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Mravec B, Szantova M. Liver Neurobiology: Regulation of Liver Functions by the Nervous System. Semin Liver Dis 2025. [PMID: 40239709 DOI: 10.1055/a-2562-2000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
The nervous system plays an important role in the regulation of liver functions during physiological as well as pathological conditions. This regulatory effect is based on the processing of signals transmitted to the brain by sensory nerves innervating the liver tissue and other visceral organs and by humoral pathways transmitting signals from peripheral tissues and organs. Based on these signals, the brain modulates metabolism, detoxification, regeneration, repair, inflammation, and other processes occurring in the liver. The nervous system thus determines the functional and morphological characteristics of the liver. Liver innervation also mediates the influence of psychosocial factors on liver functions. The aim of this review is to describe complexity of bidirectional interactions between the brain and liver and to characterize the mechanisms and pathways through which the nervous system influences liver function during physiological conditions and maintains liver and systemic homeostasis.
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Affiliation(s)
- Boris Mravec
- Department of Physiology Faculty of Medicine, Comenius University, Bratislava, Slovakia
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Maria Szantova
- 3rd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
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2
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Jun H, Liu S, Knights AJ, Zhu K, Ma Y, Gong J, Lenhart AE, Peng X, Huang Y, Ginder JP, Downie CH, Ramos ET, Kullander K, Kennedy RT, Xu XZS, Wu J. Signaling through the nicotinic acetylcholine receptor in the liver protects against the development of metabolic dysfunction-associated steatohepatitis. PLoS Biol 2024; 22:e3002728. [PMID: 39028754 PMCID: PMC11290650 DOI: 10.1371/journal.pbio.3002728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/31/2024] [Accepted: 07/02/2024] [Indexed: 07/21/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of liver steatosis, the most common liver disease, and substantially increases the mortality rate. However, limited therapies are currently available to prevent MASH development. Identifying potential pharmacological treatments for the condition has been hampered by its heterogeneous and complex nature. Here, we identified a hepatic nonneuronal cholinergic signaling pathway required for metabolic adaptation to caloric overload. We found that cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) is highly expressed in hepatocytes of mice and humans. Further, CHRNA2 is activated by a subpopulation of local acetylcholine-producing macrophages during MASH development. The activation of CHRNA2 coordinates defensive programs against a broad spectrum of MASH-related pathogenesis, including steatosis, inflammation, and fibrosis. Hepatocyte-specific loss of CHRNA2 signaling accelerates the disease onset in different MASH mouse models. Activation of this pathway via pharmacological inhibition of acetylcholine degradation protects against MASH development. Our study uncovers a hepatic nicotinic cholinergic receptor pathway that constitutes a cell-autonomous self-defense route against prolonged metabolic stress and holds therapeutic potential for combatting human MASH.
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Affiliation(s)
- Heejin Jun
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, Texas, United States of America
| | - Shanshan Liu
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Alexander J. Knights
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Kezhou Zhu
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Yingxu Ma
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jianke Gong
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
- International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Sciences and Technology, and Huazhong University of Science and Technology, Wuhan, China
| | - Ashley E. Lenhart
- Department of Chemistry, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Xiaoling Peng
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Yunying Huang
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jared P. Ginder
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Christopher H. Downie
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Erika Thalia Ramos
- Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, Texas, United States of America
| | - Klas Kullander
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Robert T. Kennedy
- Department of Chemistry, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - X. Z. Shawn Xu
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Jun Wu
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
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3
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Borgmann D, Fenselau H. Vagal pathways for systemic regulation of glucose metabolism. Semin Cell Dev Biol 2024; 156:244-252. [PMID: 37500301 DOI: 10.1016/j.semcdb.2023.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 06/20/2023] [Accepted: 07/20/2023] [Indexed: 07/29/2023]
Abstract
Maintaining blood glucose at an appropriate physiological level requires precise coordination of multiple organs and tissues. The vagus nerve bidirectionally connects the central nervous system with peripheral organs crucial to glucose mobilization, nutrient storage, and food absorption, thereby presenting a key pathway for the central control of blood glucose levels. However, the precise mechanisms by which vagal populations that target discrete tissues participate in glucoregulation are much less clear. Here we review recent advances unraveling the cellular identity, neuroanatomical organization, and functional contributions of both vagal efferents and vagal afferents in the control of systemic glucose metabolism. We focus on their involvement in relaying glucoregulatory cues from the brain to peripheral tissues, particularly the pancreatic islet, and by sensing and transmitting incoming signals from ingested food to the brain. These recent findings - largely driven by advances in viral approaches, RNA sequencing, and cell-type selective manipulations and tracings - have begun to clarify the precise vagal neuron populations involved in the central coordination of glucose levels, and raise interesting new possibilities for the treatment of glucose metabolism disorders such as diabetes.
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Affiliation(s)
- Diba Borgmann
- Synaptic Transmission in Energy Homeostasis Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Physical Activity Research (CFAS), Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Henning Fenselau
- Synaptic Transmission in Energy Homeostasis Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50937 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, Cologne 50931, Germany.
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4
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Zsombok A, Desmoulins LD, Derbenev AV. Sympathetic circuits regulating hepatic glucose metabolism: where we stand. Physiol Rev 2024; 104:85-101. [PMID: 37440208 PMCID: PMC11281813 DOI: 10.1152/physrev.00005.2023] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 06/12/2023] [Accepted: 07/10/2023] [Indexed: 07/14/2023] Open
Abstract
The prevalence of metabolic disorders, including type 2 diabetes mellitus, continues to increase worldwide. Although newer and more advanced therapies are available, current treatments are still inadequate and the search for solutions remains. The regulation of energy homeostasis, including glucose metabolism, involves an exchange of information between the nervous systems and peripheral organs and tissues; therefore, developing treatments to alter central and/or peripheral neural pathways could be an alternative solution to modulate whole body metabolism. Liver glucose production and storage are major mechanisms controlling glycemia, and the autonomic nervous system plays an important role in the regulation of hepatic functions. Autonomic nervous system imbalance contributes to excessive hepatic glucose production and thus to the development and progression of type 2 diabetes mellitus. At cellular levels, change in neuronal activity is one of the underlying mechanisms of autonomic imbalance; therefore, modulation of the excitability of neurons involved in autonomic outflow governance has the potential to improve glycemic status. Tissue-specific subsets of preautonomic neurons differentially control autonomic outflow; therefore, detailed information about neural circuits and properties of liver-related neurons is necessary for the development of strategies to regulate liver functions via the autonomic nerves. This review provides an overview of our current understanding of the hypothalamus-ventral brainstem-liver pathway involved in the sympathetic regulation of the liver, outlines strategies to identify organ-related neurons, and summarizes neuronal plasticity during diabetic conditions with a particular focus on liver-related neurons in the paraventricular nucleus.
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Affiliation(s)
- Andrea Zsombok
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, United States
- Tulane Brain Institute, Tulane University, New Orleans, Louisiana, United States
| | - Lucie D Desmoulins
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, United States
| | - Andrei V Derbenev
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, United States
- Tulane Brain Institute, Tulane University, New Orleans, Louisiana, United States
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5
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Timmermans JP. The autonomic nervous system from a morphofunctional perspective: Historical overview and current concepts over the last two centuries highlighting contributions from Eastern Europe. Anat Rec (Hoboken) 2023; 306:2222-2229. [PMID: 36733228 DOI: 10.1002/ar.25169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 02/04/2023]
Abstract
The present contribution comprises both an introductory comment and an overview of the contributions within this special issue on historical and current research on the autonomic nervous system from Eastern European colleagues, particularly focusing on the autonomic innervation of the gastrointestinal tract and of the cardiovascular system. It also gives a selected overview of interesting and seminal papers on these topics that appeared in The Anatomical Record since its foundation in 1906.
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Affiliation(s)
- Jean-Pierre Timmermans
- Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
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6
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Tanimizu N, Ichinohe N, Mitaka T. β-adrenergic receptor agonist promotes ductular expansion during 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced chronic liver injury. Sci Rep 2023; 13:7084. [PMID: 37127664 PMCID: PMC10151327 DOI: 10.1038/s41598-023-33882-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 04/20/2023] [Indexed: 05/03/2023] Open
Abstract
Intrahepatic nerves are involved in the regulation of metabolic reactions and hepatocyte-based regeneration after surgical resection, although their contribution to chronic liver injury remains unknown. Given that intrahepatic nerves are abundant in the periportal tissue, they may be correlated also with cholangiocyte-based regeneration. Here we demonstrate that isoproterenol (ISO), a β-adrenergic receptor agonist, promoted ductular expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in vivo. Immunofluorescence analysis shows that nerve fibers positive for tyrosine hydroxylase form synaptophysin-positive nerve endings on epithelial cell adhesion molecule-positive (EpCAM+) cholangiocytes as well as on Thy1+ periportal mesenchymal cells (PMCs) that surround bile ducts, suggesting that the intrahepatic biliary tissue are targeted by sympathetic nerves. In vitro analyses indicate that ISO directly increases cAMP levels in cholangiocytes and PMCs. Mechanistically, ISO expands the lumen of cholangiocyte organoids, resulting in promotion of cholangiocyte proliferation, whereas it increases expression of fibroblast growth factor 7, a growth factor for cholangiocytes, in PMCs. Taken together, the results indicate that intrahepatic sympathetic nerves regulate remodeling of bile ducts during DDC-injury by the activation of β-adrenergic receptors on cholangiocytes and PMCs.
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Affiliation(s)
- Naoki Tanimizu
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, 060-8556, Japan.
