Download PDF
CC BY-NC-ND 4.0 · Semin Liver Dis 2023; 43(02): 149-162
DOI: 10.1055/s-0043-57237
Review Article

Hepatic Innervations and Nonalcoholic Fatty Liver Disease

Monika Adori
1   Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
,
Sadam Bhat
2   Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
,
Roberto Gramignoli
3   Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
,
Ismael Valladolid-Acebes
4   Department of Molecular Medicine and Surgery, The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
,
Tore Bengtsson
5   Department of Molecular Biosciences, The Wenner-Gren Institute (MBW), Stockholm University, Stockholm, Sweden
,
Mathias Uhlèn
6   Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
7   Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden
,
Csaba Adori
5   Department of Molecular Biosciences, The Wenner-Gren Institute (MBW), Stockholm University, Stockholm, Sweden
6   Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
› Author Affiliations
› Further Information
  Permissions and Reprints


Abstract

Abbreviations graphical abstract: VMN/PVN, hypothalamic ventromedial nucleus/paraventricular nucleus; VLM/VMM, ventrolateral medulla/ventromedial medulla; SMG/CG, superior mesenteric ganglion/caeliac ganglia; NTS, nucleus of the solitary tract; NG, nodose ganglion.

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.

Keywords

nonalcoholic fatty liver disease - sympathetic nerves - parasympathetic nerves - noradrenaline - steatosis - inflammation - fibrosis - portal hypertension


Publication History

Article published online:
08 May 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Kaya E, Yılmaz Y. Non-alcoholic fatty liver disease: a growing public health problem in Turkey. Turk J Gastroenterol 2019; 30 (10) 865-871
    CrossrefPubMedSearch in Google Scholar
  • 2 Younossi ZM. Non-alcoholic fatty liver disease - a global public health perspective. J Hepatol 2019; 70 (03) 531-544
    CrossrefPubMedSearch in Google Scholar
  • 3 Yeh MM, Brunt EM. Pathology of nonalcoholic fatty liver disease. Am J Clin Pathol 2007; 128 (05) 837-847
    CrossrefPubMedSearch in Google Scholar
  • 4 Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol 2022; 10 (04) 284-296
    CrossrefPubMedSearch in Google Scholar
  • 5 Mantovani A, Scorletti E, Mosca A, Alisi A, Byrne CD, Targher G. Complications, morbidity and mortality of nonalcoholic fatty liver disease. Metabolism 2020; 111S: 154170
    CrossrefPubMedSearch in Google Scholar
  • 6 Mantovani A, Csermely A, Petracca G. et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2021; 6 (11) 903-913
    CrossrefPubMedSearch in Google Scholar
  • 7 Ibrahim SH, Hirsova P, Gores GJ. Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation. Gut 2018; 67 (05) 963-972
    CrossrefPubMedSearch in Google Scholar
  • 8 Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med 2017; 377 (21) 2063-2072
    CrossrefPubMedSearch in Google Scholar
  • 9 Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014; 20 (42) 15539-15548
    CrossrefPubMedSearch in Google Scholar
  • 10 Lau JK, Zhang X, Yu J. Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances. J Pathol 2017; 241 (01) 36-44
    CrossrefPubMedSearch in Google Scholar
  • 11 Eslam M, Newsome PN, Sarin SK. et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 2020; 73 (01) 202-209
    CrossrefPubMedSearch in Google Scholar
  • 12 Mizuno K, Ueno Y. Autonomic nervous system and the liver. Hepatol Res 2017; 47 (02) 160-165
    CrossrefPubMedSearch in Google Scholar
  • 13 Streba LA, Vere CC, Ionescu AG, Streba CT, Rogoveanu I. Role of intrahepatic innervation in regulating the activity of liver cells. World J Hepatol 2014; 6 (03) 137-143
    CrossrefPubMedSearch in Google Scholar
  • 14 Jensen KJ, Alpini G, Glaser S. Hepatic nervous system and neurobiology of the liver. Compr Physiol 2013; 3 (02) 655-665
    CrossrefPubMedSearch in Google Scholar
  • 15 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
    CrossrefPubMedSearch in Google Scholar
  • 16 Kandilis AN, Papadopoulou IP, Koskinas J, Sotiropoulos G, Tiniakos DG. Liver innervation and hepatic function: new insights. J Surg Res 2015; 194 (02) 511-519
    CrossrefPubMedSearch in Google Scholar
