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1
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Koch PS, Sandorski K, Heil J, Schmid CD, Kürschner SW, Hoffmann J, Winkler M, Staniczek T, de la Torre C, Sticht C, Schledzewski K, Taketo MM, Trogisch FA, Heineke J, Géraud C, Goerdt S, Olsavszky V. Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation. Front Physiol 2021; 12:722394. [PMID: 34658910 PMCID: PMC8511684 DOI: 10.3389/fphys.2021.722394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/19/2021] [Indexed: 01/20/2023] Open
Abstract
Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCretg/wt;Ctnnb1(Ex3)fl/wt (Ctnnb1OE−EC) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1OE−EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1OE−EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.
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Affiliation(s)
- Philipp-Sebastian Koch
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kajetan Sandorski
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Joschka Heil
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christian D Schmid
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sina W Kürschner
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Johannes Hoffmann
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Manuel Winkler
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Theresa Staniczek
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carolina de la Torre
- Next Generation Sequencing Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carsten Sticht
- Next Generation Sequencing Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai Schledzewski
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Makoto Mark Taketo
- Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Felix A Trogisch
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Joerg Heineke
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Cyrill Géraud
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Section of Clinical and Molecular Dermatology, Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sergij Goerdt
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Victor Olsavszky
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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2
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Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
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3
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Owen NE, Nyimanu D, Kuc RE, Upton PD, Morrell NW, Alexander GJ, Maguire JJ, Davenport AP. Plasma levels of apelin are reduced in patients with liver fibrosis and cirrhosis but are not correlated with circulating levels of bone morphogenetic protein 9 and 10. Peptides 2021; 136:170440. [PMID: 33171278 PMCID: PMC7883214 DOI: 10.1016/j.peptides.2020.170440] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/06/2020] [Accepted: 11/01/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND The peptide apelin is expressed in human healthy livers and is implicated in the development of hepatic fibrosis and cirrhosis. Mutations in the bone morphogenetic protein receptor type II (BMPR-II) result in reduced plasma levels of apelin in patients with heritable pulmonary arterial hypertension. Ligands for BMPR-II include bone morphogenetic protein 9 (BMP9), highly expressed in liver, and BMP10, expressed in heart and to a lesser extent liver. However, it is not known whether reductions in BMP9 and/or BMP10, with associated reduction in BMPR-II signalling, correlate with altered levels of apelin in patients with liver fibrosis and cirrhosis. METHODS Plasma from patients with liver fibrosis (n = 14), cirrhosis (n = 56), and healthy controls (n = 25) was solid-phase extracted using a method optimised for recovery of apelin, which was measured by ELISA. RESULTS Plasma apelin was significantly reduced in liver fibrosis (8.3 ± 1.2 pg/ml) and cirrhosis (6.5 ± 0.6 pg/ml) patients compared with controls (15.4 ± 2.0 pg/ml). There was no obvious relationship between apelin and BMP 9 or BMP10 previously measured in these patients. Within the cirrhotic group, there was no significant correlation between apelin levels and disease severity scores, age, sex, or treatment with β-blockers. CONCLUSIONS Apelin was significantly reduced in plasma of patients with both early (fibrosis) and late-stage (cirrhosis) liver disease. Fibrosis is more easily reversible and may represent a potential target for new therapeutic interventions. However, it remains unclear whether apelin signalling is detrimental in liver disease or is beneficial and therefore, whether an apelin antagonist or agonist have clinical use.
