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1
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Song D, Li Y, Yang LL, Luo YX, Yao XQ. Bridging systemic metabolic dysfunction and Alzheimer's disease: the liver interface. Mol Neurodegener 2025; 20:61. [PMID: 40437610 PMCID: PMC12121119 DOI: 10.1186/s13024-025-00849-6] [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: 12/31/2024] [Accepted: 05/09/2025] [Indexed: 06/01/2025] Open
Abstract
Alzheimer's disease (AD) is increasingly recognized as a systemic disorder with a substantial metabolic disorder component, where the liver significantly impacts the brain via the liver-brain axis. Key mechanisms include the liver's role in clearing peripheral β-amyloid (Aβ), the influence of hepatic enzymes and metabolites on cognitive decline, and the systemic effects of metabolic disorders on AD progression. Hepatokines, liver-secreted proteins including fibroblast growth factor (FGF)-21, selenoprotein P (SELENOP), Fetuin-A, Midbrain astrocyte-derived neurotrophic factor (MANF), apolipoprotein J (ApoJ), sex hormone-binding globulin (SHBG), Adropin and Angiopoietin-like protein 3 (ANGPTL3), could regulate insulin sensitivity, lipid metabolism, oxidative stress, immune responses, and neurotrophic support. These pathways are closely linked to core AD pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress and mitochondrial dysfunction. Lifestyle interventions, including exercise and dietary modifications, that regulate hepatokines expression may offer novel preventive and therapeutic strategies for AD. This review synthesizes current knowledge on the liver-brain crosstalk in AD, emphasizing the mechanistic role of liver in bridging metabolic dysfunction with neurodegeneration and underscores the diagnostic and therapeutic potential of hepatokines in addressing AD's complex pathology.
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Affiliation(s)
- Dan Song
- Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Yang Li
- Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Ling-Ling Yang
- Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Ya-Xi Luo
- Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
| | - Xiu-Qing Yao
- Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
- Chongqing Municipality Clinical Research Center for Geriatric Medicine, No. 76 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
- Department of Rehabilitation Therapy, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400000, China.
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2
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van de Graaf SFJ, Paulusma CC, In Het Panhuis W. Getting in the zone: Metabolite transport across liver zones. Acta Physiol (Oxf) 2024; 240:e14239. [PMID: 39364668 DOI: 10.1111/apha.14239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/16/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024]
Abstract
The liver has many functions including the regulation of nutrient and metabolite levels in the systemic circulation through efficient transport into and out of hepatocytes. To sustain these functions, hepatocytes display large functional heterogeneity. This heterogeneity is reflected by zonation of metabolic processes that take place in different zones of the liver lobule, where nutrient-rich blood enters the liver in the periportal zone and flows through the mid-zone prior to drainage by a central vein in the pericentral zone. Metabolite transport plays a pivotal role in the division of labor across liver zones, being either transport into the hepatocyte or transport between hepatocytes through the blood. Signaling pathways that regulate zonation, such as Wnt/β-catenin, have been shown to play a causal role in the development of metabolic dysfunction-associated steatohepatitis (MASH) progression, but the (patho)physiological regulation of metabolite transport remains enigmatic. Despite the practical challenges to separately study individual liver zones, technological advancements in the recent years have greatly improved insight in spatially divided metabolite transport. This review summarizes the theories behind the regulation of zonation, diurnal rhythms and their effect on metabolic zonation, contemporary techniques used to study zonation and current technological challenges, and discusses the current view on spatial and temporal metabolite transport.
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Affiliation(s)
- Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Coen C Paulusma
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Wietse In Het Panhuis
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, Amsterdam, The Netherlands
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3
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Ren W, Hua M, Cao F, Zeng W. The Sympathetic-Immune Milieu in Metabolic Health and Diseases: Insights from Pancreas, Liver, Intestine, and Adipose Tissues. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306128. [PMID: 38039489 PMCID: PMC10885671 DOI: 10.1002/advs.202306128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/28/2023] [Indexed: 12/03/2023]
Abstract
Sympathetic innervation plays a crucial role in maintaining energy balance and contributes to metabolic pathophysiology. Recent evidence has begun to uncover the innervation landscape of sympathetic projections and sheds light on their important functions in metabolic activities. Additionally, the immune system has long been studied for its essential roles in metabolic health and diseases. In this review, the aim is to provide an overview of the current research progress on the sympathetic regulation of key metabolic organs, including the pancreas, liver, intestine, and adipose tissues. In particular, efforts are made to highlight the critical roles of the peripheral nervous system and its potential interplay with immune components. Overall, it is hoped to underscore the importance of studying metabolic organs from a comprehensive and interconnected perspective, which will provide valuable insights into the complex mechanisms underlying metabolic regulation and may lead to novel therapeutic strategies for metabolic diseases.