  • 17 Colle I, Van Vlierberghe H, Troisi R, De Hemptinne B. Transplanted liver: consequences of denervation for liver functions. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (01) 924-931
    CrossrefPubMedSearch in Google Scholar
  • 18 Laryea M, Watt KD, Molinari M. et al. Metabolic syndrome in liver transplant recipients: prevalence and association with major vascular events. Liver Transpl 2007; 13 (08) 1109-1114
    CrossrefPubMedSearch in Google Scholar
  • 19 Schneiter P, Gillet M, Chioléro R. et al. Mechanisms of postprandial hyperglycemia in liver transplant recipients: comparison of liver transplant patients with kidney transplant patients and healthy controls. Diabetes Metab 2000; 26 (01) 51-56
    PubMedSearch in Google Scholar
  • 20 Hurr C, Simonyan H, Morgan DA, Rahmouni K, Young CN. Liver sympathetic denervation reverses obesity-induced hepatic steatosis. J Physiol 2019; 597 (17) 4565-4580
    CrossrefPubMedSearch in Google Scholar
  • 21 Nakade Y, Kitano R, Yamauchi T. et al. Effect of adrenergic agonists on high-fat diet-induced hepatic steatosis in mice. Int J Mol Sci 2020; 21 (24) 21
    Search in Google Scholar
  • 22 Adori C, Daraio T, Kuiper R. et al. Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging. Sci Adv 2021; 7 (30) 7
    CrossrefPubMedSearch in Google Scholar
  • 23 Liu K, Yang L, Wang G. et al. Metabolic stress drives sympathetic neuropathy within the liver. Cell Metab 2021; 33 (03) 666-675 .e4
    CrossrefPubMedSearch in Google Scholar
  • 24 Galen C. On the Usefulness of the Parts of the Body. May MT tr. New York: Cornell University Press; 1968
    Search in Google Scholar
  • 25 Pfülger E. Über die Abhängigkeit der Leber von dem Nervensystem. Arch Gesamte Physiol Mens Tiere (Pfluegers) 1869; 2: 459-491 . Accessed on April 17, 2023, at: https://link.springer.com/article/10.1007/BF01628420#citeas
    CrossrefPubMedSearch in Google Scholar
  • 26 Delalande JM, Milla PJ, Burns AJ. Hepatic nervous system development. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (01) 848-853
    CrossrefPubMedSearch in Google Scholar
  • 27 Ding WG, Kitasato H, Kimura H. Development of neuropeptide Y innervation in the liver. Microsc Res Tech 1997; 39 (04) 365-371
    CrossrefPubMedSearch in Google Scholar
  • 28 Tanimizu N, Ichinohe N, Mitaka T. Intrahepatic bile ducts guide establishment of the intrahepatic nerve network in developing and regenerating mouse liver. Development 2018; 145 (09) 145
    CrossrefPubMedSearch in Google Scholar
  • 29 Koike N, Tadokoro T, Ueno Y. et al. Development of the nervous system in mouse liver. World J Hepatol 2022; 14 (02) 386-399
    CrossrefPubMedSearch in Google Scholar
  • 30 Tiniakos DG, Mathew J, Kittas C, Burt AD. Ontogeny of human intrahepatic innervation. Virchows Arch 2008; 452 (04) 435-442
    CrossrefPubMedSearch in Google Scholar
  • 31 Shimazu T. Neuronal regulation of hepatic glucose metabolism in mammals. Diabetes Metab Rev 1987; 3 (01) 185-206
    CrossrefPubMedSearch in Google Scholar
  • 32 Shimazu T. Innervation of the liver and glucoregulation: roles of the hypothalamus and autonomic nerves. Nutrition 1996; 12 (01) 65-66
    CrossrefPubMedSearch in Google Scholar
  • 33 Burt AD, Tiniakos D, MacSween RN, Griffiths MR, Wisse E, Polak JM. Localization of adrenergic and neuropeptide tyrosine-containing nerves in the mammalian liver. Hepatology 1989; 9 (06) 839-845
    CrossrefPubMedSearch in Google Scholar
  • 34 Miller BM, Oderberg IM, Goessling W. Hepatic nervous system in development, regeneration, and disease. Hepatology 2021; 74 (06) 3513-3522
    CrossrefPubMedSearch in Google Scholar
  • 35 Lin YS, Nosaka S, Amakata Y, Maeda T. Comparative study of the mammalian liver innervation: an immunohistochemical study of protein gene product 9.5, dopamine beta-hydroxylase and tyrosine hydroxylase. Comp Biochem Physiol Part A Physiol 1995; 110 (04) 289-298
    CrossrefPubMedSearch in Google Scholar
  • 36 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 (05) 352-359
    CrossrefPubMedSearch in Google Scholar
  • 37 Forssmann WG, Ito S. Hepatocyte innervation in primates. J Cell Biol 1977; 74 (01) 299-313
    CrossrefPubMedSearch in Google Scholar