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-0071, Japan.
| | - Norihisa Ichinohe
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Toshihiro Mitaka
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, 060-8556, Japan
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Trucas M, Kowalik MA, Boi M, Serra MP, Perra A, Quartu M. The density of hepatic autonomic innervation differs between compensatory and direct hyperplasia rat models. J Peripher Nerv Syst 2023; 28:98-107. [PMID: 36371610 DOI: 10.1111/jns.12521] [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: 09/07/2022] [Revised: 10/23/2022] [Accepted: 11/07/2022] [Indexed: 11/15/2022]
Abstract
To contribute to the knowledge of the autonomic innervation in liver regeneration, here we investigate the distribution of tyrosine hydroxylase (TH)- and choline acetyltransferase (ChAT)-like immunoreactive (LI) nerve fibers, to indicate noradrenergic and cholinergic nerves, respectively, in rats under different conditions of liver damage and repair. By immunohistochemistry and assessment of nerve fiber density, three models of induced hepatic regeneration were examined: the carbon tetrachloride (CCl4 ) intoxication, with two treatment periods of 14 weeks and 18 weeks; the partial hepatectomy (PH); the thyroid hormone (T3) treatment. TH- and ChAT-LI nerve fibers were detectable mostly in the portal spaces, the TH-LI ones occurring only around blood vessels while the ChAT-LI nerve fibers were also associated with secretory ducts. The density of TH-like immunoreactivity in the portal areas decreased after the CCl4 14 weeks treatment and PH and increased after T3. By contrast, ChAT-LI nerve fibers appeared particularly abundant around the neoductal elements in the CCl4 rats and were rare to absent in the PH and T3-treated groups. The ChAT-LI nerve fiber density within the portal areas revealed an increase in the CCl4 -treated rats while showing no change in the PH and T3-treated rats. The changes in the density of perivascular TH- and ChAT-containing nerve fibers suggest a finely tuned autonomic modulation of hepatic blood flow depending on the type of subacute/chronic induced hyperplasia, while the characteristic occurrence of the periductal cholinergic innervation after the CCl4 treatment implies a selective parasympathetic role in regulating the physiopathological regenerative potential of the rat liver.
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Affiliation(s)
- Marcello Trucas
- Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy.,Department of Biomedical Sciences, Section of Pathology, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, Section of Pathology, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy
| | - Marianna Boi
- Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy
| | - Maria Pina Serra
- Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, Section of Pathology, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy
| | - Marina Quartu
- Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy
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8
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Martinez-Sanchez N, Sweeney O, Sidarta-Oliveira D, Caron A, Stanley SA, Domingos AI. The sympathetic nervous system in the 21st century: Neuroimmune interactions in metabolic homeostasis and obesity. Neuron 2022; 110:3597-3626. [PMID: 36327900 PMCID: PMC9986959 DOI: 10.1016/j.neuron.2022.10.017] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 08/23/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022]
Abstract
The sympathetic nervous system maintains metabolic homeostasis by orchestrating the activity of organs such as the pancreas, liver, and white and brown adipose tissues. From the first renderings by Thomas Willis to contemporary techniques for visualization, tracing, and functional probing of axonal arborizations within organs, our understanding of the sympathetic nervous system has started to grow beyond classical models. In the present review, we outline the evolution of these findings and provide updated neuroanatomical maps of sympathetic innervation. We offer an autonomic framework for the neuroendocrine loop of leptin action, and we discuss the role of immune cells in regulating sympathetic terminals and metabolism. We highlight potential anti-obesity therapeutic approaches that emerge from the modern appreciation of SNS as a neural network vis a vis the historical fear of sympathomimetic pharmacology, while shifting focus from post- to pre-synaptic targeting. Finally, we critically appraise the field and where it needs to go.
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Affiliation(s)
| | - Owen Sweeney
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK
| | - Davi Sidarta-Oliveira
- Physician-Scientist Graduate Program, Obesity and Comorbidities Research Center, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Alexandre Caron
- Faculty of Pharmacy, Université Laval, Québec City, QC G1V 0A6, Canada
| | - Sarah A Stanley
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ana I Domingos
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
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Keasey MP, Lovins C, Jia C, Hagg T. Liver vitronectin release into the bloodstream increases due to reduced vagal muscarinic signaling after cerebral stroke in female mice. Physiol Rep 2022; 10:e15301. [PMID: 35531929 PMCID: PMC9082388 DOI: 10.14814/phy2.15301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/21/2022] [Accepted: 04/27/2022] [Indexed: 11/24/2022] Open
Abstract
Vitronectin (VTN) is a glycoprotein enriched in the blood and activates integrin receptors. VTN blood levels increase only in female mice 24 h after an ischemic stroke and exacerbate brain injury through IL-6-driven inflammation, but the VTN induction mechanism is unknown. Here, a 30 min middle cerebral artery occlusion (MCAO) in female mice induced VTN protein in the liver (normally the main source) in concert with plasma VTN. Male mice were excluded as VTN is not induced after stroke. MCAO also increased plasma VTN levels after de novo expression of VTN in the liver of VTN-/- female mice, using a hepatocyte-specific (SERPINA1) promoter. MCAO did not affect SERPINA1 or VTN mRNA in the liver, brain, or several peripheral organs, or platelet VTN, compared to sham mice. Thus, hepatocytes are the source of stroke-induced increases in plasma VTN, which is independent of transcription. The cholinergic innervation by the parasympathetic vagus nerve is a potential source of brain-liver signaling after stroke. Right-sided vagotomy at the cervical level led to increased plasma VTN levels, suggesting that VTN release is inhibited by vagal tone. Co-culture of hepatocytes with cholinergic neurons or treatment with acetylcholine, but not noradrenaline (sympathetic transmitter), suppressed VTN expression. Hepatocytes have muscarinic receptors and the M1/M3 agonist bethanechol decreased VTN mRNA and protein release in vitro via M1 receptors. Finally, systemic bethanechol treatment blocked stroke-induced plasma VTN. Thus, VTN translation and release are inhibited by muscarinic signaling from the vagus nerve and presents a novel target for lessening detrimental VTN expression.
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Affiliation(s)
- Matthew P. Keasey
- Department of Biomedical SciencesQuillen College of MedicineEast Tennessee State UniversityJohnson CityTennesseeUnited States
| | - Chiharu Lovins
- Department of Biomedical SciencesQuillen College of MedicineEast Tennessee State UniversityJohnson CityTennesseeUnited States
| | - Cuihong Jia
- Department of Biomedical SciencesQuillen College of MedicineEast Tennessee State UniversityJohnson CityTennesseeUnited States
| | - Theo Hagg
- Department of Biomedical SciencesQuillen College of MedicineEast Tennessee State UniversityJohnson CityTennesseeUnited States
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Verma A, Manchel A, Narayanan R, Hoek JB, Ogunnaike BA, Vadigepalli R. A Spatial Model of Hepatic Calcium Signaling and Glucose Metabolism Under Autonomic Control Reveals Functional Consequences of Varying Liver Innervation Patterns Across Species. Front Physiol 2021; 12:748962. [PMID: 34899380 PMCID: PMC8662697 DOI: 10.3389/fphys.2021.748962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/11/2021] [Indexed: 11/25/2022] Open
Abstract
Rapid breakdown of hepatic glycogen stores into glucose plays an important role during intense physical exercise to maintain systemic euglycemia. Hepatic glycogenolysis is governed by several different liver-intrinsic and systemic factors such as hepatic zonation, circulating catecholamines, hepatocellular calcium signaling, hepatic neuroanatomy, and the central nervous system (CNS). Of the factors regulating hepatic glycogenolysis, the extent of lobular innervation varies significantly between humans and rodents. While rodents display very few autonomic nerve terminals in the liver, nearly every hepatic layer in the human liver receives neural input. In the present study, we developed a multi-scale, multi-organ model of hepatic metabolism incorporating liver zonation, lobular scale calcium signaling, hepatic innervation, and direct and peripheral organ-mediated communication between the liver and the CNS. We evaluated the effect of each of these governing factors on the total hepatic glucose output and zonal glycogenolytic patterns within liver lobules during simulated physical exercise. Our simulations revealed that direct neuronal stimulation of the liver and an increase in circulating catecholamines increases hepatic glucose output mediated by mobilization of intracellular calcium stores and lobular scale calcium waves. Comparing simulated glycogenolysis between human-like and rodent-like hepatic innervation patterns (extensive vs. minimal) suggested that propagation of calcium transients across liver lobules acts as a compensatory mechanism to improve hepatic glucose output in sparsely innervated livers. Interestingly, our simulations suggested that catecholamine-driven glycogenolysis is reduced under portal hypertension. However, increased innervation coupled with strong intercellular communication can improve the total hepatic glucose output under portal hypertension. In summary, our modeling and simulation study reveals a complex interplay of intercellular and multi-organ interactions that can lead to differing calcium dynamics and spatial distributions of glycogenolysis at the lobular scale in the liver.
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Affiliation(s)
- Aalap Verma
- Department of Biomedical Engineering, University of Delaware, Newark, DE, United States.,Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Alexandra Manchel
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Rahul Narayanan
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Jan B Hoek
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Babatunde A Ogunnaike
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, United States
| | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States
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11
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Torres H, Huesing C, Burk DH, Molinas AJR, Neuhuber WL, Berthoud HR, Münzberg H, Derbenev AV, Zsombok A. Sympathetic innervation of the mouse kidney and liver arising from prevertebral ganglia. Am J Physiol Regul Integr Comp Physiol 2021; 321:R328-R337. [PMID: 34231420 PMCID: PMC8530761 DOI: 10.1152/ajpregu.00079.2021] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/11/2021] [Accepted: 06/29/2021] [Indexed: 11/22/2022]
Abstract
The sympathetic nervous system (SNS) plays a crucial role in the regulation of renal and hepatic functions. Although sympathetic nerves to the kidney and liver have been identified in many species, specific details are lacking in the mouse. In the absence of detailed information of sympathetic prevertebral innervation of specific organs, selective manipulation of a specific function will remain challenging. Despite providing major postganglionic inputs to abdominal organs, limited data are available about the mouse celiac-superior mesenteric complex. We used tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DbH) reporter mice to visualize abdominal prevertebral ganglia. We found that both the TH and DbH reporter mice are useful models for identification of ganglia and nerve bundles. We further tested if the celiac-superior mesenteric complex provides differential inputs to the mouse kidney and liver. The retrograde viral tracer, pseudorabies virus (PRV)-152 was injected into the cortex of the left kidney or the main lobe of the liver to identify kidney-projecting and liver-projecting neurons in the celiac-superior mesenteric complex. iDISCO immunostaining and tissue clearing were used to visualize unprecedented anatomical detail of kidney-related and liver-related postganglionic neurons in the celiac-superior mesenteric complex and aorticorenal and suprarenal ganglia compared with TH-positive neurons. Kidney-projecting neurons were restricted to the suprarenal and aorticorenal ganglia, whereas only sparse labeling was observed in the celiac-superior mesenteric complex. In contrast, liver-projecting postganglionic neurons were observed in the celiac-superior mesenteric complex and aorticorenal and suprarenal ganglia, suggesting spatial separation between the sympathetic innervation of the mouse kidney and liver.