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Affiliation(s)
- Wenran Ren
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
| | - Meng Hua
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
| | - Fang Cao
- Department of NeurosurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhou563000China
| | - Wenwen Zeng
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
- SXMU‐Tsinghua Collaborative Innovation Center for Frontier MedicineTaiyuan030001China
- Beijing Key Laboratory for Immunological Research on Chronic DiseasesBeijing100084China
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Yang K, Huang Z, Wang S, Zhao Z, Yi P, Chen Y, Xiao M, Quan J, Hu X. The Hepatic Nerves Regulated Inflammatory Effect in the Process of Liver Injury: Is Nerve the Key Treating Target for Liver Inflammation? Inflammation 2023; 46:1602-1611. [PMID: 37490221 DOI: 10.1007/s10753-023-01854-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 05/09/2023] [Accepted: 06/05/2023] [Indexed: 07/26/2023]
Abstract
Liver injury is a common pathological basis for various liver diseases. Chronic liver injury is often an important initiating factor in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Currently, hepatitis A and E infections are the most common causes of acute liver injury worldwide, whereas drug toxicity (paracetamol overdose) in the USA and part of Western Europe. In recent years, chronic liver injury has become a common disease that harms human health. Meanwhile, the main causes of chronic liver injury are viral hepatitis (B, C) and long-term alcohol consumption worldwide. During the process of liver injury, massive inflammatory cytokines are stimulated by these hazardous factors, leading to a systemic inflammatory response syndrome, followed by a compensatory anti-inflammatory response, which causes immune cell dysfunction and sepsis, subsequent multi-organ failure. Cytokine release and immune cell infiltration-mediated aseptic inflammation are the most important features of the pathobiology of liver failure. From this perspective, diminishing the onset and progression of liver inflammation is of clinical importance in the treatment of liver injury. Although many studies have hinted at the critical role of nerves in regulating inflammation, there largely remains undetermined how hepatic nerves mediate immune inflammation and how the inflammatory factors released by these nerves are involved in the process of liver injury. Therefore, the purpose of this article is to summarize previous studies in the field related to hepatic nerve and inflammation as well as future perspectives on the aforementioned questions. Our findings were presented in three aspects: types of nerve distribution in the liver, how these nerves regulate immunity, and the role of liver nerves in hepatitis and liver failure.
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Affiliation(s)
- Kaili Yang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zebing Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Shuyi Wang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhihong Zhao
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Panpan Yi
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yayu Chen
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Meifang Xiao
- Department of Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Jun Quan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Xingwang Hu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87Th of Xiangya Road, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
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Adori M, Bhat S, Gramignoli R, Valladolid-Acebes I, Bengtsson T, Uhlèn M, Adori C. Hepatic Innervations and Nonalcoholic Fatty Liver Disease. Semin Liver Dis 2023; 43:149-162. [PMID: 37156523 PMCID: PMC10348844 DOI: 10.1055/s-0043-57237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.
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Affiliation(s)
- Monika Adori
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Sadam Bhat
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ismael Valladolid-Acebes
- Department of Molecular Medicine and Surgery, The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Tore Bengtsson
- Department of Molecular Biosciences, The Wenner-Gren Institute (MBW), Stockholm University, Stockholm, Sweden
| | - Mathias Uhlèn
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden
| | - Csaba Adori
- Department of Molecular Biosciences, The Wenner-Gren Institute (MBW), Stockholm University, Stockholm, Sweden
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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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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Koike N, Tadokoro T, Ueno Y, Okamoto S, Kobayashi T, Murata S, Taniguchi H. Development of the nervous system in mouse liver. World J Hepatol 2022; 14:386-399. [PMID: 35317173 PMCID: PMC8891673 DOI: 10.4254/wjh.v14.i2.386] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/12/2021] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The role of the hepatic nervous system in liver development remains unclear. We previously created functional human micro-hepatic tissue in mice by co-culturing human hepatic endodermal cells with endothelial and mesenchymal cells. However, they lacked Glisson’s sheath [the portal tract (PT)]. The PT consists of branches of the hepatic artery (HA), portal vein, and intrahepatic bile duct (IHBD), collectively called the portal triad, together with autonomic nerves.