  • 38 Nobin A, Baumgarten HG, Falck B, Ingemansson S, Moghimzadeh E, Rosengren E. Organization of the sympathetic innervation in liver tissue from monkey and man. Cell Tissue Res 1978; 195 (03) 371-380
    CrossrefPubMedSearch in Google Scholar
  • 39 Mundinger TO, Verchere CB, Baskin DG, Boyle MR, Kowalyk S, Taborsky Jr GJ. Galanin is localized in sympathetic neurons of the dog liver. Am J Physiol 1997; 273 (06) E1194-E1202
    PubMedSearch in Google Scholar
  • 40 Berthoud HR. Anatomy and function of sensory hepatic nerves. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (01) 827-835
    CrossrefPubMedSearch in Google Scholar
  • 41 Berthoud HR, Kressel M, Neuhuber WL. An anterograde tracing study of the vagal innervation of rat liver, portal vein and biliary system. Anat Embryol (Berl) 1992; 186 (05) 431-442
    CrossrefPubMedSearch in Google Scholar
  • 42 Amenta F, Cavallotti C, Ferrante F, Tonelli F. Cholinergic nerves in the human liver. Histochem J 1981; 13 (03) 419-424
    CrossrefPubMedSearch in Google Scholar
  • 43 Schäfer MK, Eiden LE, Weihe E. Cholinergic neurons and terminal fields revealed by immunohistochemistry for the vesicular acetylcholine transporter. II. The peripheral nervous system. Neuroscience 1998; 84 (02) 361-376
    CrossrefPubMedSearch in Google Scholar
  • 44 Berthoud HR, Neuhuber WL. Vagal mechanisms as neuromodulatory targets for the treatment of metabolic disease. Ann N Y Acad Sci 2019; 1454 (01) 42-55
    CrossrefPubMedSearch in Google Scholar
  • 45 Berthoud HR, Powley TL. Characterization of vagal innervation to the rat celiac, suprarenal and mesenteric ganglia. J Auton Nerv Syst 1993; 42 (02) 153-169
    CrossrefPubMedSearch in Google Scholar
  • 46 Uyama N, Geerts A, Reynaert H. Neural connections between the hypothalamus and the liver. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (01) 808-820
    CrossrefPubMedSearch in Google Scholar
  • 47 Seseke FG, Gardemann A, Jungermann K. Signal propagation via gap junctions, a key step in the regulation of liver metabolism by the sympathetic hepatic nerves. FEBS Lett 1992; 301 (03) 265-270
    CrossrefPubMedSearch in Google Scholar
  • 48 Miyashita T, Takeda A, Iwai M, Shimazu T. Single administration of hepatotoxic chemicals transiently decreases the gap-junction-protein levels of connexin 32 in rat liver. Eur J Biochem 1991; 196 (01) 37-42
    CrossrefPubMedSearch in Google Scholar
  • 49 Temme A, Stümpel F, Söhl G. et al. Dilated bile canaliculi and attenuated decrease of nerve-dependent bile secretion in connexin32-deficient mouse liver. Pflugers Arch 2001; 442 (06) 961-966
    CrossrefPubMedSearch in Google Scholar
  • 50 McKee C, Soeda J, Asilmaz E. et al. Propranolol, a β-adrenoceptor antagonist, worsens liver injury in a model of non-alcoholic steatohepatitis. Biochem Biophys Res Commun 2013; 437 (04) 597-602
    CrossrefPubMedSearch in Google Scholar
  • 51 Kajiyama Y, Ui M. Switching from alpha 1- to beta-subtypes in adrenergic response during primary culture of adult-rat hepatocytes as affected by the cell-to-cell interaction through plasma membranes. Biochem J 1994; 303 (Pt 1): 313-321
    CrossrefPubMedSearch in Google Scholar
  • 52 Tao X, Chen C, Chen Y. et al. β2-adrenergic receptor promotes liver regeneration partially through crosstalk with c-met. Cell Death Dis 2022; 13 (06) 571
    CrossrefPubMedSearch in Google Scholar
  • 53 Oben JA, Roskams T, Yang S. et al. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut 2004; 53 (03) 438-445
    CrossrefPubMedSearch in Google Scholar
  • 54 Sigala B, McKee C, Soeda J. et al. Sympathetic nervous system catecholamines and neuropeptide Y neurotransmitters are upregulated in human NAFLD and modulate the fibrogenic function of hepatic stellate cells. PLoS One 2013; 8 (09) e72928
    CrossrefPubMedSearch in Google Scholar
  • 55 Sancho-Bru P, Bataller R, Colmenero J. et al. Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2006; 291 (05) G877-G884
    CrossrefPubMedSearch in Google Scholar
  • 56 Huan HB, Wen XD, Chen XJ. et al. Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells. Brain Behav Immun 2017; 59: 118-134
    CrossrefPubMedSearch in Google Scholar