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Affiliation(s)
- Nicola E Owen
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Duuamene Nyimanu
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Rhoda E Kuc
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Paul D Upton
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Nicholas W Morrell
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Graeme J Alexander
- Institute for Liver and Digestive Health, Upper 3rd Floor, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Janet J Maguire
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Anthony P Davenport
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
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Huang Z, Luo X, Liu M, Chen L. Function and regulation of apelin/APJ system in digestive physiology and pathology. J Cell Physiol 2018; 234:7796-7810. [PMID: 30390294 DOI: 10.1002/jcp.27720] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 10/16/2018] [Indexed: 12/11/2022]
Abstract
Apelin is an endogenous ligand of seven-transmembrane G-protein-coupled receptor APJ. Apelin and APJ are distributed in various tissues, including the heart, lung, liver, kidney, and gastrointestinal tract and even in tumor tissues. Studies show that apelin messenger RNA is widely expressed in gastrointestinal (GI) tissues, including stomach and small intestine, which is closely correlated with GI function. Thus, the apelin/APJ system may exert a broad range of activities in the digestive system. In this paper, we review the role of the apelin/APJ system in the digestive system in physiological conditions, such as gastric acid secretion, control of appetite and food intake, cell proliferation, cholecystokinin secretion and histamine release, gut-brain axis, GI motility, and others. In pathological conditions, the apelin/APJ system plays an important role in the healing process of stress gastric injury, the clinical features and prognosis of patients with gastric cancers, the reduction of inflammatory response to enteritis and pancreatitis, the mediation of liver fibrogenesis, the promotion of liver damage, the inhibition of liver regeneration, the contribution of splanchnic neovascularization in portal hypertension, the treatment of colon cancer, and GI oxidative damage. Overall, the apelin/APJ system plays diversified functions and regulatory roles in digestive physiology and pathology. Further exploration of the relationship between the apelin/APJ system and the digestive system will help to find new and effective drugs for treating and alleviating the pain of digestive diseases.
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Affiliation(s)
- Zhen Huang
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China.,Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Xuling Luo
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China
| | - Meiqing Liu
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China
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5
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Garbuzenko DV, Arefyev NO, Kazachkov EL. Antiangiogenic therapy for portal hypertension in liver cirrhosis: Current progress and perspectives. World J Gastroenterol 2018; 24:3738-3748. [PMID: 30197479 PMCID: PMC6127663 DOI: 10.3748/wjg.v24.i33.3738] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/09/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Developing medicines for hemodynamic disorders that are characteristic of cirrhosis of the liver is a relevant problem in modern hepatology. The increase in hepatic vascular resistance to portal blood flow and subsequent hyperdynamic circulation underlie portal hypertension (PH) and promote its progression, despite the formation of portosystemic collaterals. Angiogenesis and vascular bed restructurization play an important role in PH pathogenesis as well. In this regard, strategic directions in the therapy for PH in cirrhosis include selectively decreasing hepatic vascular resistance while preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis. The aim of this review is to describe the mechanisms of angiogenesis in PH and the methods of antiangiogenic therapy. The PubMed database, the Google Scholar retrieval system, and the reference lists from related articles were used to search for relevant publications. Articles corresponding to the aim of the review were selected for 2000-2017 using the keywords: "liver cirrhosis", "portal hypertension", "pathogenesis", "angiogenesis", and "antiangiogenic therapy". Antiangiogenic therapy for PH was the inclusion criterion. In this review, we have described angiogenesis inhibitors and their mechanism of action in relation to PH. Although most of them were studied only in animal experiments, this selective therapy for abnormally growing newly formed vessels is pathogenetically reasonable to treat PH and associated complications.
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Affiliation(s)
| | - Nikolay Olegovich Arefyev
- Department of Pathological Anatomy and Forensic Medicine, South Ural State Medical University, Chelyabinsk 454092, Russia
| | - Evgeniy Leonidovich Kazachkov
- Department of Pathological Anatomy and Forensic Medicine, South Ural State Medical University, Chelyabinsk 454092, Russia
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6
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Bertrand C, Pradère JP, Geoffre N, Deleruyelle S, Masri B, Personnaz J, Le Gonidec S, Batut A, Louche K, Moro C, Valet P, Castan-Laurell I. Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism. Endocrine 2018; 60:112-121. [PMID: 29392617 DOI: 10.1007/s12020-018-1536-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 01/15/2018] [Indexed: 12/11/2022]
Abstract
PURPOSE Apelin treatment has been shown to improve insulin sensitivity in insulin resistant mice by acting in skeletal muscles. However, the effects of systemic apelin on the hepatic energy metabolism have not been addressed. We thus aimed to determine the effect of chronic apelin treatment on the hepatic lipid metabolism in insulin resistant mice. The apelin receptor (APJ) expression was also studied in this context since its regulation has only been reported in severe liver pathologies. METHODS Mice were fed a high-fat diet (HFD) in order to become obese and insulin resistant compared to chow fed mice (CD). HFD mice then received a daily intraperitoneal injection of apelin (0.1 µmol/kg) or PBS during 28 days. RESULTS Triglycerides content and the expression of different lipogenesis-related genes were significantly decreased in the liver of HFD apelin-treated compared to PBS-treated mice. Moreover, at this stage of insulin resistance, the beta-oxidation was increased in liver homogenates of HFD PBS-treated mice compared to CD mice and reduced in HFD apelin-treated mice. Finally, APJ expression was not up-regulated in the liver of insulin resistant mice. In isolated hepatocytes from chow and HFD fed mice, apelin did not induce significant effect. CONCLUSIONS Altogether, these results suggest that systemic apelin treatment decreases steatosis in insulin resistant mice without directly targeting hepatocytes.