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Affiliation(s)
- Hayden Torres
- Neurobiology of Nutrition and Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
| | - Clara Huesing
- Neurobiology of Nutrition and Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
| | - David H Burk
- Neurobiology of Nutrition and Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
| | - Adrien J R Molinas
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana
| | | | - Hans-Rudolf Berthoud
- Neurobiology of Nutrition and Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
| | - Heike Münzberg
- Neurobiology of Nutrition and Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
| | - Andrei V Derbenev
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana
- Brain Institute, Tulane University, New Orleans, Louisiana
| | - Andrea Zsombok
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana
- Brain Institute, Tulane University, New Orleans, Louisiana
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Adori C, Daraio T, Kuiper R, Barde S, Horvathova L, Yoshitake T, Ihnatko R, Valladolid-Acebes I, Vercruysse P, Wellendorf AM, Gramignoli R, Bozoky B, Kehr J, Theodorsson E, Cancelas JA, Mravec B, Jorns C, Ellis E, Mulder J, Uhlén M, Bark C, Hökfelt T. Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging. SCIENCE ADVANCES 2021; 7:7/30/eabg5733. [PMID: 34290096 PMCID: PMC8294768 DOI: 10.1126/sciadv.abg5733] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 06/04/2021] [Indexed: 05/08/2023]
Abstract
Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.
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Affiliation(s)
- Csaba Adori
- Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
| | - Teresa Daraio
- The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Raoul Kuiper
- Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Swapnali Barde
- Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Lubica Horvathova
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Takashi Yoshitake
- Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Robert Ihnatko
- Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, 58285 Linköping, Sweden
| | - Ismael Valladolid-Acebes
- The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Pauline Vercruysse
- The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Ashley M Wellendorf
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Bela Bozoky
- Department of Clinical Pathology/Cytology, Karolinska University Hospital, Huddinge, Sweden
| | - Jan Kehr
- Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Elvar Theodorsson
- Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, 58285 Linköping, Sweden
| | - Jose A Cancelas
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0055, USA
| | - Boris Mravec
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Slovak Republic
| | - Carl Jorns
- PO Transplantation, Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden
| | - Ewa Ellis
- Department of Transplantation Surgery and Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska University Hospital, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Jan Mulder
- Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Mathias Uhlén
- Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
- Science for Life Laboratory, Royal Institute of Technology, 10691 Stockholm, Sweden
| | - Christina Bark
- Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Tomas Hökfelt
- Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
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Liu K, Yang L, Wang G, Liu J, Zhao X, Wang Y, Li J, Yang J. Metabolic stress drives sympathetic neuropathy within the liver. Cell Metab 2021; 33:666-675.e4. [PMID: 33545051 DOI: 10.1016/j.cmet.2021.01.012] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/18/2020] [Accepted: 01/11/2021] [Indexed: 12/12/2022]
Abstract
The nervous system instructs the body's metabolism, including that in the liver. However, the neural anatomy of the liver under either normal or metabolically stressed conditions remains to be unequivocally assessed. Here, we examined neural distributions in the mouse, nonhuman primate, and human livers with advanced 3D imaging. We observed that neural innervations within the liver are predominantly sympathetic, but not parasympathetic, inputs. Moreover, we discovered the profound and reversible loss of such sympathetic innervations during metabolic challenges. This hepatic sympathetic neuropathy was caused by TNFα derived from CD11b+ F4/80+ immune cells under high-fat-diet (HFD) condition. We further demonstrated that the Sarm1 deletion mitigated the hepatic sympathetic neuropathy and improved metabolic parameters in HFD-challenged mice. Mechanistically, the sympathetic neurotransmitter norepinephrine attenuated the immune-cell inflammation that would otherwise trigger the insulin insensitivity of hepatocytes. These results together reveal the previously unrecognized neuropathic event in the liver with metabolic relevance.
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Affiliation(s)
- Kaili Liu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing 100871, China
| | - Lu Yang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing 100871, China
| | - Gang Wang
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Jiaqi Liu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing 100871, China
| | - Xuan Zhao
- School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yi Wang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing 100871, China
| | - Jiali Li
- IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Jing Yang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing 100871, China; IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China; Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518055, China; Chinese Institute for Brain Research, Beijing 102206, China.
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14
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The Medullary Targets of Neurally Conveyed Sensory Information from the Rat Hepatic Portal and Superior Mesenteric Veins. eNeuro 2021; 8:ENEURO.0419-20.2021. [PMID: 33495245 PMCID: PMC8114873 DOI: 10.1523/eneuro.0419-20.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 12/17/2022] Open
Abstract
Vagal and spinal sensory endings in the wall of the hepatic portal and superior mesenteric veins (PMV) provide the brain with chemosensory information important for energy balance and other functions. To determine their medullary neuronal targets, we injected the transsynaptic anterograde viral tracer HSV-1 H129-772 (H129) into the PMV wall or left nodose ganglion (LNG) of male rats, followed by immunohistochemistry (IHC) and high-resolution imaging. We also determined the chemical phenotype of H129-infected neurons, and potential vagal and spinal axon terminal appositions in the dorsal motor nucleus of the vagus (DMX) and the nucleus of the solitary tract (NTS). PMV wall injections generated H129-infected neurons in both nodose ganglia and in thoracic dorsal root ganglia (DRGs). In the medulla, cholinergic preganglionic parasympathetic neurons in the DMX were virtually the only targets of chemosensory information from the PMV wall. H129-infected terminal appositions were identified on H129-infected somata and dendrites in the DMX, and on H129-infected DMX dendrites that extend into the NTS. Sensory transmission via vagal and possibly spinal routes from the PMV wall therefore reaches DMX neurons via axo-somatic appositions in the DMX and axo-dendritic appositions in the NTS. However, the dearth of H129-infected NTS neurons indicates that sensory information from the PMV wall terminates on DMX neurons without engaging NTS neurons. These previously underappreciated direct sensory routes into the DMX enable a vago-vagal and possibly spino-vagal reflexes that can directly influence visceral function.
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15
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Fonseca RC, Bassi GS, Brito CC, Rosa LB, David BA, Araújo AM, Nóbrega N, Diniz AB, Jesus ICG, Barcelos LS, Fontes MAP, Bonaventura D, Kanashiro A, Cunha TM, Guatimosim S, Cardoso VN, Fernandes SOA, Menezes GB, de Lartigue G, Oliveira AG. Vagus nerve regulates the phagocytic and secretory activity of resident macrophages in the liver. Brain Behav Immun 2019; 81:444-454. [PMID: 31271871 PMCID: PMC7826199 DOI: 10.1016/j.bbi.2019.06.041] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 06/24/2019] [Accepted: 06/26/2019] [Indexed: 02/08/2023] Open
Abstract
The gastrointestinal (GI) tract harbors commensal microorganisms as well as invasive bacteria, toxins and other pathogens and, therefore, plays a pivotal barrier and immunological role against pathogenic agents. The vagus nerve is an important regulator of the GI tract-associated immune system, having profound effects on inflammatory responses. Among GI tract organs, the liver is a key site of immune surveillance, as it has a large population of resident macrophages and receives the blood drained from the guts through the hepatic portal circulation. Although it is widely accepted that the hepatic tissue is a major target for vagus nerve fibers, the role of this neural circuit in liver immune functions is still poorly understood. Herein we used in vivo imaging techniques, including confocal microscopy and scintigraphy, to show that vagus nerve stimulation increases the phagocytosis activity by resident macrophages in the liver, even on the absence of an immune challenge. The activation of this neural circuit in a non-lethal model of sepsis optimized the removal of bacteria in the liver and resulted in the production of anti-inflammatory and pro-regenerative cytokines. Our findings provide new insights into the neural regulation of the immune system in the liver.
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Affiliation(s)
- Roberta Cristelli Fonseca
- Universidade Federal de Minas Gerais, Department of Physiology and Biophysics, Belo Horizonte, Minas Gerais, Brazil,Universidade Federal de Minas Gerais, Liver Center, Belo Horizonte, Minas Gerais, Brazil
| | - Gabriel Shimizu Bassi
- Universidade de São Paulo, Ribeirão Preto Medical School, Department of Pharmacology, Ribeirão Preto, Brazil
| | - Camila Carvalho Brito
- Universidade Federal de Minas Gerais, Department of Physiology and Biophysics, Belo Horizonte, Minas Gerais, Brazil,Universidade Federal de Minas Gerais, Liver Center, Belo Horizonte, Minas Gerais, Brazil
| | - Lorena Barreto Rosa
- Universidade Federal de Minas Gerais, Department of Physiology and Biophysics, Belo Horizonte, Minas Gerais, Brazil,Universidade Federal de Minas Gerais, Liver Center, Belo Horizonte, Minas Gerais, Brazil
| | - Bruna Araújo David
- Universidade Federal de Minas Gerais, Department of Morphology, Belo Horizonte, Minas Gerais, Brazil
| | - Alan Moreira Araújo
- University of Florida, College of Pharmacy, Department of Pharmacodynamics, Gainesville, FL, USA
| | - Natália Nóbrega
- Universidade Federal de Minas Gerais, Department of Pharmacology, Belo Horizonte, Minas Gerais, Brazil
| | - Ariane Barros Diniz
- Universidade Federal de Minas Gerais, Department of Morphology, Belo Horizonte, Minas Gerais, Brazil
| | - Itamar Couto Guedes Jesus
- Universidade Federal de Minas Gerais, Department of Physiology and Biophysics, Belo Horizonte, Minas Gerais, Brazil
| | - Lucíola Silva Barcelos
- Universidade Federal de Minas Gerais, Department of Physiology and Biophysics, Belo Horizonte, Minas Gerais, Brazil
| | - Marco Antônio Peliky Fontes
- Universidade Federal de Minas Gerais, Department of Physiology and Biophysics, Belo Horizonte, Minas Gerais, Brazil
| | - Daniella Bonaventura
- Universidade Federal de Minas Gerais, Department of Pharmacology, Belo Horizonte, Minas Gerais, Brazil
| | - Alexandre Kanashiro
- Universidade de São Paulo, Ribeirão Preto Medical School, Department of Pharmacology, Ribeirão Preto, Brazil
| | - Thiago Mattar Cunha
- Universidade de São Paulo, Ribeirão Preto Medical School, Department of Pharmacology, Ribeirão Preto, Brazil
| | - Sílvia Guatimosim
- Universidade Federal de Minas Gerais, Department of Physiology and Biophysics, Belo Horizonte, Minas Gerais, Brazil
| | - Valbert Nascimento Cardoso
- Universidade Federal de Minas Gerais, College of Pharmacy, Department of Clinical and Toxicological Analysis, Belo Horizonte, Minas Gerais, Brazil
| | - Simone Odília Antunes Fernandes
- Universidade Federal de Minas Gerais, College of Pharmacy, Department of Clinical and Toxicological Analysis, Belo Horizonte, Minas Gerais, Brazil
| | - Gustavo Batista Menezes
- Universidade Federal de Minas Gerais, Department of Morphology, Belo Horizonte, Minas Gerais, Brazil
| | - Guillaume de Lartigue
- University of Florida, College of Pharmacy, Department of Pharmacodynamics, Gainesville, FL, USA
| | - André Gustavo Oliveira
- Universidade Federal de Minas Gerais, Department of Physiology and Biophysics, Belo Horizonte, Minas Gerais, Brazil; Universidade Federal de Minas Gerais, Liver Center, Belo Horizonte, Minas Gerais, Brazil.