  • 57 Ko S, Russell JO, Molina LM, Monga SP. Liver progenitors and adult cell plasticity in hepatic injury and repair: knowns and unknowns. Annu Rev Pathol 2020; 15: 23-50
    CrossrefPubMedSearch in Google Scholar
  • 58 Reilly FD, McCuskey RS, Cilento EV. Hepatic microvascular regulatory mechanisms. I. Adrenergic mechanisms. Microvasc Res 1981; 21 (01) 103-116
    CrossrefPubMedSearch in Google Scholar
  • 59 Huang YT, Lin LC, Chern JW, Lin HC, Hong CY. Portal hypotensive effects of combined terlipressin and DL-028, a synthetic alpha 1 adrenoceptor antagonist administration on anesthetized portal hypertensive rats. Liver 1999; 19 (02) 129-134
    CrossrefPubMedSearch in Google Scholar
  • 60 Vasina V, Giannone F, Domenicali M. et al. Portal hypertension and liver cirrhosis in rats: effect of the β3-adrenoceptor agonist SR58611A. Br J Pharmacol 2012; 167 (05) 1137-1147
    CrossrefPubMedSearch in Google Scholar
  • 61 Alpini G, Franchitto A, Demorrow S. et al. Activation of alpha(1) -adrenergic receptors stimulate the growth of small mouse cholangiocytes via calcium-dependent activation of nuclear factor of activated T cells 2 and specificity protein 1. Hepatology 2011; 53 (02) 628-639
    CrossrefPubMedSearch in Google Scholar
  • 62 Glaser S, Alvaro D, Francis H. et al. 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 (04) G813-G826
    CrossrefPubMedSearch in Google Scholar
  • 63 Aizarani N, Saviano A. Sagar, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 2019; 572 (7768): 199-204
    CrossrefPubMedSearch in Google Scholar
  • 64 Lelou E, Corlu A, Nesseler N. et al. The role of catecholamines in pathophysiological liver processes. Cells 2022; 11 (06) 11
    CrossrefPubMedSearch in Google Scholar
  • 65 Oben JA, Roskams T, Yang S. et al. Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury. Hepatology 2003; 38 (03) 664-673
    CrossrefPubMedSearch in Google Scholar
  • 66 Morgan ML, Sigala B, Soeda J. et al. Acetylcholine induces fibrogenic effects via M2/M3 acetylcholine receptors in non-alcoholic steatohepatitis and in primary human hepatic stellate cells. J Gastroenterol Hepatol 2016; 31 (02) 475-483
    CrossrefPubMedSearch in Google Scholar
  • 67 Lechner SG, Markworth S, Poole K. et al. The molecular and cellular identity of peripheral osmoreceptors. Neuron 2011; 69 (02) 332-344
    CrossrefPubMedSearch in Google Scholar
  • 68 Sabath E, Báez-Ruiz A, Buijs RM. Non-alcoholic fatty liver disease as a consequence of autonomic imbalance and circadian desynchronization. Obes Rev 2015; 16 (10) 871-882
    CrossrefPubMedSearch in Google Scholar
  • 69 Licht CM, Vreeburg SA, van Reedt Dortland AK. et al. Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities. J Clin Endocrinol Metab 2010; 95 (05) 2458-2466
    CrossrefPubMedSearch in Google Scholar
  • 70 Bruinstroop E, Eliveld J, Foppen E. et al. Hepatic denervation and dyslipidemia in obese Zucker (fa/fa) rats. Int J Obes 2015; 39 (11) 1655-1658
    CrossrefPubMedSearch in Google Scholar
  • 71 Gao H, Molinas AJR, Miyata K, Qiao X, Zsombok A. Overactivity of liver-related neurons in the paraventricular nucleus of the hypothalamus: electrophysiological findings in db/db mice. J Neurosci 2017; 37 (46) 11140-11150
    CrossrefPubMedSearch in Google Scholar
  • 72 Menacho-Márquez M, Nogueiras R, Fabbiano S. et al. Chronic sympathoexcitation through loss of Vav3, a Rac1 activator, results in divergent effects on metabolic syndrome and obesity depending on diet. Cell Metab 2013; 18 (02) 199-211
    CrossrefPubMedSearch in Google Scholar
  • 73 Jung I, Lee DY, Lee MY. et al. Autonomic imbalance increases the risk for non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2021; 12: 752944
    CrossrefPubMedSearch in Google Scholar
  • 74 Targher G, Mantovani A, Grander C. et al. Association between non-alcoholic fatty liver disease and impaired cardiac sympathetic/parasympathetic balance in subjects with and without type 2 diabetes - the Cooperative Health Research in South Tyrol (CHRIS)-NAFLD sub-study. Nutr Metab Cardiovasc Dis 2021; 31 (12) 3464-3473
    CrossrefPubMedSearch in Google Scholar
  • 75 Wider MD. Metabolic syndrome and the hepatorenal reflex. Surg Neurol Int 2016; 7: 99
    CrossrefPubMedSearch in Google Scholar