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Affiliation(s)
- Chantal Bertrand
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Jean-Philippe Pradère
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Nancy Geoffre
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Simon Deleruyelle
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Bernard Masri
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Jean Personnaz
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Sophie Le Gonidec
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Aurélie Batut
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Katie Louche
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Cédric Moro
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Philippe Valet
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Isabelle Castan-Laurell
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France.
- Université de Toulouse, Université Paul Sabatier, Toulouse, France.
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Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring. PLoS One 2018; 13:e0192606. [PMID: 29447215 PMCID: PMC5813940 DOI: 10.1371/journal.pone.0192606] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 01/28/2018] [Indexed: 12/18/2022] Open
Abstract
We investigated maternal obesity in inbred SM/J mice by assigning females to a high-fat diet or a low-fat diet at weaning, mating them to low-fat-fed males, cross-fostering the offspring to low-fat-fed SM/J nurses at birth, and weaning the offspring onto a high-fat or low-fat diet. A maternal high-fat diet exacerbated obesity in the high-fat-fed daughters, causing them to weigh more, have more fat, and have higher serum levels of leptin as adults, accompanied by dozens of gene expression changes and thousands of DNA methylation changes in their livers and hearts. Maternal diet particularly affected genes involved in RNA processing, immune response, and mitochondria. Between one-quarter and one-third of differentially expressed genes contained a differentially methylated region associated with maternal diet. An offspring high-fat diet reduced overall variation in DNA methylation, increased body weight and organ weights, increased long bone lengths and weights, decreased insulin sensitivity, and changed the expression of 3,908 genes in the liver. Although the offspring were more affected by their own diet, their maternal diet had epigenetic effects lasting through adulthood, and in the daughters these effects were accompanied by phenotypic changes relevant to obesity and diabetes.
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Lv SY, Cui B, Chen WD, Wang YD. Apelin/APJ system: A key therapeutic target for liver disease. Oncotarget 2017; 8:112145-112151. [PMID: 29340118 PMCID: PMC5762386 DOI: 10.18632/oncotarget.22841] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 11/11/2017] [Indexed: 12/12/2022] Open
Abstract
Apelin, a new bioactive peptide, was identified as an endogenous ligand for APJ (Angiotensin II receptor-like 1). Apelin and its receptor have an abundant distribution in central nervous system and peripheral tissues, including liver. Apelin/APJ has diverse physiological and pathological effects, including regulation of cardiovascular function, angiogenesis, fluid homeostasis and so on. Apelin/APJ system may act as a novel potential therapeutic target for liver disease. In this article, we review the role of apelin/APJ system in liver fibrosis, hepatitis, hepatic cirrhosis, liver injury and metabolic liver disease.
