Institute, Nagoya, Japan.,Division of Advanced Cancer Diagnostics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
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Morón-Ros S, Uriarte I, Berasain C, Avila MA, Sabater-Masdeu M, Moreno-Navarrete JM, Fernández-Real JM, Giralt M, Villarroya F, Gavaldà-Navarro A. FGF15/19 is required for adipose tissue plasticity in response to thermogenic adaptations. Mol Metab 2020; 43:101113. [PMID: 33171307 PMCID: PMC7691747 DOI: 10.1016/j.molmet.2020.101113] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 12/12/2022] Open
Abstract
Objective To determine the role of enterokine FGF15/19 in adipose tissue thermogenic adaptations. Methods Circulating FGF19 and gene expression (qRT-PCR) levels were assessed in subcutaneous adipose tissue from obese human patients. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral and adeno-associated vectors. Adipose tissues were characterized in FGF15-null mice under distinct cold-related thermogenic challenges. The analyses spanned metabolic profiling, tissue characterization, histology, gene expression, and immunoblot assays. Results In humans, FGF19 levels are directly associated with UCP1 gene expression in subcutaneous adipose tissue. Experimental increases in FGF15 or FGF19 induced white fat browning in mice as demonstrated by the appearance of multilocular beige cells and markers indicative of a beige phenotype, including increased UCP1 protein levels. Mice lacking FGF15 showed markedly impaired white adipose tissue browning and a mild reduction in parameters indicative of BAT activity in response to cold-induced environmental thermogenic challenges. This was concomitant with signs of altered systemic metabolism, such as reduced glucose tolerance and impaired cold-induced insulin sensitization. Conclusions Enterokine FGF15/19 is a key factor required for adipose tissue plasticity in response to thermogenic adaptations.
Circulating FGF19 levels correlate positively with signs of fat browning in humans. Adaptive adipose tissue browning in response to cold is impaired in mice lacking FGF15. Experimentally induced increase in FGF15 or FGF19 promotes fat browning in mice. FGF15/19 signaling is required for thermogenic challenge-induced plasticity of adipose tissue.
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Affiliation(s)
- Samantha Morón-Ros
- Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain; CIBEROBN, Carlos III Health Institute, Spain
| | - Iker Uriarte
- Hepatology Program, CIMA, University of Navarra, IdiSNA, Pamplona, Spain; CIBEREHD, Carlos III Health Institute, Spain
| | - Carmen Berasain
- Hepatology Program, CIMA, University of Navarra, IdiSNA, Pamplona, Spain; CIBEREHD, Carlos III Health Institute, Spain
| | - Matías A Avila
- Hepatology Program, CIMA, University of Navarra, IdiSNA, Pamplona, Spain; CIBEREHD, Carlos III Health Institute, Spain
| | - Mònica Sabater-Masdeu
- CIBEROBN, Carlos III Health Institute, Spain; Department of Diabetes, Endocrinology and Nutrition, de Girona Biomedical Research Institute (IdIBGi), Girona, Spain
| | - José María Moreno-Navarrete
- CIBEROBN, Carlos III Health Institute, Spain; Department of Diabetes, Endocrinology and Nutrition, de Girona Biomedical Research Institute (IdIBGi), Girona, Spain
| | - José Manuel Fernández-Real
- CIBEROBN, Carlos III Health Institute, Spain; Department of Diabetes, Endocrinology and Nutrition, de Girona Biomedical Research Institute (IdIBGi), Girona, Spain
| | - Marta Giralt
- Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain; CIBEROBN, Carlos III Health Institute, Spain
| | - Francesc Villarroya
- Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain; CIBEROBN, Carlos III Health Institute, Spain.
| | - Aleix Gavaldà-Navarro
- Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain; CIBEROBN, Carlos III Health Institute, Spain.