  • 76 Nam SW, Song HJ, Back SJ. et al. Decreased hepatic nerve fiber innervation in patients with liver cirrhosis. Gut Liver 2007; 1 (02) 165-170
    CrossrefPubMedSearch in Google Scholar
  • 77 Scoazec JY, Racine L, Couvelard A. et al. Parenchymal innervation of normal and cirrhotic human liver: a light and electron microscopic study using monoclonal antibodies against the neural cell-adhesion molecule. J Histochem Cytochem 1993; 41 (06) 899-908
    CrossrefPubMedSearch in Google Scholar
  • 78 Miyazawa Y, Fukuda Y, Imoto M, Koyama Y, Nagura H. Immunohistochemical studies on the distribution of nerve fibers in chronic liver diseases. Am J Gastroenterol 1988; 83 (10) 1108-1114
    PubMedSearch in Google Scholar
  • 79 Lee JA, Ahmed Q, Hines JE, Burt AD. Disappearance of hepatic parenchymal nerves in human liver cirrhosis. Gut 1992; 33 (01) 87-91
    CrossrefPubMedSearch in Google Scholar
  • 80 Jaskiewicz K, Robson SC, Banach L. Toxic hepatic injury is associated with proliferation of portal nerve fibers. Pathol Res Pract 1993; 189 (10) 1191-1194
    CrossrefPubMedSearch in Google Scholar
  • 81 Ueno T, Sata M, Sakata R. et al. Hepatic stellate cells and intralobular innervation in human liver cirrhosis. Hum Pathol 1997; 28 (08) 953-959
    CrossrefPubMedSearch in Google Scholar
  • 82 Grant WF, Nicol LE, Thorn SR, Grove KL, Friedman JE, Marks DL. Perinatal exposure to a high-fat diet is associated with reduced hepatic sympathetic innervation in one-year old male Japanese macaques. PLoS One 2012; 7 (10) e48119
    CrossrefPubMedSearch in Google Scholar
  • 83 Lin B, Ma Y, Wu S, Liu Y, Liu L, Wu L. Novel serum biomarkers for noninvasive diagnosis and screening of nonalcoholic fatty liver disease-related hepatic fibrosis. OMICS 2019; 23 (04) 181-189
    CrossrefPubMedSearch in Google Scholar
  • 84 Ádori C, Glück L, Barde S. et al. Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease. Acta Neuropathol 2015; 129 (04) 541-563
    CrossrefPubMedSearch in Google Scholar
  • 85 Adori C, Low P, Andó RD. et al. Ultrastructural characterization of tryptophan hydroxylase 2-specific cortical serotonergic fibers and dorsal raphe neuronal cell bodies after MDMA treatment in rat. Psychopharmacology (Berl) 2011; 213 (2-3): 377-391
    CrossrefPubMedSearch in Google Scholar
  • 86 Adori C, Andó RD, Szekeres M. et al. Recovery and aging of serotonergic fibers after single and intermittent MDMA treatment in Dark Agouti rat. J Comp Neurol 2011; 519 (12) 2353-2378
    CrossrefPubMedSearch in Google Scholar
  • 87 Wang Z, Li S, Wang R. et al. The protective effects of the β3 adrenergic receptor agonist BRL37344 against liver steatosis and inflammation in a rat model of high-fat diet-induced nonalcoholic fatty liver disease (NAFLD). Mol Med 2020; 26 (01) 54
    CrossrefPubMedSearch in Google Scholar
  • 88 Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28 (04) 370-379
    Thieme ConnectPubMedSearch in Google Scholar
  • 89 Tavares FL, Seelaender MC. Hepatic denervation impairs the assembly and secretion of VLDL-TAG. Cell Biochem Funct 2008; 26 (05) 557-565
    CrossrefPubMedSearch in Google Scholar
  • 90 Carreño FR, Seelaender MC. Liver denervation affects hepatocyte mitochondrial fatty acid transport capacity. Cell Biochem Funct 2004; 22 (01) 9-17
    CrossrefPubMedSearch in Google Scholar
  • 91 Shi Y, Pizzini J, Wang H. et al. β 2-Adrenergic receptor agonist induced hepatic steatosis in mice: modeling nonalcoholic fatty liver disease in hyperadrenergic states. Am J Physiol Endocrinol Metab 2021; 321 (01) E90-E104
    CrossrefPubMedSearch in Google Scholar
  • 92 Shi Y, Shu ZJ, Wang H. et al. Altered expression of hepatic β-adrenergic receptors in aging rats: implications for age-related metabolic dysfunction in liver. Am J Physiol Regul Integr Comp Physiol 2018; 314 (04) R574-R583
    CrossrefPubMedSearch in Google Scholar
  • 93 Shi Y, Shu ZJ, Xue X, Yeh CK, Katz MS, Kamat A. β2-Adrenergic receptor ablation modulates hepatic lipid accumulation and glucose tolerance in aging mice. Exp Gerontol 2016; 78: 32-38
    CrossrefPubMedSearch in Google Scholar
  • 94 Schott MB, Rasineni K, Weller SG. et al. β-Adrenergic induction of lipolysis in hepatocytes is inhibited by ethanol exposure. J Biol Chem 2017; 292 (28) 11815-11828