AIM To evaluate the development of the mouse hepatic nervous network in the PT using immunohistochemistry.
METHODS Liver samples from C57BL/6J mice were harvested at different developmental time periods, from embryonic day (E) 10.5 to postnatal day (P) 56. Thin sections of the surface cut through the hepatic hilus were examined using protein gene product 9.5 (PGP9.5) and cytokeratin 19 (CK19) antibodies, markers of nerve fibers (NFs), and biliary epithelial cells (BECs), respectively. The numbers of NFs and IHBDs were separately counted in a PT around the hepatic hilus (center) and the peripheral area (periphery) of the liver, comparing the average values between the center and the periphery at each developmental stage. NF-IHBD and NF-HA contacts in a PT were counted, and their relationship was quantified. SRY-related high mobility group-box gene 9 (SOX9), another BEC marker; hepatocyte nuclear factor 4α (HNF4α), a marker of hepatocytes; and Jagged-1, a Notch ligand, were also immunostained to observe the PT development.
RESULTS HNF4α was expressed in the nucleus, and Jagged-1 was diffusely positive in the primitive liver at E10.5; however, the PGP9.5 and CK19 were negative in the fetal liver. SOX9-positive cells were scattered in the periportal area in the liver at E12.5. The Jagged-1 was mainly expressed in the periportal tissue, and the number of SOX9-positive cells increased at E16.5. SOX9-positive cells constructed the ductal plate and primitive IHBDs mainly at the center, and SOX-9-positive IHBDs partly acquired CK19 positivity at the same period. PGP9.5-positive bodies were first found at E16.5 and HAs were first found at P0 in the periportal tissue of the center. Therefore, primitive PT structures were first constructed at P0 in the center. Along with remodeling of the periportal tissue, the number of CK19-positive IHBDs and PGP9.5-positive NFs gradually increased, and PTs were also formed in the periphery until P5. The numbers of NFs and IHBDs were significantly higher in the center than in the periphery from E16.5 to P5. The numbers of NFs and IHBDs reached the adult level at P28, with decreased differences between the center and periphery. NFs associated more frequently with HAs than IHBDs in PTs at the early phase after birth, after which the number of NF-IHBD contacts gradually increased.
CONCLUSION Mouse hepatic NFs first emerge at the center just before birth and extend toward the periphery. The interaction between NFs and IHBDs or HAs plays important roles in the morphogenesis of PT structure.
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Affiliation(s)
- Naoto Koike
- Department of Surgery, Seirei Sakura Citizen Hospital, Sakura 285-8765, Chiba, Japan
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan
| | - Tomomi Tadokoro
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan
| | - Yasuharu Ueno
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Satoshi Okamoto
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan
| | - Tatsuya Kobayashi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan
| | - Soichiro Murata
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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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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10
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Benetti E, Giliberti A, Emiliozzi A, Valentino F, Bergantini L, Fallerini C, Anedda F, Amitrano S, Conticini E, Tita R, d’Alessandro M, Fava F, Marcantonio S, Baldassarri M, Bruttini M, Mazzei MA, Montagnani F, Mandalà M, Bargagli E, Furini S, GEN-COVID Multicenter Study, Renieri A, Mari F. Clinical and molecular characterization of COVID-19 hospitalized patients. PLoS One 2020; 15:e0242534. [PMID: 33206719 PMCID: PMC7673557 DOI: 10.1371/journal.pone.0242534] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/05/2020] [Indexed: 01/08/2023] Open
Abstract
Clinical and molecular characterization by Whole Exome Sequencing (WES) is reported in 35 COVID-19 patients attending the University Hospital in Siena, Italy, from April 7 to May 7, 2020. Eighty percent of patients required respiratory assistance, half of them being on mechanical ventilation. Fiftyone percent had hepatic involvement and hyposmia was ascertained in 3 patients. Searching for common genes by collapsing methods against 150 WES of controls of the Italian population failed to give straightforward statistically significant results with the exception of two genes. This result is not unexpected since we are facing the most challenging common disorder triggered by environmental factors with a strong underlying heritability (50%). The lesson learned from Autism-Spectrum-Disorders prompted us to re-analyse the cohort treating each patient as an independent case, following a Mendelian-like model. We identified for each patient an average of 2.5 pathogenic mutations involved in virus infection susceptibility and pinpointing to one or more rare disorder(s). To our knowledge, this is the first report on WES and COVID-19. Our results suggest a combined model for COVID-19 susceptibility with a number of common susceptibility genes which represent the favorite background in which additional host private mutations may determine disease progression.