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Mukherjee S. Advances in the treatment of nonalcoholic steatohepatitis. World J Pharmacol 2020; 9:1-12. [DOI: 10.5497/wjp.v9.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 09/19/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023] Open
Affiliation(s)
- Sandeep Mukherjee
- Department of Medicine, Creighton University Medical Center, Division of Gastroenterology, Omaha, NE 68124, United States
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45
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Yan S, Khambu B, Chen X, Dong Z, Guo G, Yin XM. Hepatic Autophagy Deficiency Remodels Gut Microbiota for Adaptive Protection via FGF15-FGFR4 Signaling. Cell Mol Gastroenterol Hepatol 2020; 11:973-997. [PMID: 33127558 PMCID: PMC7898036 DOI: 10.1016/j.jcmgh.2020.10.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The functions of the liver and the intestine are closely tied in both physiological and pathologic conditions. The gut microbiota (GM) often cause deleterious effects during hepatic pathogenesis. Autophagy is essential for liver homeostasis, but the impact of hepatic autophagy function on liver-gut interaction remains unknown. Here we investigated the effect of hepatic autophagy deficiency (Atg5Δhep) on GM and in turn the effect of GM on the liver pathology. METHODS Fecal microbiota were analyzed by 16S sequencing. Antibiotics were used to modulate GM. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene or in mice given a fibroblast growth factor receptor-4 (FGFR4) inhibitor. RESULTS Atg5Δhep causes liver injury and alterations of intestinal BA composition, with a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs. The composition of GM is significantly changed with an increase in BA-metabolizing bacteria, leading to an increased expression of ileal FGF15 driven by FXR that has a higher affinity to unconjugated BAs. Notably, antibiotics or cholestyramine treatment decreased FGF15 expression and exacerbated liver injury. Consistently, inhibition of FGF15 signaling in the liver enhances liver injury. CONCLUSIONS Deficiency of autophagy function in the liver can affect intestinal environment, leading to gut dysbiosis. Surprisingly, such changes provide an adaptive protection against the liver injury through the FGF15-FGFR4 signaling. Antibiotics use in the condition of liver injury may thus have unexpected adverse consequences via the gut-liver axis.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Xiaoyun Chen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Zheng Dong
- Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia; Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Grace Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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Myronovych A, Bhattacharjee J, Salazar-Gonzalez RM, Tan B, Mowery S, Ferguson D, Ryan KK, Zhang W, Zhao X, Oehrle M, Setchell KD, Seeley RJ, Sandoval DA, Kohli R. Assessment of the role of FGF15 in mediating the metabolic outcomes of murine Vertical Sleeve Gastrectomy (VSG). Am J Physiol Gastrointest Liver Physiol 2020; 319:G669-G684. [PMID: 32967428 PMCID: PMC7792670 DOI: 10.1152/ajpgi.00175.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/16/2020] [Accepted: 09/16/2020] [Indexed: 01/31/2023]
Abstract
Vertical sleeve gastrectomy (VSG) is the best current therapy for remission of obesity and its co-morbidities. It is understood to alter the enterohepatic circulation of bile acids in vivo. Fibroblast growth factor 19 (FGF19) in human and its murine orthologue Fgf15 plays a pivotal role in this bile acid driven enterohepatic signaling. The present study evaluated the metabolic outcomes of VSG in Fgf15 deficient mice. 6-8 weeks old male wildtype mice (WT) and Fgf15 deficient mice (KO) were fed a high fat diet (HFD) for 8 weeks. At 8th week of diet, both WT and KO mice were randomly distributed to VSG or sham surgery. Post-surgery, mice were observed for 8 weeks while fed a HFD and then euthanized to collect tissues for experimental analysis. Fgf15 deficient (KO) mice lost weight post VSG, but glucose tolerance in KO mice did not improve post VSG compared to WT mice. Enteroids derived from WT and KO mice proliferated with bile acid exposure in vitro. Post VSG both WT and KO mice had similarly altered bile acid enterohepatic flux, however Fgf15 deficient mice post VSG had increased hepatic accumulation of free and esterified cholesterol leading to lipotoxicity related ER stress, inflammasome activation, and increased Fgf21 expression. Intact Fgf15 mediated enterohepatic bile acid signaling, but not changes in bile acid flux, appear to be important for the metabolic improvements post-murine bariatric surgery. These novel data introduce a potential point of distinction between bile acids acting as ligands compared to their canonical downstream signaling pathways.
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Affiliation(s)
| | | | | | - Brandon Tan
- Pediatrics, Cincinnati Children's Hospital Medical Center, United States
| | - Sarah Mowery
- Pediatrics, Cincinnati Children's Hospital Medical Center, United States
| | - Danielle Ferguson
- Pediatrics, Cincinnati Children's Hospital Medical Center, United States
| | | | - Wujuan Zhang
- Human Genetics, Cincinnati Children's Hospital Medical Center, United States
| | - Xueheng Zhao
- Pediatrics, Cincinnati Children's Hospital Medical Center, United States
| | - Melissa Oehrle
- Pediatrics, Cincinnati Children's Hospital Medical Center, United States
| | | | - Randy J Seeley
- Surgery, University of Michigan-Ann Arbor, United States
| | - Darleen A Sandoval
- Department of Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Rohit Kohli
- Pediatrics, Children's Hospital of Los Angeles, United States
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Xie Y, Su N, Yang J, Tan Q, Huang S, Jin M, Ni Z, Zhang B, Zhang D, Luo F, Chen H, Sun X, Feng JQ, Qi H, Chen L. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther 2020; 5:181. [PMID: 32879300 PMCID: PMC7468161 DOI: 10.1038/s41392-020-00222-7] [Citation(s) in RCA: 473] [Impact Index Per Article: 94.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/28/2020] [Accepted: 06/15/2020] [Indexed: 12/13/2022] Open
Abstract
Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, and apoptosis of various types of cells. In this review, we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development, injury repair, and the pathophysiology of spectrum of diseases, which is a consequence of FGF signaling dysregulation, including cancers and chronic kidney disease (CKD). In this context, the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.