    CrossrefPubMedSearch in Google Scholar
  • 95 Tao X, Hu Y, Li L. et al. Genetic deletion of β2 adrenergic receptors exacerbates hepatocellular lipid accumulation in high-fat diet mice. Biochem Biophys Res Commun 2019; 511 (01) 73-78
    CrossrefPubMedSearch in Google Scholar
  • 96 Cox JE, Kelm GR, Meller ST, Spraggins DS, Randich A. Truncal and hepatic vagotomy reduce suppression of feeding by jejunal lipid infusions. Physiol Behav 2004; 81 (01) 29-36
    CrossrefPubMedSearch in Google Scholar
  • 97 Morita H, Abe C. Negative feedforward control of body fluid homeostasis by hepatorenal reflex. Hypertens Res 2011; 34 (08) 895-905
    CrossrefPubMedSearch in Google Scholar
  • 98 Randich A, Spraggins DS, Cox JE, Meller ST, Kelm GR. Jejunal or portal vein infusions of lipids increase hepatic vagal afferent activity. Neuroreport 2001; 12 (14) 3101-3105
    CrossrefPubMedSearch in Google Scholar
  • 99 Lorenzo-Martín LF, Menacho-Márquez M, Fabbiano S. et al. Vagal afferents contribute to sympathoexcitation-driven metabolic dysfunctions. J Endocrinol 2019; 240 (03) 483-496
    CrossrefPubMedSearch in Google Scholar
  • 100 Benthem L, Keizer K, Wiegman CH. et al; de Boer SF. Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation. Am J Physiol Endocrinol Metab 2000; 279 (06) E1286-E1293
    CrossrefPubMedSearch in Google Scholar
  • 101 Hackl MT, Fürnsinn C, Schuh CM. et al. Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis. Nat Commun 2019; 10 (01) 2717
    CrossrefPubMedSearch in Google Scholar
  • 102 Metz M, Beghini M, Wolf P. et al. Leptin increases hepatic triglyceride export via a vagal mechanism in humans. Cell Metab 2022; 34 (11) 1719-1731 .e5
    CrossrefPubMedSearch in Google Scholar
  • 103 Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52 (05) 1836-1846
    CrossrefPubMedSearch in Google Scholar
  • 104 Chen J, Deng X, Liu Y. et al. Kupffer cells in non-alcoholic fatty liver disease: friend or foe?. Int J Biol Sci 2020; 16 (13) 2367-2378
    CrossrefPubMedSearch in Google Scholar
  • 105 Heymann F, Tacke F. Immunology in the liver – from homeostasis to disease. Nat Rev Gastroenterol Hepatol 2016; 13 (02) 88-110
    CrossrefPubMedSearch in Google Scholar
  • 106 Alisi A, Carpino G, Oliveira FL, Panera N, Nobili V, Gaudio E. The role of tissue macrophage-mediated inflammation on NAFLD pathogenesis and its clinical implications. Mediators Inflamm 2017; 2017: 8162421
    CrossrefPubMedSearch in Google Scholar
  • 107 Benlagha K, Kyin T, Beavis A, Teyton L, Bendelac A. A thymic precursor to the NK T cell lineage. Science 2002; 296 (5567): 553-555
    CrossrefPubMedSearch in Google Scholar
  • 108 Clària J, González-Périz A, López-Vicario C, Rius B, Titos E. New insights into the role of macrophages in adipose tissue inflammation and fatty liver disease: modulation by endogenous omega-3 fatty acid-derived lipid mediators. Front Immunol 2011; 2: 49
    CrossrefPubMedSearch in Google Scholar
  • 109 Pradere JP, Kluwe J, De Minicis S. et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013; 58 (04) 1461-1473
    CrossrefPubMedSearch in Google Scholar
  • 110 Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 2007; 47 (04) 571-579
    CrossrefPubMedSearch in Google Scholar
  • 111 Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol 2012; 302 (11) G1310-G1321
    CrossrefPubMedSearch in Google Scholar
  • 112 Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J Biol Chem 2012; 287 (48) 40161-40172
    CrossrefPubMedSearch in Google Scholar
  • 113 Park JW, Kim SE, Lee NY. et al. Role of microbiota-derived metabolites in alcoholic and non-alcoholic fatty liver diseases. Int J Mol Sci 2021; 23 (01) 23
    CrossrefPubMedSearch in Google Scholar
  • 114 Imajo K, Fujita K, Yoneda M. et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab 2012; 16 (01) 44-54
    CrossrefPubMedSearch in Google Scholar
  • 115 Yang S, Koo DJ, Zhou M, Chaudry IH, Wang P. Gut-derived norepinephrine plays a critical role in producing hepatocellular dysfunction during early sepsis. Am J Physiol Gastrointest Liver Physiol 2000; 279 (06) G1274-G1281
    CrossrefPubMedSearch in Google Scholar
  • 116 Li Z, Yang S, Lin H. et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003; 37 (02) 343-350