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Affiliation(s)
- Elisa Benetti
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | | | - Arianna Emiliozzi
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Department of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | | | - Laura Bergantini
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
| | | | - Federico Anedda
- Department of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy
| | - Sara Amitrano
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Edoardo Conticini
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
| | - Rossella Tita
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Miriana d’Alessandro
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
| | - Francesca Fava
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Simona Marcantonio
- Department of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy
| | | | - Mirella Bruttini
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Maria Antonietta Mazzei
- Department of Medical, Surgical and Neuro Sciences and Radiological Sciences, Unit of Diagnostic Imaging, University of Siena, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Francesca Montagnani
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Department of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Marco Mandalà
- Otolaryngology Unit, University of Siena, Siena, Italy
| | - Elena Bargagli
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
| | - Simone Furini
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | | | - Alessandra Renieri
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Francesca Mari
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
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11
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Amir M, Yu M, He P, Srinivasan S. Hepatic Autonomic Nervous System and Neurotrophic Factors Regulate the Pathogenesis and Progression of Non-alcoholic Fatty Liver Disease. Front Med (Lausanne) 2020; 7:62. [PMID: 32175323 PMCID: PMC7056867 DOI: 10.3389/fmed.2020.00062] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/11/2020] [Indexed: 12/21/2022] Open
Abstract
Non-alcoholic fatty liver disease represents a continuum of excessive hepatic steatosis, inflammation and fibrosis. It is a growing epidemic in the United States of America and worldwide. Progression of non-alcoholic fatty liver disease can lead to morbidity and mortality due to complications such as cirrhosis or hepatocellular carcinoma. Pathogenesis of non-alcoholic fatty liver disease is centered on increased hepatic lipogenesis and decreased hepatic lipolysis in the setting of hepatic and systemic insulin resistance. Adipose tissue and hepatic inflammation can further perpetuate the severity of illness. Currently there are no approved therapies for non-alcoholic fatty liver disease. Most of the drugs being explored for non-alcoholic fatty liver disease focus on classical pathogenic pathways surrounding hepatic lipid accumulation, inflammation or fibrosis. Studies have demonstrated that the autonomic nervous system innervating the liver plays a crucial role in regulation of hepatic lipid homeostasis, inflammation and fibrosis. Additionally, there is growing evidence that neurotrophic factors can modulate all stages of non-alcoholic fatty liver disease. Both the autonomic nervous system and neurotrophic factors are altered in patients and murine models of non-alcoholic fatty liver disease. In this review we focus on the pathophysiological role of the autonomic nervous system and neurotrophic factors that could be potential targets for novel therapeutic approaches to treat non-alcoholic fatty liver disease.
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Affiliation(s)
- Muhammad Amir
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Michael Yu
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Peijian He
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Shanthi Srinivasan
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States.,Research-Gastroenterology, Atlanta VA Health Care System, Decatur, GA, United States
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12
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Park D, Lee J, Chung JJ, Jung Y, Kim SH. Integrating Organs-on-Chips: Multiplexing, Scaling, Vascularization, and Innervation. Trends Biotechnol 2019; 38:99-112. [PMID: 31345572 DOI: 10.1016/j.tibtech.2019.06.006] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 06/18/2019] [Accepted: 06/21/2019] [Indexed: 12/29/2022]
Abstract
Organs-on-chips (OoCs) have attracted significant attention because they can be designed to mimic in vivo environments. Beyond constructing a single OoC, recent efforts have tried to integrate multiple OoCs to broaden potential applications such as disease modeling and drug discoveries. However, various challenges remain for integrating OoCs towards in vivo-like operation, such as incorporating various connections for integrating multiple OoCs. We review multiplexed OoCs and challenges they face: scaling, vascularization, and innervation. In our opinion, future OoCs will be constructed to have increased predictive power for in vivo phenomena and will ultimately become a mainstream tool for high quality biomedical and pharmaceutical research.