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Affiliation(s)
- Yangli Xie
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
| | - Nan Su
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jing Yang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Qiaoyan Tan
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Shuo Huang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Min Jin
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Zhenhong Ni
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Bin Zhang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Dali Zhang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Fengtao Luo
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Hangang Chen
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xianding Sun
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jian Q Feng
- Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX, 75246, USA
| | - Huabing Qi
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
| | - Lin Chen
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
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Gut-Pancreas-Liver Axis as a Target for Treatment of NAFLD/NASH. Int J Mol Sci 2020; 21:ijms21165820. [PMID: 32823659 PMCID: PMC7461212 DOI: 10.3390/ijms21165820] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/04/2020] [Accepted: 08/09/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the fall in hepatitis C virus morbidity, cirrhosis in NAFLD is becoming the most frequent indication to liver transplantation, but the pathogenetic mechanisms are still not completely understood. The so-called gut-liver axis has gained enormous interest when data showed that its alteration can lead to NAFLD development and might favor the occurrence of non-alcoholic steatohepatitis (NASH). Moreover, several therapeutic approaches targeting the gut-pancreas-liver axis, e.g., incretins, showed promising results in NASH treatment. In this review, we describe the role of incretin hormones in NAFLD/NASH pathogenesis and treatment and how metagenomic/metabolomic alterations in the gut microbiota can lead to NASH in the presence of gut barrier modifications favoring the passage of bacteria or bacterial products in the portal circulation, i.e., bacterial translocation.
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Manieri E, Folgueira C, Rodríguez ME, Leiva-Vega L, Esteban-Lafuente L, Chen C, Cubero FJ, Barrett T, Cavanagh-Kyros J, Seruggia D, Rosell A, Sanchez-Cabo F, Gómez MJ, Monte MJ, G Marin JJ, Davis RJ, Mora A, Sabio G. JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma. Proc Natl Acad Sci U S A 2020; 117:16492-16499. [PMID: 32601222 PMCID: PMC7368313 DOI: 10.1073/pnas.2002672117] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.
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Affiliation(s)
- Elisa Manieri
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain
- Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain
| | - Cintia Folgueira
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain
| | - María Elena Rodríguez
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain
| | - Luis Leiva-Vega
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain
| | - Laura Esteban-Lafuente
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain
| | - Chaobo Chen
- Department of Immunology, Ophthalmology, and ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology, and ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Tamera Barrett
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Julie Cavanagh-Kyros
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Davide Seruggia
- Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215
| | - Alejandro Rosell
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain
| | - Fátima Sanchez-Cabo
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain
| | - Manuel Jose Gómez
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain
| | - Maria J Monte
- Laboratory of Experimental Hepatology and Drug Targeting, National Institute for Study of Liver and Gastrointestinal Diseases (CIBERehd), University of Salamanca, 37007 Salamanca, Spain
| | - Jose J G Marin
- Laboratory of Experimental Hepatology and Drug Targeting, National Institute for Study of Liver and Gastrointestinal Diseases (CIBERehd), University of Salamanca, 37007 Salamanca, Spain
| | - Roger J Davis
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
| | - Alfonso Mora
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain;
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain;
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Neuschwander-Tetri BA. Therapeutic Landscape for NAFLD in 2020. Gastroenterology 2020; 158:1984-1998.e3. [PMID: 32061596 DOI: 10.1053/j.gastro.2020.01.051] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/19/2020] [Accepted: 01/21/2020] [Indexed: 12/13/2022]
Abstract
Lifestyle modifications focused on healthy eating and regular exercise are the primary recommendations for patients with nonalcoholic steatohepatitis (NASH). However, for multiple societal, psychological, physical, genetic, and epigenetic reasons, the ability of people to adopt and sustain such changes is challenging and typically not successful. To end the epidemic of NASH and prevent its complications, including cirrhosis and hepatocellular carcinoma, pharmacological interventions are now being evaluated in clinical trials. Treatments include drugs targeting energy intake, energy disposal, lipotoxic liver injury, and the resulting inflammation and fibrogenesis that lead to cirrhosis. It is likely that patients develop the phenotype of NASH by multiple mechanisms, and thus the optimal treatments of NASH will likely evolve to personalized therapy once we understand the mechanistic underpinnings of NASH in each patient. Reviewed here is the treatment landscape in this rapidly evolving field with an emphasis on drugs in Phase 2 and Phase 3 trials.
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