    CrossrefPubMedSearch in Google Scholar
  • 117 Johnston JL, Romsos DR, Bergen WG. Reduced brain norepinephrine metabolism in obese (ob/ob) mice is not normalized by tyrosine supplementation. J Nutr 1986; 116 (03) 435-445
    CrossrefPubMedSearch in Google Scholar
  • 118 Li Z, Oben JA, Yang S. et al. Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis. Hepatology 2004; 40 (02) 434-441
    CrossrefPubMedSearch in Google Scholar
  • 119 Nishio T, Taura K, Iwaisako K. et al. Hepatic vagus nerve regulates Kupffer cell activation via α7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis. J Gastroenterol 2017; 52 (08) 965-976
    CrossrefPubMedSearch in Google Scholar
  • 120 Fonseca RC, Bassi GS, Brito CC. et al. Vagus nerve regulates the phagocytic and secretory activity of resident macrophages in the liver. Brain Behav Immun 2019; 81: 444-454
    CrossrefPubMedSearch in Google Scholar
  • 121 Roskams T, Yang SQ, Koteish A. et al. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 2003; 163 (04) 1301-1311
    CrossrefPubMedSearch in Google Scholar
  • 122 Soeda J, Mouralidarane A, Ray S. et al. The β-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice. Hepatology 2014; 60 (03) 1023-1034
    CrossrefPubMedSearch in Google Scholar
  • 123 Yin C, Evason KJ, Asahina K, Stainier DY. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest 2013; 123 (05) 1902-1910
    CrossrefPubMedSearch in Google Scholar
  • 124 Kitto LJ, Henderson NC. Hepatic stellate cell regulation of liver regeneration and repair. Hepatol Commun 2020; 5 (03) 358-370
    CrossrefPubMedSearch in Google Scholar
  • 125 Schachtrup C, Le Moan N, Passino MA, Akassoglou K. Hepatic stellate cells and astrocytes: stars of scar formation and tissue repair. Cell Cycle 2011; 10 (11) 1764-1771
    CrossrefPubMedSearch in Google Scholar
  • 126 Cassiman D, van Pelt J, De Vos R. et al. Synaptophysin: a novel marker for human and rat hepatic stellate cells. Am J Pathol 1999; 155 (06) 1831-1839
    CrossrefPubMedSearch in Google Scholar
  • 127 Buniatian G, Gebhardt R, Schrenk D, Hamprecht B. Colocalization of three types of intermediate filament proteins in perisinusoidal stellate cells: glial fibrillary acidic protein as a new cellular marker. Eur J Cell Biol 1996; 70 (01) 23-32
    PubMedSearch in Google Scholar
  • 128 Payen VL, Lavergne A, Alevra Sarika N. et al. Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep 2021; 3 (03) 100278
    CrossrefPubMedSearch in Google Scholar
  • 129 Rohn F, Kordes C, Buschmann T. et al. Impaired integrin α5 /β1 -mediated hepatocyte growth factor release by stellate cells of the aged liver. Aging Cell 2020; 19 (04) e13131
    CrossrefPubMedSearch in Google Scholar
  • 130 Oben JA, Diehl AM. Sympathetic nervous system regulation of liver repair. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (01) 874-883
    CrossrefPubMedSearch in Google Scholar
  • 131 Kordes C, Bock HH, Reichert D, May P, Häussinger D. Hepatic stellate cells: current state and open questions. Biol Chem 2021; 402 (09) 1021-1032
    CrossrefPubMedSearch in Google Scholar
  • 132 Oben JA, Yang S, Lin H, Ono M, Diehl AM. Norepinephrine and neuropeptide Y promote proliferation and collagen gene expression of hepatic myofibroblastic stellate cells. Biochem Biophys Res Commun 2003; 302 (04) 685-690
    CrossrefPubMedSearch in Google Scholar
  • 133 Honda H, Ikejima K, Hirose M. et al. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology 2002; 36 (01) 12-21
    CrossrefPubMedSearch in Google Scholar
  • 134 Dubuisson L, Desmoulière A, Decourt B. et al. Inhibition of rat liver fibrogenesis through noradrenergic antagonism. Hepatology 2002; 35 (02) 325-331
    CrossrefPubMedSearch in Google Scholar
  • 135 Iwakiri Y. Pathophysiology of portal hypertension. Clin Liver Dis 2014; 18 (02) 281-291
    CrossrefPubMedSearch in Google Scholar
  • 136 Ryou M, Stylopoulos N, Baffy G. Nonalcoholic fatty liver disease and portal hypertension. Explor Med 2020; 1: 149-169
    CrossrefPubMedSearch in Google Scholar
  • 137 Van der Graaff D, Kwanten WJ, Couturier FJ. et al. Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats. Lab Invest 2018; 98 (10) 1263-1275