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Affiliation(s)
- DoYeun Park
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Jaeseo Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Justin J Chung
- Biomaterials Research Center, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea
| | - Youngmee Jung
- Biomaterials Research Center, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea
| | - Soo Hyun Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Biomaterials Research Center, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
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13
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Baik SJ, Kim TH, Yoo K, Moon IH, Choi JY, Chung KW, Song DE. Decreased S100B expression in chronic liver diseases. Korean J Intern Med 2017; 32:269-276. [PMID: 27255110 PMCID: PMC5339465 DOI: 10.3904/kjim.2015.296] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 08/24/2015] [Accepted: 08/29/2015] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS Hepatic innervation in liver diseases is not fully understood. We here evaluated S100B expression as a marker of hepatic nerves in patients with various chronic liver diseases, topographically and semi-quantitatively. METHODS Liver specimens were obtained from 70 subjects (three controls, and 32 chronic hepatitis B, 14 chronic hepatitis C, 14 liver cirrhosis, and seven hepatocellular carcinoma patients). The hepatic nerve density was calculated based on immunohistochemical staining of S100B protein in the portal tracts and hepatic lobules. S100B mRNA levels were semi-quantitatively assessed as the S100B/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA ratio. RESULTS The densities of the hepatic nerves in portal tracts of chronic liver diseases were not significantly different from those of normal controls but the hepatic nerve densities in lobular areas of liver cirrhosis were significantly decreased (p = 0.025). Compared to the control, the S100B/GAPDH mRNA ratio was significantly decreased in chronic liver diseases (p = 0.006) and most decreased in chronic hepatitis C patients (p = 0.023). In chronic liver diseases, The S100B/GAPDH mRNA ratio tended to decrease as the fibrosis score > 0 (p = 0.453) but the overall correlation between the S100B/GAPDH mRNA ratio and fibrosis score was not statistically significant (r = 0.061, p = 0.657). CONCLUSIONS Hepatic innervation is decreased in cirrhotic regenerating nodules compared to the control group and seems to decrease in early stages of fibrosis progression. Further studies are needed to clarify the association between changes of hepatic innervation and chronic liver disease progression.
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Affiliation(s)
- Su Jung Baik
- Healthcare Research Team, Health Promotion Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Hun Kim
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
- Correspondence to Tae Hun Kim, M.D. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ewha Womans University School of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 07985, Korea Tel: +82-2-2019-1290 Fax: +82-2-2019-4802 E-mail:
| | - Kwon Yoo
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Il Hwan Moon
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ju Young Choi
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Kyu Won Chung
- Department of Hepatobiliary, College of Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea, Incheon, Korea
| | - Dong Eun Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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15
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Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:3190617. [PMID: 26798417 PMCID: PMC4699022 DOI: 10.1155/2016/3190617] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 08/17/2015] [Accepted: 09/29/2015] [Indexed: 12/14/2022]
Abstract
In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.
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Schleicher J, Tokarski C, Marbach E, Matz-Soja M, Zellmer S, Gebhardt R, Schuster S. Zonation of hepatic fatty acid metabolism - The diversity of its regulation and the benefit of modeling. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1851:641-56. [PMID: 25677822 DOI: 10.1016/j.bbalip.2015.02.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 01/26/2015] [Accepted: 02/03/2015] [Indexed: 02/07/2023]
Abstract
A pronounced heterogeneity between hepatocytes in subcellular structure and enzyme activities was discovered more than 50years ago and initiated the idea of metabolic zonation. In the last decades zonation patterns of liver metabolism were extensively investigated for carbohydrate, nitrogen and lipid metabolism. The present review focuses on zonation patterns of the latter. We review recent findings regarding the zonation of fatty acid uptake and oxidation, ketogenesis, triglyceride synthesis and secretion, de novo lipogenesis, as well as bile acid and cholesterol metabolism. In doing so, we expose knowledge gaps and discuss contradictory experimental results, for example on the zonation pattern of fatty acid oxidation and de novo lipogenesis. Thus, possible rewarding directions of further research are identified. Furthermore, recent findings about the regulation of metabolic zonation are summarized, especially regarding the role of hormones, nerve innervation, morphogens, gender differences and the influence of the circadian clock. In the last part of the review, a short collection of models considering hepatic lipid metabolism is provided. We conclude that modeling, despite its proven benefit for understanding of hepatic carbohydrate and ammonia metabolisms, has so far been largely disregarded in the study of lipid metabolism; therefore some possible fields of modeling interest are presented.
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Affiliation(s)
- J Schleicher
- Department of Bioinformatics, University of Jena, Jena, Germany.
| | - C Tokarski
- Department of Bioinformatics, University of Jena, Jena, Germany
| | - E Marbach
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - M Matz-Soja
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - S Zellmer
- Department of Chemicals and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - R Gebhardt
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - S Schuster
- Department of Bioinformatics, University of Jena, Jena, Germany
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