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16
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The stellate cell system (vitamin A-storing cell system). Anat Sci Int 2017; 92:387-455. [PMID: 28299597 DOI: 10.1007/s12565-017-0395-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/15/2017] [Indexed: 01/18/2023]
Abstract
Past, present, and future research into hepatic stellate cells (HSCs, also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, or Ito cells) are summarized and discussed in this review. Kupffer discovered black-stained cells in the liver using the gold chloride method and named them stellate cells (Sternzellen in German) in 1876. Wake rediscovered the cells in 1971 using the same gold chloride method and various modern histological techniques including electron microscopy. Between their discovery and rediscovery, HSCs disappeared from the research history. Their identification, the establishment of cell isolation and culture methods, and the development of cellular and molecular biological techniques promoted HSC research after their rediscovery. In mammals, HSCs exist in the space between liver parenchymal cells (PCs) or hepatocytes and liver sinusoidal endothelial cells (LSECs) of the hepatic lobule, and store 50-80% of all vitamin A in the body as retinyl ester in lipid droplets in the cytoplasm. SCs also exist in extrahepatic organs such as pancreas, lung, and kidney. Hepatic (HSCs) and extrahepatic stellate cells (EHSCs) form the stellate cell (SC) system or SC family; the main storage site of vitamin A in the body is HSCs in the liver. In pathological conditions such as liver fibrosis, HSCs lose vitamin A, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, glycosaminoglycan, and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped HSCs to that of fibroblasts or myofibroblasts.
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17
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Franchitto A, Onori P, Renzi A, Carpino G, Mancinelli R, Alvaro D, Gaudio E. Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. ANNALS OF TRANSLATIONAL MEDICINE 2014; 1:27. [PMID: 25332971 DOI: 10.3978/j.issn.2305-5839.2012.10.03] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 10/15/2012] [Indexed: 12/14/2022]
Abstract
Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases.
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Affiliation(s)
- Antonio Franchitto
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Paolo Onori
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Anastasia Renzi
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Guido Carpino
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Romina Mancinelli
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Domenico Alvaro
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Eugenio Gaudio
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
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Streba LAM, Vere CC, Ionescu AG, Streba CT, Rogoveanu I. Role of intrahepatic innervation in regulating the activity of liver cells. World J Hepatol 2014; 6:137-143. [PMID: 24672643 PMCID: PMC3959114 DOI: 10.4254/wjh.v6.i3.137] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/05/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Liver innervation comprises sympathetic, parasympathetic and peptidergic nerve fibers, organized as either afferent or efferent nerves with different origins and roles. Their anatomy and physiology have been studied in the past 30 years, with different results published over time. Hepatocytes are the main cell population of the liver, making up almost 80% of the total liver volume. The interaction between hepatocytes and nerve fibers is accomplished through a wealth of neurotransmitters and signaling pathways. In this short review, we have taken the task of condensing the most important data related to how the nervous system interacts with the liver and especially with the hepatocyte population, how it influences their metabolism and functions, and how different receptors and transmitters are involved in this complex process.
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Affiliation(s)
- Letitia Adela Maria Streba
- Letitia Adela Maria Streba, Alin Gabriel Ionescu, University of Medicine and Pharmacy of Craiova, 200348 Craiova, Romania
| | - Cristin Constantin Vere
- Letitia Adela Maria Streba, Alin Gabriel Ionescu, University of Medicine and Pharmacy of Craiova, 200348 Craiova, Romania
| | - Alin Gabriel Ionescu
- Letitia Adela Maria Streba, Alin Gabriel Ionescu, University of Medicine and Pharmacy of Craiova, 200348 Craiova, Romania
| | - Costin Teodor Streba
- Letitia Adela Maria Streba, Alin Gabriel Ionescu, University of Medicine and Pharmacy of Craiova, 200348 Craiova, Romania
| | - Ion Rogoveanu
- Letitia Adela Maria Streba, Alin Gabriel Ionescu, University of Medicine and Pharmacy of Craiova, 200348 Craiova, Romania
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19
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Munshi MK, Priester S, Gaudio E, Yang F, Alpini G, Mancinelli R, Wise C, Meng F, Franchitto A, Onori P, Glaser SS. Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:472-84. [PMID: 21281779 DOI: 10.1016/j.ajpath.2010.09.043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2010] [Revised: 08/23/2010] [Accepted: 09/02/2010] [Indexed: 12/15/2022]
Abstract
The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction.
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20
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Hepatic stellate cell (vitamin A-storing cell) and its relative--past, present and future. Cell Biol Int 2011; 34:1247-72. [PMID: 21067523 DOI: 10.1042/cbi20100321] [Citation(s) in RCA: 143] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
HSCs (hepatic stellate cells) (also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells or Ito cells) exist in the space between parenchymal cells and liver sinusoidal endothelial cells of the hepatic lobule and store 50-80% of vitamin A in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of vitamin A homoeostasis. In pathological conditions, such as hepatic fibrosis or liver cirrhosis, HSCs lose vitamin A and synthesize a large amount of extracellular matrix components including collagen, proteoglycan, glycosaminoglycan and adhesive glycoproteins. Morphology of these cells also changes from the star-shaped SCs (stellate cells) to that of fibroblasts or myofibroblasts. The hepatic SCs are now considered to be targets of therapy of hepatic fibrosis or liver cirrhosis. HSCs are activated by adhering to the parenchymal cells and lose stored vitamin A during hepatic regeneration. Vitamin A-storing cells exist in extrahepatic organs such as the pancreas, lungs, kidneys and intestines. Vitamin A-storing cells in the liver and extrahepatic organs form a cellular system. The research of the vitamin A-storing cells has developed and expanded vigorously. The past, present and future of the research of the vitamin A-storing cells (SCs) will be summarized and discussed in this review.
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21
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Abstract
Bile duct damage is present in virtually all cholangiopathies, which share the biliary epithelial cells (i.e. cholangiocytes) as a common pathogenic target. Cholangiocyte cell death largely occurs through the process of apoptosis. In this review, we will summarize the mechanisms through which biliary damage occurs in a variety of animal and in vitro models, such as extrahepatic cholestasis induced by bile duct ligation (BDL), cytotoxin- and hepatotoxin-induced liver injury, and biliary atresia. Although we have increased our knowledge of the factors that regulate cholangiocyte cell death mechanisms during cholangiopathies, especially in experimental models, there is still a lack of effective treatment modalities for these biliary disorders. However, future studies will hopefully provide for new therapeutic modalities for the prevention or restoration of biliary mass and function lost during the progression of cholangiopathies.
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Affiliation(s)
- Fuquan Yang
- Department of Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas
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22
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Marzioni M, Fava G, Alvaro D, Alpini G, Benedetti A. Control of cholangiocyte adaptive responses by visceral hormones and neuropeptides. Clin Rev Allergy Immunol 2009; 36:13-22. [PMID: 18548352 PMCID: PMC2628969 DOI: 10.1007/s12016-008-8090-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholangiocytes, the epithelial cells lining the biliary tree, are the target cells in several liver diseases, termed cholangiopathies. Cholangiopathies are a challenge for clinicians and an enigma for scientists, as the pathogenetic mechanisms by which they develop, and the therapeutic tools for these diseases are still undefined. Several studies demonstrate that many visceral hormones, neuropeptides, and neurotransmitters modulate the adaptive changes of cholangiocytes to chronic cholestatic injury. The aim of this review is to present the recent findings that contributed to clarify the role of visceral hormones and neuropeptides in the regulation of the pathophysiology of cholestasis. These studies helped to shed light on some aspects of cholangiocyte pathophysiology, revealing novel perspectives for the clinical managements of cholangiopathies.
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Affiliation(s)
- Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Miarche, Nuovo Polo Didattico, III piano, Via Tronto 10, 60020, Ancona, Italy.
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Chapman GB, Eagles DA. A light and transmission electron microscope study of hepatic portal tracts in the rhesus monkey (Macacus rhesus). Tissue Cell 2008; 40:271-82. [PMID: 18466942 DOI: 10.1016/j.tice.2008.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This study reports on morphological features of hepatic portal tracts in the liver of a rhesus monkey. The light microscope shows that the number of each type of principal component comprising a portal tract varies but that there are usually one to five lymphatics, one bile ductule, one bile duct, one arteriolar and one arterial branch of the hepatic artery, and one hepatic portal vein. Bile ductules, in cross section, have 6-10 cells (mostly low pyramidal, but with a few cuboidal) bordering the lumen, an outside diameter of from about 20 to 25 microm, and a luminal diameter of from 2 to 10 microm. Bile ducts, in cross section, have more than 10 cells (about equal numbers of low pyramidal and cuboidal) bordering the lumen, an outside diameter greater than 25 microm and a luminal diameter of greater than 10 microm. The term "pyramidal" has not previously been applied to the cells of the ductules and ducts. The monkey tracts show several cytological features previously undescribed, viz., abortive cilia and basal bodies in the duct cells, abortive cilia in the ductule cells, and an occasional aggregation of ribosomes in arterial endothelial cells. They also show a major histological feature previously mentioned but not illustrated, viz., bundles of nerve processes which exhibit a preferential location, i.e., proximity to the arterioles and arteries.
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Affiliation(s)
- G B Chapman
- Department of Biology, Georgetown University, Washington, DC 20057-1229, United States
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Fava G, Marzioni M, Francis H, Glaser S, Demorrrow S, Ueno Y, Benedetti A, Alpini G. Novel interaction of bile acid and neural signaling in the regulation of cholangiocyte function. Hepatol Res 2007; 37 Suppl 3:S420-S429. [PMID: 17931197 DOI: 10.1111/j.1872-034x.2007.00228.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cholangiocytes, the epithelial cells that line the intrahepatic biliary tree, are the target of cholangiopathies, a wide array of chronic disorders that are characterized by the progressive vanishing of bile ducts, leading to ductopenia and liver failure. The loss of bile ducts is a consequence of cholangiocyte death by apoptosis and impaired proliferative response of these cells to injury. The factors that regulate cholangiocyte proliferation and survival are poorly understood. In this regard, a major role is played by the interaction between bile acids and the autonomic nervous system. It has been shown that adrenergic and cholinergic denervation of the liver results in the induction of cell death and impaired proliferative responses of the biliary epithelium to cholestasis. In addition,bile acids have been shown to enter cholangiocytes through the apical, Na(+)-dependent bile acid transporter, ASBT, which has a marked impact on cholangiocyte pathobiology. Recent evidence shows that bile acids and autonomic innervation interact in modulating cholangiocyte response to liver injury. In this review, we describe the recent advances in understanding the molecular mechanisms by which such events occur.