    CrossrefPubMedSearch in Google Scholar
  • 138 Kurosawa M, Unno T, Aikawa Y, Yoneda M. Neural regulation of hepatic blood flow in rats: an in vivo study. Neurosci Lett 2002; 321 (03) 145-148
    CrossrefPubMedSearch in Google Scholar
  • 139 Hanson KM. Escape of the liver vasculature from adrenergic vasoconstriction. Proc Soc Exp Biol Med 1972; 141 (01) 385-390
    CrossrefPubMedSearch in Google Scholar
  • 140 Greenway CV, Lawson AE, Mellander S. The effects of stimulation of the hepatic nerves, infusions of noradrenaline and occlusion of the carotid arteries on liver blood flow in the anaesthetized cat. J Physiol 1967; 192 (01) 21-41
    CrossrefPubMedSearch in Google Scholar
  • 141 Lautt WW, Côté MG. Functional evaluation of 6-hydroxydopamine-induced sympathectomy in the liver of the cat. J Pharmacol Exp Ther 1976; 198 (03) 562-567
    PubMedSearch in Google Scholar
  • 142 Beckh K, Balks HJ, Jungermann K. Activation of glycogenolysis and norepinephrine overflow in the perfused rat liver during repetitive perivascular nerve stimulation. FEBS Lett 1982; 149 (02) 261-265
    CrossrefPubMedSearch in Google Scholar
  • 143 Henriksen JH, Ring-Larsen H, Kanstrup IL, Christensen NJ. Splanchnic and renal elimination and release of catecholamines in cirrhosis. Evidence of enhanced sympathetic nervous activity in patients with decompensated cirrhosis. Gut 1984; 25 (10) 1034-1043
    CrossrefPubMedSearch in Google Scholar
  • 144 Ueno T, Bioulac-Sage P, Balabaud C, Rosenbaum J. Innervation of the sinusoidal wall: regulation of the sinusoidal diameter. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (01) 868-873
    CrossrefPubMedSearch in Google Scholar
  • 145 Ueno T, Tanikawa K. Intralobular innervation and lipocyte contractility in the liver. Nutrition 1997; 13 (02) 141-148
    CrossrefPubMedSearch in Google Scholar
  • 146 Kostreva DR, Castaner A, Kampine JP. Reflex effects of hepatic baroreceptors on renal and cardiac sympathetic nerve activity. Am J Physiol 1980; 238 (05) R390-R394
    PubMedSearch in Google Scholar
  • 147 Smith K. Liver disease: Kupffer cells regulate the progression of ALD and NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10 (09) 503
    CrossrefPubMedSearch in Google Scholar
  • 148 Chhatar S, Lal G. Role of adrenergic receptor signalling in neuroimmune communication. Curr Res Immunol 2021; 2: 202-217
    CrossrefPubMedSearch in Google Scholar
  • 149 Lamkin DM, Ho HY, Ong TH. et al. β-Adrenergic-stimulated macrophages: comprehensive localization in the M1-M2 spectrum. Brain Behav Immun 2016; 57: 338-346
    CrossrefPubMedSearch in Google Scholar
  • 150 Silva A, Caron A. Pathophysiological mechanisms that alter the autonomic brain-liver communication in metabolic diseases. Endocrinology 2021; 162 (11) 162
    CrossrefPubMedSearch in Google Scholar
  • 151 Wang Z, Liang X, Lu Y. et al. Insomnia promotes hepatic steatosis in rats possibly by mediating sympathetic overactivation. Front Physiol 2021; 12: 734009
    CrossrefPubMedSearch in Google Scholar
  • 152 Kim D, Kim HJ, Kushida CA, Heo NY, Ahmed A, Kim WR. Short sleep duration is associated with abnormal serum aminotransferase activities and nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2018; 16 (04) 588-590
    CrossrefPubMedSearch in Google Scholar
  • 153 Okamura T, Hashimoto Y, Hamaguchi M, Obora A, Kojima T, Fukui M. Short sleep duration is a risk of incident nonalcoholic fatty liver disease: a population-based longitudinal study. J Gastrointestin Liver Dis 2019; 28 (01) 73-81
    CrossrefPubMedSearch in Google Scholar
  • 154 Prechtl JC, Powley TL. A light and electron microscopic examination of the vagal hepatic branch of the rat. Anat Embryol (Berl) 1987; 176 (01) 115-126
    CrossrefPubMedSearch in Google Scholar
  • 155 Carnagarin R, Tan K, Adams L. et al. Metabolic dysfunction-associated fatty liver disease (MAFLD) - a condition associated with heightened sympathetic activation. Int J Mol Sci 2021; 22 (08) 22
    Search in Google Scholar
  • 156 Yi CX, la Fleur SE, Fliers E, Kalsbeek A. The role of the autonomic nervous liver innervation in the control of energy metabolism. Biochim Biophys Acta 2010; 1802 (04) 416-431
    CrossrefPubMedSearch in Google Scholar