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Affiliation(s)
- Shuang-Yu Lv
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, Henan, P. R. China
| | - Binbin Cui
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, Henan, P. R. China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, Henan, P. R. China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia, P. R. China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, P. R. China
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Apelin/APJ system: A novel promising therapy target for pathological angiogenesis. Clin Chim Acta 2016; 466:78-84. [PMID: 28025030 DOI: 10.1016/j.cca.2016.12.023] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 12/19/2016] [Accepted: 12/22/2016] [Indexed: 12/21/2022]
Abstract
Apelin is the endogenous ligand of the G protein-coupled receptor APJ. Both Apelin and APJ receptor are widely distributed in various tissues such as heart, brain, limbs, retina and liver. Recent research indicates that the Apelin/APJ system plays an important role in pathological angiogenesis which is a progress of new blood branches developing from preexisting vessels via sprouting. In this paper, we review the important role of the Apelin/APJ system in pathological angiogenesis. The Apelin/APJ system promotes angiogenesis in myocardial infarction, ischemic stroke, critical limb ischemia, tumor, retinal angiogenesis diseases, cirrhosis, obesity, diabetes and other related diseases. Furthermore, we illustrate the detailed mechanism of pathological angiogenesis induced by the Apelin/APJ system. In conclusion, the Apelin/APJ system would be a promising therapeutic target for angiogenesis-related diseases.
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10
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Garbuzenko DV, Arefyev NO, Belov DV. Mechanisms of adaptation of the hepatic vasculature to the deteriorating conditions of blood circulation in liver cirrhosis. World J Hepatol 2016; 8:665-672. [PMID: 27326313 PMCID: PMC4909428 DOI: 10.4254/wjh.v8.i16.665] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Revised: 04/25/2016] [Accepted: 05/17/2016] [Indexed: 02/06/2023] Open
Abstract
PubMed, EMBASE, Orphanet, MIDLINE, Google Scholar and Cochrane Library were searched for articles published between 1983 and 2015. Relevant articles were selected by using the following terms: "Liver cirrhosis", "Endothelial dysfunction", "Sinusoidal remodeling", "Intrahepatic angiogenesis" and "Pathogenesis of portal hypertension". Then the reference lists of identified articles were searched for other relevant publications as well. Besides gross hepatic structural disorders related to diffuse fibrosis and formation of regenerative nodules, the complex morphofunctional rearrangement of the hepatic microvascular bed and intrahepatic angiogenesis also play important roles in hemodynamic disturbances in liver cirrhosis. It is characterized by endothelial dysfunction and impaired paracrine interaction between activated stellate hepatocytes and sinusoidal endotheliocytes, sinusoidal remodeling and capillarization, as well as development of the collateral microcirculation. In spite of the fact that complex morphofunctional rearrangement of the hepatic microvascular bed and intrahepatic angiogenesis in liver cirrhosis are the compensatory-adaptive reaction to the deteriorating conditions of blood circulation, they contribute to progression of disease and development of serious complications, in particular, related to portal hypertension.
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Affiliation(s)
- Dmitry Victorovich Garbuzenko
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
| | - Nikolay Olegovich Arefyev
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
| | - Dmitry Vladimirovich Belov
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
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11
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Butruille L, Drougard A, Knauf C, Moitrot E, Valet P, Storme L, Deruelle P, Lesage J. The apelinergic system: sexual dimorphism and tissue-specific modulations by obesity and insulin resistance in female mice. Peptides 2013; 46:94-101. [PMID: 23747606 DOI: 10.1016/j.peptides.2013.05.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 05/28/2013] [Accepted: 05/28/2013] [Indexed: 12/14/2022]
Abstract
It has been proposed that the apelinergic system (apelin and its receptor APJ) may be a promising therapeutic target in obesity-associated insulin resistance syndrome. However, due to the extended tissue-distribution of this system, the therapeutic use of specific ligands for APJ may target numerous tissues resulting putatively to collateral deleterious effects. To unravel specific tissular dysfunctions of this system under obesity and insulin-resistance conditions, we measured the apelinemia and gene-expression level of both apelin (APL) and APJ in 12-selected tissues of insulin-resistant obese female mice fed with a high fat (HF) diet. In a preliminary study, we compared between adult male and female mice, the circadian plasma apelin variation and the effect of fasting on apelinemia. No significant differences were found for these parameters suggesting that the apelinemia is not affected by the sex. Moreover, plasma apelin level was not modulated during the four days of the estrous cycle in females. In obese and insulin-resistant HF female mice, plasma apelin concentration after fasting was not modified but, the gene-expression level of the APL/APJ system was augmented in the white adipose tissue (WAT) and reduced in the brown adipose tissue (BAT), the liver and in kidneys. BAT apelin content was reduced in HF female mice. Our data suggest that the apelinergic system may be implicated into specific dysfunctions of these tissues under obesity and diabetes and that, pharmacologic modulations of this system may be of interest particularly in the treatment of adipose, liver and renal dysfunctions that occur during these pathologies.