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Affiliation(s)
- Giammarco Fava
- Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy
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Francis H, LeSage G, DeMorrow S, Alvaro D, Ueno Y, Venter J, Glaser S, Mancino MG, Marucci L, Benedetti A, Alpini G. The alpha2-adrenergic receptor agonist UK 14,304 inhibits secretin-stimulated ductal secretion by downregulation of the cAMP system in bile duct-ligated rats. Am J Physiol Cell Physiol 2007; 293:C1252-62. [PMID: 17634418 DOI: 10.1152/ajpcell.00031.2007] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Secretin stimulates ductal secretion by activation of cAMP --> PKA --> CFTR --> Cl(-)/HCO(3)(-) exchanger in cholangiocytes. We evaluated the expression of alpha(2A)-, alpha(2B)-, and alpha(2C)-adrenergic receptors in cholangiocytes and the effects of the selective alpha(2)-adrenergic agonist UK 14,304, on basal and secretin-stimulated ductal secretion. In normal rats, we evaluated the effect of UK 14,304 on bile and bicarbonate secretion. In bile duct-ligated (BDL) rats, we evaluated the effect of UK 14,304 on basal and secretin-stimulated 1) bile and bicarbonate secretion; 2) duct secretion in intrahepatic bile duct units (IBDU) in the absence or presence of 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of the Na(+)/H(+) exchanger isoform NHE3; and 3) cAMP levels, PKA activity, Cl(-) efflux, and Cl(-)/HCO(3)(-) exchanger activity in purified cholangiocytes. alpha(2)-Adrenergic receptors were expressed by all cholangiocytes in normal and BDL liver sections. UK 14,304 did not change bile and bicarbonate secretion of normal rats. In BDL rats, UK 14,304 inhibited secretin-stimulated 1) bile and bicarbonate secretion, 2) expansion of IBDU luminal spaces, and 3) cAMP levels, PKA activity, Cl(-) efflux, and Cl(-)/HCO(3)(-) exchanger activity in cholangiocytes. There was decreased lumen size after removal of secretin in IBDU pretreated with UK 14,304. In IBDU pretreated with EIPA, there was no significant decrease in luminal space after removal of secretin in either the absence or presence of UK 14,304. The inhibitory effect of UK 14,304 on ductal secretion is not mediated by the apical cholangiocyte NHE3. alpha(2)-Adrenergic receptors play a role in counterregulating enhanced ductal secretion associated with cholangiocyte proliferation in chronic cholestatic liver diseases.
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Affiliation(s)
- Heather Francis
- Central Texas Veterans Health Care System, The Texas A & M University System Health Science Center College of Medicine, Medical Research Bldg, Temple, TX 76504, USA
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DiCostanzo CA, Dardevet DP, Williams PE, Moore MC, Hastings JR, Neal DW, Cherrington AD. The effect of vagal cooling on canine hepatic glucose metabolism in the presence of hyperglycemia of peripheral origin. Metabolism 2007; 56:814-24. [PMID: 17512315 DOI: 10.1016/j.metabol.2007.01.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2006] [Accepted: 01/19/2007] [Indexed: 01/24/2023]
Abstract
We examined the role of vagus nerves in the transmission of the portal glucose signal in conscious dogs. At time 0, somatostatin infusion was started along with intraportal insulin and glucagon at 4-fold basal and basal rates, respectively. Glucose was infused via a peripheral vein to create hyperglycemia ( approximately 2 fold basal). At t = 90, hollow coils around the vagus nerves were perfused with -10 degrees C or 37 degrees C solution in the vagally cooled (COOL) and sham-cooled (SHAM) groups, respectively (n = 6 per group). Effectiveness of vagal blockade was demonstrated by increase in heart rate during perfusion in the COOL vs SHAM groups (183 +/- 3 vs 102 +/- 5 beats per minute, respectively) and by prolapse of the third eyelid in the COOL group. Arterial plasma insulin (22 +/- 2 and 24 +/- 3 micro U/mL) and glucagon (37 +/- 5 and 40 +/- 4 pg/mL) concentrations did not change significantly between the first experimental period and the coil perfusion period in either the SHAM or COOL group, respectively. The hepatic glucose load throughout the entire experiment was 46 +/- 1 and 50 +/- 2 mg . kg(-1) . min(-1) in the SHAM and COOL groups, respectively. Net hepatic glucose uptake (NHGU) did not differ in the SHAM and COOL groups before (2.2 +/- 0.5 and 2.9 +/- 0.8 mg . kg(-1) . min(-1), respectively) or during the cooling period (3.0 +/- 0.5 and 3.4 +/- 0.6 mg . kg(-1) . min(-1), respectively). Likewise, net hepatic glucose fractional extraction and nonhepatic glucose uptake and clearance were not different between groups during coil perfusion. Interruption of vagal signaling in the presence of hyperinsulinemia and hyperglycemia resulting from peripheral glucose infusion did not affect NHGU, further supporting our previous suggestion that vagal input to the liver is not a primary determinant of NHGU.
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Affiliation(s)
- Catherine A DiCostanzo
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA
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Abstract
BACKGROUND The rat is the most used experimental model in surgical research. Virtually all procedures in clinical liver surgery can be performed in the rat. However, the use of the rat model in liver surgery is limited by its small size and limited knowledge of the liver anatomy. As in humans, the rat liver vasculature and biliary system have many anatomical variations. The development of surgical techniques, and the study of liver function and diseases require detailed knowledge of the regional anatomy. AIM The objective of this study was to describe and illustrate systematically the surgical anatomy of the rat liver to facilitate the planning and performance of studies in this animal. Knowledge of the diameter and length of liver vessels is also important for the selection of catheters and perivascular devices. METHODS Twelve Wistar rat livers were dissected using a surgical microscope. Hepatic and extrahepatic anatomical structures were measured under magnification with a millimeter scale. CONCLUSION In this study, we describe the rat liver topographical anatomy, compare it with the human liver and review the literature. Increased knowledge of the rat liver anatomy and microsurgical skills permit individualized dissection, parenchymal section, embolization and ligature of vascular and biliary branches.
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Affiliation(s)
- Paulo Ney Aguiar Martins
- Department of General-Visceral and Transplantation Surgery, Virchow Clinic, Charité-University Medicine Berlin, Berlin, Germany.
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Alvaro D, Mancino MG, Glaser S, Gaudio E, Marzioni M, Francis H, Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 2007; 132:415-31. [PMID: 17241889 DOI: 10.1053/j.gastro.2006.07.023] [Citation(s) in RCA: 224] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Accepted: 07/12/2006] [Indexed: 12/16/2022]
Abstract
In the last 15 years, the intrahepatic biliary tree has become the object of extensive studies, which highlighted the extraordinary biologic properties of cholangiocytes involved in bile formation, proliferation, injury repair, fibrosis, angiogenesis, and regulation of blood flow. Proliferation is a "typical" property of cholangiocytes and is key as a mechanism of repair responsible for maintaining the integrity of the biliary tree. Cholangiocyte proliferation occurs virtually in all pathologic conditions of liver injury where it is associated with inflammation, regeneration, and repair, thus conditioning the evolution of liver damage. Interestingly, proliferating cholangiocytes acquire the phenotype of neuroendocrine cells, and secrete different cytokines, growth factors, neuropeptides, and hormones, which represent potential mechanisms for cross talk with other liver cells. Many studies suggest the generation of a neuroendocrine compartment in the injured liver, mostly constituted by cells with cholangiocyte features, which functionally conditions the progression of liver disease. These insights on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte biology.
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, Department of Clinical Medicine, University La Sapienza, via R. Rossellini 51, 00137 Rome, Italy.
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Marzioni M, Fava G, Benedetti A. Nervous and Neuroendocrine regulation of the pathophysiology of cholestasis and of biliary carcinogenesis. World J Gastroenterol 2006; 12:3471-3480. [PMID: 16773704 PMCID: PMC4087563 DOI: 10.3748/wjg.v12.i22.3471] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Revised: 02/06/2006] [Accepted: 02/18/2006] [Indexed: 02/06/2023] Open
Abstract
Cholangiocytes, the epithelial cells lining the biliary ducts, are the target cells in several liver diseases. Cholangiopathies and cholangiocarcinoma generate interest in many scientists since the genesis. The developing mechanisms, and the therapeutic tools of these diseases are still undefined. Several studies demonstrate that many hormones, neuropeptides and neurotransmitters regulate malignant and non-malignant cholangiocyte pathophysiology in the course of chronic biliary diseases. The aim of this review is to present the findings of several studies published in the recent years that contributed to clarifying the role of nervous and neuroendocrine regulation of the pathophysiologic events associated with cholestasis and cholangiocarcinoma development. This manuscript is organized into two parts. The first part offers an overview of the innervation of the liver and the origin of neuroendocrine hormones, neurotransmitters and neuropeptides affecting cholangiocyte function and metabolism. The first section also reviews the effects played by several neuroendocrine hormones and nervous system on cholangiocyte growth, survival and functional activity in the course of cholestasis. In the second section, we summarize the results of some studies describing the role of nervous system and neuroendocrine hormones in the regulation of malignant cholangiocyte growth.
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Affiliation(s)
- Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Marche, Nuovo Polo Didattico, III piano, Via Tronto 10, 60020 Ancona, Italy.
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Glaser S, Francis H, Demorrow S, Lesage G, Fava G, Marzioni M, Venter J, Alpini G. Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 2006; 12:3523-3536. [PMID: 16773709 PMCID: PMC4087568 DOI: 10.3748/wjg.v12.i22.3523] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2006] [Revised: 05/10/2006] [Accepted: 05/18/2006] [Indexed: 02/06/2023] Open
Abstract
The objectives of this review are to outline the recent findings related to the morphological heterogeneity of the biliary epithelium and the heterogeneous pathophysiological responses of different sized bile ducts to liver gastrointestinal hormones and peptides and liver injury/toxins with changes in apoptotic, proliferative and secretory activities. The knowledge of biliary function is rapidly increasing because of the recognition that biliary epithelial cells (cholangiocytes) are the targets of human cholangiopathies, which are characterized by proliferation/damage of bile ducts within a small range of sizes. The unique anatomy, morphology, innervation and vascularization of the biliary epithelium are consistent with function of cholangiocytes within different regions of the biliary tree. The in vivo models [e.g., bile duct ligation (BDL), partial hepatectomy, feeding of bile acids, carbon tetrachloride (CCl4) or alpha-naphthylisothiocyanate (ANIT)] and the in vivo experimental tools [e.g., freshly isolated small and large cholangiocytes or intrahepatic bile duct units (IBDU) and primary cultures of small and large murine cholangiocytes] have allowed us to demonstrate the morphological and functional heterogeneity of the intrahepatic biliary epithelium. These models demonstrated the differential secretory activities and the heterogeneous apoptotic and proliferative responses of different sized ducts. Similar to animal models of cholangiocyte proliferation/injury restricted to specific sized ducts, in human liver diseases bile duct damage predominates specific sized bile ducts. Future studies related to the functional heterogeneity of the intrahepatic biliary epithelium may disclose new pathophysiological treatments for patients with cholangiopathies.
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Affiliation(s)
- Shannon Glaser
- Department of Medicine, Division of R&E, Scott and White Memorial Hospital and The Texas A&M University System Health Science Center College of Medicine, MRB, 702 South West H.K. Dodgen Loop, Temple, Texas 76504, USA.
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Glaser S, Alvaro D, Francis H, Ueno Y, Marucci L, Benedetti A, De Morrow S, Marzioni M, Mancino MG, Phinizy JL, Reichenbach R, Fava G, Summers R, Venter J, Alpini G. Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt. Am J Physiol Gastrointest Liver Physiol 2006; 290:G813-G826. [PMID: 16339297 DOI: 10.1152/ajpgi.00306.2005] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Loss of parasympathetic innervation after vagotomy impairs cholangiocyte proliferation, which is associated with depressed cAMP levels, impaired ductal secretion, and enhanced apoptosis. Agonists that elevate cAMP levels prevent cholangiocyte apoptosis and restore cholangiocyte proliferation and ductal secretion. No information exists regarding the role of adrenergic innervation in the regulation of cholangiocyte function. In the present studies, we investigated the role of adrenergic innervation on cholangiocyte proliferative and secretory responses to bile duct ligation (BDL). Adrenergic denervation by treatment with 6-hydroxydopamine (6-OHDA) during BDL decreased cholangiocyte proliferation and secretin-stimulated ductal secretion with concomitant increased apoptosis, which was associated with depressed cholangiocyte cAMP levels. Chronic administration of forskolin (an adenylyl cyclase activator) or beta(1)- and beta(2)-adrenergic receptor agonists (clenbuterol or dobutamine) prevented the decrease in cholangiocyte cAMP levels, maintained cholangiocyte secretory and proliferative activities, and decreased cholangiocyte apoptosis resulting from adrenergic denervation. This was associated with enhanced phosphorylation of Akt. The protective effects of clenbuterol, dobutamine, and forskolin on 6-OHDA-induced changes in cholangiocyte apoptosis and proliferation were partially blocked by chronic in vivo administration of wortmannin. In conclusion, we propose that adrenergic innervation plays a role in the regulation of biliary mass and cholangiocyte functions during BDL by modulating intracellular cAMP levels.
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Affiliation(s)
- Shannon Glaser
- Division of Research and Education, College of Medicine, Scott and White Hospital and The Texas A & M University System Health Science Center, Temple, 76504, USA
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Dicostanzo CA, Dardevet DP, Neal DW, Lautz M, Allen E, Snead W, Cherrington AD. Role of the hepatic sympathetic nerves in the regulation of net hepatic glucose uptake and the mediation of the portal glucose signal. Am J Physiol Endocrinol Metab 2006; 290:E9-E16. [PMID: 16105863 DOI: 10.1152/ajpendo.00184.2005] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Portal glucose delivery enhances net hepatic glucose uptake (NHGU) relative to peripheral glucose delivery. We hypothesize that the sympathetic nervous system normally restrains NHGU, and portal glucose delivery relieves the inhibition. Two groups of 42-h-fasted conscious dogs were studied using arteriovenous difference techniques. Denervated dogs (DEN; n=10) underwent selective sympathetic denervation by cutting the nerves at the celiac nerve bundle near the common hepatic artery; control dogs (CON; n=10) underwent a sham procedure. After a 140-min basal period, somatostatin was given along with basal intraportal infusions of insulin and glucagon. Glucose was infused peripherally to double the hepatic glucose load (HGL) for 90 min (P1). In P2, glucose was infused intraportally (3-4 mg.kg(-1).min(-1)), and the peripheral glucose infusion was reduced to maintain the HGL for 90 min. This was followed by 90 min (P3) in which portal glucose infusion was terminated and peripheral glucose infusion was increased to maintain the HGL. P1 and P3 were averaged as the peripheral glucose infusion period (PE). The average HGLs (mg.kg(-1).min(-1)) in CON and DEN were 55+/-3 and 54+/-4 in the peripheral periods and 55+/-3 and 55+/-4 in P2, respectively. The arterial insulin and glucagon levels remained basal in both groups. NHGU (mg.kg(-1).min(-1)) in CON averaged 1.7+/-0.3 during PE and increased to 2.9+/-0.3 during P2. NHGU (mg.kg(-1).min(-1)) was greater in DEN than CON (P<0.05) during PE (2.9+/-0.4) and failed to increase significantly (3.2+/-0.2) during P2 (not significant vs. CON). Selective sympathetic denervation increased NHGU during hyperglycemia but significantly blunted the response to portal glucose delivery.
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Affiliation(s)
- Catherine A Dicostanzo
- Dept. of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN 37232-0615, USA.
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Püschel GP. Control of hepatocyte metabolism by sympathetic and parasympathetic hepatic nerves. ACTA ACUST UNITED AC 2005; 280:854-67. [PMID: 15382015 DOI: 10.1002/ar.a.20091] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
More than any other organ, the liver contributes to maintaining metabolic equilibrium of the body, most importantly of glucose homeostasis. It can store or release large quantities of glucose according to changing demands. This homeostasis is controlled by circulating hormones and direct innervation of the liver by autonomous hepatic nerves. Sympathetic hepatic nerves can increase hepatic glucose output; they appear, however, to contribute little to the stimulation of hepatic glucose output under physiological conditions. Parasympathetic hepatic nerves potentiate the insulin-dependent hepatic glucose extraction when a portal glucose sensor detects prandial glucose delivery from the gut. In addition, they might coordinate the hepatic and extrahepatic glucose utilization to prevent hypoglycemia and, at the same time, warrant efficient disposal of excess glucose.
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Affiliation(s)
- Gerhard P Püschel
- Institut für Ernährungswissenschaft, Universität Potsdam, Nuthetal, Germany.
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Abstract
During embryonic development, the liver emerges from the foregut as a thickening of the ventral endodermal epithelium. The embryonic liver then develops into a bud of cells that proliferates and differentiates to eventually form the largest gland of the body. Prior to birth, the primary function of the liver is hematopoietic, and the organ receives little innervation during early development. Postnatally, the role of the liver changes and many different nerve types modulate its function. Although the liver shares a common embryonic origin with other foregut derivatives, such as the gallbladder and the pancreas, the development of its innervation exhibits distinct characteristics. In this review, we summarize what is known about the development of the hepatic innervation, draw comparisons with the intrinsic innervation of the gastrointestinal tract and associated organs, and discuss the potential role of molecular signals in guiding the nerves that innervate the liver.
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Affiliation(s)
- Jean-Marie Delalande
- Neural Development Unit, Institute of Child Health, University College London, UK
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Uyama N, Geerts A, Reynaert H. Neural connections between the hypothalamus and the liver. ACTA ACUST UNITED AC 2004; 280:808-20. [PMID: 15382020 DOI: 10.1002/ar.a.20086] [Citation(s) in RCA: 140] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
After receiving information from afferent nerves, the hypothalamus sends signals to peripheral organs, including the liver, to keep homeostasis. There are two ways for the hypothalamus to signal to the peripheral organs: by stimulating the autonomic nerves and by releasing hormones from the pituitary gland. In order to reveal the involvement of the autonomic nervous system in liver function, we focus in this study on autonomic nerves and neuroendocrine connections between the hypothalamus and the liver. The hypothalamus consists of three major areas: lateral, medial, and periventricular. Each area has some nuclei. There are two important nuclei and one area in the hypothalamus that send out the neural autonomic information to the peripheral organs: the ventromedial hypothalamic nucleus (VMH) in the medial area, the lateral hypothalamic area (LHA), and the periventricular hypothalamic nucleus (PVN) in the periventricular area. VMH sends sympathetic signals to the liver via the celiac ganglia, the LHA sends parasympathetic signals to the liver via the vagal nerve, and the PVN integrates information from other areas of the hypothalamus and sends both autonomic signals to the liver. As for the afferent nerves, there are two pathways: a vagal afferent and a dorsal afferent nerve pathway. Vagal afferent nerves are thought to play a role as sensors in the peripheral organs and to send signals to the brain, including the hypothalamus, via nodosa ganglia of the vagal nerve. On the other hand, dorsal afferent nerves are primary sensory nerves that send signals to the brain via lower thoracic dorsal root ganglia. In the liver, many nerves contain classical neurotransmitters (noradrenaline and acetylcholine) and neuropeptides (substance P, calcitonin gene-related peptide, neuropeptide Y, vasoactive intestinal polypeptide, somatostatin, glucagon, glucagon-like peptide, neurotensin, serotonin, and galanin). Their distribution in the liver is species-dependent. Some of these nerves are thought to be involved in the regulation of hepatic function as well as of hemodynamics. In addition to direct neural connections, the hypothalamus can affect metabolic functions by neuroendocrine connections: the hypothalamus-pancreas axis, the hypothalamus-adrenal axis, and the hypothalamus-pituitary axis. In the hypothalamus-pancreas axis, autonomic nerves release glucagon and insulin, which directly enter the liver and affect liver metabolism. In the hypothalamus-adrenal axis, autonomic nerves release catecholamines such as adrenaline and noradrenaline from the adrenal medulla, which also affects liver metabolism. In the hypothalamus-pituitary axis, release of glucocorticoids and thyroid hormones is stimulated by pituitary hormones. Both groups of hormones modulate hepatic metabolism. Taken together, the hypothalamus controls liver functions by neural and neuroendocrine connections.