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Affiliation(s)
- Laura Butruille
- Unité Environnement Périnatal et Croissance, EA 4489, Faculté de Médecine, Université Lille Nord de France, Pôle Recherche, IFR 114, 59045 Lille, France
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Yasuzaki H, Yoshida SI, Hashimoto T, Shibata W, Inamori M, Toya Y, Tamura K, Maeda S, Umemura S. Involvement of the apelin receptor APJ in Fas-induced liver injury. Liver Int 2013; 33:118-26. [PMID: 23121371 DOI: 10.1111/liv.12006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 09/05/2012] [Indexed: 01/05/2023]
Abstract
BACKGROUND Apelin-APJ signalling is known to play important roles in heart physiology and pathology; however, its functions in liver physiology and pathology remain unclear. On the other hand, Fas is an important molecule in hepatitis and other liver disease that belongs to the death receptor family. The aim of this study was to assess the relationship between apelin-APJ signaling and Fas-mediated liver injury in mice. METHODS APJ(-/-) mice and wild type (WT) mice were administered an intraperitoneal injection of an agonistic anti-Fas antibody (clone; Jo2), and sacrificed after 3 or 6 h to assess the liver histology. The expression levels of apelin and APJ, plasma levels of transaminases, activities of hepatic caspases and activations of stress-activated protein kinases were also analysed. RESULTS Before the Jo2 injection, APJ was weakly expressed in the hepatocytes in spots; on the other hand, after the Jo2 injection, it had spread into whole hepatocytes. Moreover, the mRNA expression level of apelin and APJ in the liver increased after Jo2 injection. In the APJ(-/-) mice, the liver injuries and apoptotic changes were significantly inhibited as compared with those in the WT mice. Dramatic increase in JNK activation was observed in the WT mice after Jo2 injection, whereas such activation was completely absent in the APJ(-/-) mice. JNK inhibitor partially, but significantly suppressed Jo2-mediated liver injury in WT mice. CONCLUSION Apelin-APJ signalling may promote Fas-induced liver injury at least partially via JNK activation, and may thus serve as a potential therapeutic target in cases of acute liver injury.
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Affiliation(s)
- Hiroaki Yasuzaki
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Apelin is a marker of the progression of liver fibrosis and portal hypertension in patients with biliary atresia. Pediatr Surg Int 2013; 29:79-85. [PMID: 23160902 DOI: 10.1007/s00383-012-3210-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
PURPOSE Apelin, the endogenous ligand of the angiotensin-like-receptor 1 (APJ), is thought to play an important role in liver disease. This study investigated the apelin expression in different stages of biliary atresia (BA) and investigated whether it is associated with the progression of disease. METHODS Liver tissues were obtained from patients at Kasai's procedure (KP), the follow-up stage after KP (Post-KP) and at liver transplantation (LT). Immunohistochemistry for apelin and its receptor APJ and real-time quantitative reverse transcriptase polymerase chain reaction for apelin mRNA expression were conducted. RESULTS The immunohistochemical study revealed that apelin was mainly localized in the perivenular areas of control liver tissue, and slightly detected in the hepatic stellate cells (HSC) and hepatocytes, whereas intense apelin immunoreactivity was detected in perivenular areas, HSC and hepatocytes of LT liver tissue. The apelin mRNA expression level was significantly higher in the LT group than in the KP and Post-KP group. Significant linear correlations were observed between the apelin mRNA level and liver fibrosis, serum total bilirubin and the grade of esophageal varices. CONCLUSIONS The hepatic apelin-APJ system is markedly activated in the progression of BA, especially in end-stage cirrhosis. The apelin expression level accurately reflects the severity of hepatic fibrosis and esophageal varices and therefore could be used as a prognostic factor in BA patients.
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