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Affiliation(s)
- Naoki Uyama
- Laboratory for Molecular Liver Cell Biology, Vrije Universiteit Brussel, Belgium.
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Abstract
The role of neural elements in regulating blood flow through the hepatic sinusoids, solute exchange, and parenchymal function is incompletely understood. This is due in part to limited investigation in only a few species whose hepatic innervation may differ significantly from humans. For example, most experimental studies have used rats and mice having livers with little or no intralobular innervation. In contrast, most other mammals, including humans, have aminergic and peptidergic nerves extending from perivascular plexus in the portal space into the lobule, where they course in Disse's space in close relationship to stellate cells (fat storing cells of Ito) and hepatic parenchymal cells. While these fibers extend throughout the lobule, they predominate in the periportal region. Cholinergic innervation, however, appears to be restricted to structures in the portal space and immediately adjacent hepatic parenchymal cells. Neuropeptides have been colocalized with neurotransmitters in both adrenergic and cholinergic nerves. Neuropeptide Y (NPY) has been colocalized in aminergic nerves supplying all segments of the hepatic-portal venous and the hepatic arterial and biliary systems. Nerve fibers immunoreactive for substance P and somatostatin follow a similar distribution. Intralobular distribution of all of these nerve fibers is species-dependent and similar to that reported for aminergic fibers. Vasoactive intestinal peptide and calcitonin gene-related peptide (CGRP) are reported to coexist in cholinergic and sensory afferent nerves innervating portal veins and hepatic arteries and their branches, but not the other vascular segments or the bile ducts. Nitrergic nerves immunoreactive for neuronal nitric oxide (nNOS) are located in the portal tract where nNOS colocalizes with both NPY- and CGRP-containing fibers. In summary, the liver is innervated by aminergic, cholinergic, peptidergic, and nitrergic nerves. While innervation of structures in the portal tract is relatively similar between species, the extent and distribution of intralobular innervation are highly variable as well as species-dependent and may be inversely related to the density of gap junctions between contiguous hepatic parenchymal cells.
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Affiliation(s)
- Robert S McCuskey
- Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson 85724, USA.
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Vatamaniuk MZ, Horyn OV, Vatamaniuk OK, Doliba NM. Acetylcholine affects rat liver metabolism via type 3 muscarinic receptors in hepatocytes. Life Sci 2003; 72:1871-82. [PMID: 12586224 DOI: 10.1016/s0024-3205(02)02506-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Although the role of acetylcholine (Ach) in hepatic glucose metabolism is well elucidated, it is still unclear if it influences gluconeogenesis, glycogenolysis and high-energy phosphate metabolism, and if it does what the mechanisms of this influence are. Therefore, using isolated perfused rat liver as a model, we have studied the effect of Ach on oxygen consumption, synthesis of glucose from lactate and pyruvate, glycogen formation, mitochondrial oxidative phosphorylation and ATP-synthesis. We have established that effects of Ach on oxygen consumption depend on its concentration. When used at a concentration of 10(-7) M, Ach exerts maximum stimulatory effect, while its infusion at 10(-6) M causes a decrease of oxygen consumption by the liver. Moreover, when used at a concentration of 10(-6) M or 10(-7) M, Ach increases rates of glucose production from the gluconeogenic substrates lactate and pyruvate, leading to enhanced glycogen content in perfused liver. It was also shown that Ach possesses a stimulating effect on alanine and aspartate aminotransferases. As detected by 31P NMR spectroscopy, continuous liver perfusion with pyruvate and lactate in the presence of Ach leads to a significant decrease of ATP level, implying enhanced energy requirements for gluconeogenesis under these conditions. Elimination of the described effects of Ach by atropine, the antagonist of muscarinic receptors, and identification of the type 3 muscarinic receptors (m3) in isolated hepatocytes as well as in whole liver, imply that Ach may exert its effect on liver metabolism through m3 receptors.
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Affiliation(s)
- M Z Vatamaniuk
- Biochemistry & Biophysics Department, University of Pennsylvania, 501 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104, USA.
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Sakamoto I, Takahashi T, Kakita A, Hayashi I, Majima M, Yamashina S. Experimental study on hepatic reinnervation after orthotopic liver transplantation in rats. J Hepatol 2002; 37:814-23. [PMID: 12445423 DOI: 10.1016/s0168-8278(02)00283-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS The present study examined whether extrinsic hepatic reinnervation occurred after orthotopic liver transplantation (OLT) in rats. METHODS Inbred male Lewis rats were the recipients and females the donors. Tissue specimens were obtained postoperatively from the stump of a recipient's hepatoduodenal ligament (A), and the hepatic hilus (B) and peripheral parenchyma (C) of liver allografts, up to 6 months post-operation. Specimens were subjected to immunohistochemical examination using growth-associated protein (GAP)-43 as an axonal marker and transmission electron microscopy (TEM) for observing regenerating axons, as well as the polymerase chain reaction assay to detect the rat sex-determining region Y (SRY) protein gene of the regenerating nerves. RESULTS At site A, GAP-43-positive nerve axons were identified from day 1 to 1 month post-OLT and SRY protein genes were expressed at and after 3 days post-OLT. At site B, GAP-43-positive axons were observed between 3 days and 1 month, and SRY protein genes were detected at 1 month post-OLT and thereafter. TEM confirmed the presence of regenerating axons at and after 3 days post-OLT. CONCLUSIONS The results demonstrated that regenerating nerve fibers originating from the recipients reinnervated liver allografts. This extrinsic innervation occurred shortly after OLT, and most likely terminated after about 3 months.
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Affiliation(s)
- Izumi Sakamoto
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
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Yoneda M, Kurosawa M, Watanobe H, Shimada T, Terano A. Brain-gut axis of the liver: the role of central neuropeptides. J Gastroenterol 2002; 37 Suppl 14:151-6. [PMID: 12572884 DOI: 10.1007/bf03326435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Masashi Yoneda
- Department of Gastroenterology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
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Lutz TA, Estermann A, Geary N, Scharrer E. Physiological effect of circulating glucagon on the hepatic membrane potential. Am J Physiol Regul Integr Comp Physiol 2001; 281:R1540-4. [PMID: 11641126 DOI: 10.1152/ajpregu.2001.281.5.r1540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The pancreatic hormone glucagon hyperpolarizes the liver cell membrane under various conditions. Here we investigated the physiological relevance of this effect by testing the influence of infusions of glucagon antiserum on the liver cell membrane potential in vivo. Intracellular microelectrode recordings of liver cells (up to 60/rat over 2 h) were done in anesthetized male rats. Livers were fixed in place, and recordings were done 10-30 min after intraperitoneal injections of glucagon or hepatic portal vein infusions of glucagon or specific polyclonal glucagon antibodies raised in rabbits. The isotonic lactose vehicle was used as a control for glucagon, and equal amounts of nonimmunized rabbit IgG were used as a control for glucagon antibodies. Intraperitoneal glucagon (400 microg/kg) hyperpolarized the liver cell membrane up to 12 mV, and intraportal glucagon (10 or 60 microg/kg) dose dependently hyperpolarized the liver cell membrane by 3-7 mV. Intraportal infusion of glucagon antiserum (in vitro binding capacity of 4 ng glucagon/rat) significantly depolarized the liver cell membrane by approximately 2.5 mV. The effects of both glucagon and glucagon antiserum reversed after 60-90 min. We conclude that glucagon is a physiologically important modulator of the liver cell membrane potential.
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Affiliation(s)
- T A Lutz
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland.
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Takahashi T, Kakita A, Sakamoto I, Takahashi Y, Hayashi K, Tadokoro F, Yamashina S. Immunohistochemical and electron microscopic study of extrinsic hepatic reinnervation following orthotopic liver transplantation in rats. LIVER 2001; 21:300-8. [PMID: 11589766 DOI: 10.1034/j.1600-0676.2001.210502.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND/AIMS Because little has been known about the morphological and functional consequences of liver transplantation on hepatic autonomic nerves, we examined the time-course of extrinsic hepatic innervation at the level of the porta hepatis of liver allografts. METHODS Orthotopic liver transplantation was performed using male Lewis rats. Crosscut tissue specimens were obtained postoperatively for up to 6 months from the porta hepatis of transplanted livers, and processed for immunohistochemical staining for protein gene product 9.5 (PGP 9.5) and growth-associated protein 43 (GAP-43), and for transmission electron microscopy (TEM). RESULTS Extrinsic nerve fibers at the porta hepatis stained positively for PGP 9.5 throughout the entire study period. In contrast, the immunoreactivity of GAP-43 was negative at postoperative day (POD) 1 and 2. GAP-43-positive nerves were first observed to appear in the porta hepatis at POD 3. The immunoreactivity of GAP-43 remained positive thereafter until 3 months post-OLT, and became negative in all the specimens at 4 months post-OLT. Transmission electron microscopy demonstrated a small number of regenerating axons existing among many degenerating axons at POD 3. At 3 months post-OLT, most regenerating axons had been fully ensheathed by the cytoplasm of Schwann cells, although their density remained at a lower level compared with normal. CONCLUSION The results of this study suggest that liver allografts become extrinsically reinnervated, with the regenerating axons reaching the hepatic hilus 3 days after transplantation. The process of extrinsic hepatic reinnervation is considered to almost terminate 4 months after transplantation in rats.
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Affiliation(s)
- T Takahashi
- Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
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Abstract
The objective of this review article is to discuss the role of secretin and its receptor in the regulation of the secretory activity of intrahepatic bile duct epithelial cells (i.e., cholangiocytes). After a brief overview of cholangiocyte functions, we provide an historical background for the role of secretin and its receptor in the regulation of ductal secretion. We review the newly developed experimental in vivo and in vitro tools, which lead to understanding of the mechanisms of secretin regulation of cholangiocyte functions. After a description of the intracellular mechanisms by which secretin stimulates ductal secretion, we discuss the heterogeneous responses of different-sized intrahepatic bile ducts to gastrointestinal hormones. Furthermore, we outline the role of a number of cooperative factors (e.g., nerves, alkaline phosphatase, gastrointestinal hormones, neuropeptides, and bile acids) in the regulation of secretin-stimulated ductal secretion. Finally, we discuss other factors that may also play an important role in the regulation of secretin-stimulated ductal secretion.
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Affiliation(s)
- N Kanno
- Department of Internal Medicine, Scott & White Hospital and Texas A&M University System Health Science Center, College of Medicine, TX 76504, USA
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Sakamoto I, Takahashi T, Tadokoro F, Takahashi Y, Hayashi K, Ito Y, Iino Z, Kakita A. Immunohistochemical study of the regeneration process of extrinsic hepatic nerves following liver transplantation in rats. Transplant Proc 2000; 32:2352-4. [PMID: 11120197 DOI: 10.1016/s0041-1345(00)01696-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- I Sakamoto
- Kitasato University School of Medicine, Department of Surgery, Kanagawa, Japan
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Abstract
Fatty acid oxidation seems to provide an important stimulus for metabolic control of food intake, because various inhibitors of fatty acid oxidation (mercaptoacetate, methyl palmoxirate, R-3-amino-4-trimethylaminobutyric acid) stimulated feeding in rats and/or mice, in particular when fed a fat-enriched diet, and long-term intravascular infusion of lipids reduced voluntary food intake in various species, including humans. The feeding response to decreased fatty acid oxidation was due to a shortening of the intermeal interval with meal size remaining unaffected. Thus, energy derived from fatty acid oxidation seems to contribute to control of the duration of postmeal satiety and meal onset. Since inhibition of glucose metabolism by 2-deoxy-D-glucose affects feeding pattern similarly, and spontaneous meals were shown to be preceded by a transient decline in blood glucose in rats and humans, a decrease in energy availability from glucose and fatty acid oxidation seems to be instrumental in eliciting eating. Since the feeding response of rats to inhibition of fatty acid oxidation was abolished by total abdominal vagotomy and pretreatment with capsaicin destroying non-myelinated afferents and attenuated by hepatic branch vagotomy, fatty acid oxidation in abdominal tissues, especially in the liver, apparently is signalled to the brain by vagal afferents to affect eating. Brain lesions and Fos immunohistochemistry were employed to identify pathways within the brain mediating eating in response to decreased fatty acid oxidation. According to these studies, the nucleus tractus solitarii (NTS) of the medulla oblongata represents the gate for central processing of vagally mediated afferent information related to fatty acid oxidation. The lateral parabrachial nucleus of the pons seems to be a major relay for pertinent ascending input from the NTS. In particular the central nucleus of the amygdala, a projection area of the parabrachial nucleus, appears to be crucial for eating in response to decreased fatty acid oxidation. As ketones are products of hepatic fatty acid oxidation that are released into the circulation and peripheral (and central) administration of 3-hydroxybutyrate reduced voluntary food intake in rats, ketones being utilized as fuels by the peripheral and central nervous system might contribute to control of eating by fatty acid oxidation, especially when high levels of circulating ketones occur. Whether a modulation of the hepatic membrane potential resulting from changes in the rate of fatty acid oxidation and/or ketogenesis represent a signal for control of eating transmitted to the brain by vagal afferents remains to be established. Recent in vivo studies investigating the effects of mercaptoacetate on the hepatic membrane potential and on afferent activity of the hepatic vagus branch are consistent with this notion. Further investigations are necessary to delineate the coding mechanisms by which fatty acid oxidation and/or ketogenesis modulate vagal afferent activity.
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Affiliation(s)
- E Scharrer
- Institute of Veterinary Physiology, University of Zurich, Switzerland.
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Akiyoshi H, Gonda T, Terada T. A comparative histochemical and immunohistochemical study of aminergic, cholinergic and peptidergic innervation in rat, hamster, guinea pig, dog and human livers. LIVER 1998; 18:352-9. [PMID: 9831365 DOI: 10.1111/j.1600-0676.1998.tb00817.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIMS/BACKGROUND The mammalian liver receives both sympathetic and parasympathetic nerves that contain aminergic, cholinergic and peptidergic components. The intrahepatic distribution of nerve fibers are highly species-dependent; and also, even within one species, there are notable variations. To reveal the pattern and type of hepatic innervation in different species, we examined the distribution and density of these nerve fibers. METHODS The livers of rats, golden hamsters, guinea pigs, dogs and humans were used. Aminergic and peptidergic nerve fibers were identified by immunohistochemistry for tyrosine hydroxylase (TH), neuropeptide Y (NPY), substance P (SP), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), and galanin (GAL), and cholinergic fibers were identified by the acetylcholinesterase (AChE) neurohistochemistry method. RESULTS AChE-, TH-, NPY-, CGRP-, VIP-, and SP-positive nerves were observed in the connective tissue of the portal region, and they were in close contact with hepatic arteries, portal veins and bile ducts in all five species. Within the parenchyma of guinea pig, dog and human livers, TH-, NPY- and SP-positive fibers were observed, but no AChE- and CGRP-positive fibers were observed. In rat and hamster livers, no parenchymal nerve fibers could be demonstrated, but CGRP-, NPY- and SP-positive fibers were observed in the border of periportal areas. The density of CGRP-positive nerve fibers were slightly higher around bile ducts than around hepatic arteries and portal veins. GAL-positive fibers were not detected in any animal. CONCLUSIONS These data indicate that there were differences in the patterns of hepatic innervation among rats, golden hamsters, guinea pigs, dogs and humans. The data also show that: 1) in rat and hamster livers, hepatic functions may be regulated by both sympathetic and parasympathetic nerves in the portal region; 2) in guinea pig, dog and human livers they may be regulated by these fibers both in the interlobular region (parasympathetic and sympathetic systems) and in the intraparenchymal region (sympathetic system); and thus, 3) in the latter three species, hepatocytes and sinusoidal cells may be innervated by sympathetic nerves.
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Affiliation(s)
- H Akiyoshi
- Second Department of Pathology, Faculty of Medicine, Tottori University, Japan
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Yoneda M. Regulation of hepatic function by brain neuropeptides. World J Gastroenterol 1998; 4:192-196. [PMID: 11819273 PMCID: PMC4723454 DOI: 10.3748/wjg.v4.i3.192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/1998] [Revised: 05/15/1998] [Accepted: 06/02/1998] [Indexed: 02/06/2023] Open
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Eugenín EA, González H, Sáez CG, Sáez JC. Gap junctional communication coordinates vasopressin-induced glycogenolysis in rat hepatocytes. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 274:G1109-16. [PMID: 9696712 DOI: 10.1152/ajpgi.1998.274.6.g1109] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Because hepatocytes communicate via gap junctions, it has been proposed that Ca2+ waves propagate through this pathway and in the process activate Ca2+-dependent cellular responses. We testedthis hypothesis by measuring vasopressin-induced glycogenolysis in short-term cultures of rat hepatocytes. A 15-min vasopressin (10(-8) M) stimulation induced a reduction of glycogen content that reached a maximum 1-3 h later. Gap junction blockers, octanol or 18alpha-glycyrrhetinic acid, reduced the effect by 70%. The glycogenolytic response induced by Ca2+ ionophore 8-bromo-A-21387, which acts on each hepatocyte, was not affected by gap junction blockers. Moreover, the vasopressin-induced glycogenolysis was lower (70%) in dispersed than in reaggregated hepatocytes and in dispersed hepatocytes was not affected by gap junction blockers. In hepatocytes reaggregated in the presence of a synthetic peptide homologous to a domain of the extracellular loop 1 of the main hepatocyte gap junctional protein, vasopressin-induced glycogenolysis and incidence of dye coupling were drastically reduced. Moreover, gap junctional communication was detected between reaggregated cells, suggesting that hepatocytes with different vasopressin receptor densities become coupled to each other. The vasopressin-induced effect was not affected by suramin, ruling out ATP as a paracrine mediator. We propose that gap junctions allow for a coordinated vasopressin-induced glycogenolytic response despite the heterogeneity among hepatocytes.
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Affiliation(s)
- E A Eugenín
- Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiogo, Chile
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Shiraishi S, Okamura T, Kodama M, Toda N. Mechanisms underlying the neurogenic relaxation in dog isolated hepatic arteries. J Cardiovasc Pharmacol 1998; 31:372-6. [PMID: 9514181 DOI: 10.1097/00005344-199803000-00007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In canine hepatic arterial strips responding to nicotine with contraction, prazosin abolished the response or reversed it to a relaxation. Mechanisms underlying the relaxation were analyzed in hepatic and coronary arterial strips denuded of the endothelium and treated with prazosin and indomethacin. In the hepatic arterial strips precontracted with prostaglandin (PG) F2alpha, nicotine-induced relaxations were not influenced by atropine but were inhibited by timolol and abolished by hexamethonium. Treatment with [8-37] calcitonin gene-related peptide ([8-37] CGRP), a selective CGRP1-receptor antagonist, also attenuated the nicotine-induced relaxation, but a vasoactive intestinal polypeptide antagonist was without effect. Combined treatment with timolol and [8-37] CGRP depressed the response to a greater extent than either antagonist alone. The slight relaxation remaining under the combined treatment was abolished by NG-nitro-L-arginine (L-NA) and restored by L-arginine. In coronary arterial strips precontracted with PGF2alpha, nicotine produced a moderate relaxation, which was abolished or markedly inhibited by treatment with hexamethonium or timolol but was unaffected by L-NA. It is concluded that the nicotine-induced relaxation is mediated by norepinephrine, CGRP, and NO released from perivascular nerves in dog hepatic arterial strips; the responses associated with activations of beta-adrenoceptors and CGRP1 receptors are predominant over those to NO. The coronary arterial relaxation seems to be mediated by neurogenic norepinephrine but not by NO.
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Affiliation(s)
- S Shiraishi
- Department of Pharmacology, Shiga University of Medical Science, Seta, Ohtsu, Japan
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Ito Y, Takahashi T, Tadokoro F, Hayashi K, Iino Z, Sato K, Akira K. Regeneration of the hepatic nerves following surgical denervation of the liver in dogs. LIVER 1998; 18:20-6. [PMID: 9548263 DOI: 10.1111/j.1600-0676.1998.tb00122.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
This study was conducted to examine the regeneration process of hepatic nerves following surgical hepatic denervation in dogs. A denervation model was surgically created by removing all visible nerves around the hepatoduodenal ligament along with the peri-hepatic tissues. The hepatic nerves were examined on the hepatic specimens taken at 1 week, 1 month and 3 months post-denervation by means of immunohistochemical staining, and also electron microscopy. At 1 week post-denervation, the extrinsic hepatic nerves were observed not to have regenerated. However, at 1 month post-denervation, GAP-43-positive nerves were identified and regenerating axons were shown to be present on electron microscopic observation. The immunoreactivity for anti-GAP-43 antibody was not shown any longer at 3 months post-denervation, and the regenerated nerve axons were shown to be similar to those at pre-denervation on ultrastructural study. Results of the present study suggested that regeneration of the extrinsic hepatic nerves began to appear about 1 month after the hepatic denervation, and was completed by 3 months post-denervation.
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Affiliation(s)
- Y Ito
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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