The Role of the Autonomic Nervous System in Liver Regeneration and Apoptosis – Recent Developments

Kiba, Takayoshi

doi:10.1159/000065594

Cited by 57 publications

(63 citation statements)

References 64 publications

(85 reference statements)

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“…In Xenopus tadpole, inhibition of caspase-dependent apoptosis resulted in a failure to induce proliferation in the growth zone, a mispatterning of axons in the regenerate, and the appearance of ectopic otoliths in the neural tube (83). The requirement of apoptosis may be non-cell autonomous for some cells during regeneration (83,84). Distinct with necrosis, cells undergoing programmed cell death induce negligible inflammation in the surrounding tissue, due to the retention of HMGB1 within the apoptotic cells (13,85).…”

Section: Discussionmentioning

confidence: 99%

HMGB1 Protein Does Not Mediate the Inflammatory Response in Spontaneous Spinal Cord Regeneration

Dong

Huan

et al. 2013

Journal of Biological Chemistry

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Background: HMGB1 in spontaneously regenerating spinal cord does not trigger the inflammation in contrast to those in injured mammalian cords. Results: Gecko HMGB1 paralogs failed to interact with TLR2 and TLR4 but do with RAGE receptors to activate the signaling pathway. Conclusion: HMGB1 is beneficial for spontaneous spinal cord regeneration by eliciting negligible inflammation and promoting oligodendrocyte migration. Significance: HMGB1 displays distinct functions in regenerative vertebrates.

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Section: Discussionmentioning

confidence: 99%

HMGB1 Protein Does Not Mediate the Inflammatory Response in Spontaneous Spinal Cord Regeneration

Dong

Huan

et al. 2013

Journal of Biological Chemistry

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“…Branches of the vagus nerve provide parasympathetic innervation to the liver (Kiba, 2002). Previously, vagus nerve stimulation and transection were used to investigate the cholinergic regulation of liver injury (LeSag et al, 1999;Bernik et al, 2002;Cassiman et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Cholinergic stimulation via the vagus nerve is reported to modulate hepatocyte proliferation (Ohtake et al, 1993;Kiba et al, 1994;Kiba, 2002). To determine the effects of scopolamine treatment on hepatocyte restoration, we measured cell Fig.…”

Section: Effects Of Scopolamine Treatment On Gross Livermentioning

confidence: 99%

Scopolamine Treatment and Muscarinic Receptor Subtype-3 Gene Ablation Augment Azoxymethane-Induced Murine Liver Injury

Khurana

Shah

Cheng

et al. 2010

J Pharmacol Exp Ther

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Previous work suggests that vagus nerve disruption reduces hepatocyte and oval cell expansion after liver injury. The role of postneuronal receptor activation in response to liver injury has not been ascertained. We investigated the actions of scopolamine, a nonselective muscarinic receptor antagonist, and specific genetic ablation of a key cholinergic receptor, muscarinic subtype-3 (Chrm3), on azoxymethane (AOM)-induced liver injury in mice. Animal weights and survival were measured as was liver injury using both gross and microscopic examination. To assess hepatocyte proliferation and apoptosis, ductular hyperplasia, and oval cell expansion, we used morphometric analysis of 5-bromo-2Ј-deoxyuridine-, activated caspase-3-, hematoxylin and eosin-, cytokeratin-19-, and epithelial cell adhesion molecule-stained liver sections. Sirius red staining was used as a measure of collagen deposition and its association with oval cell reaction. In AOM-treated mice, both muscarinic receptor blockade with scopolamine and Chrm3 ablation attenuated hepatocyte proliferation and augmented gross liver nodularity, apoptosis, and fibrosis. Compared with control, scopolamine-treated and Chrm3(Ϫ/Ϫ) AOM-treated mice had augmented oval cell reaction with increased ductular hyperplasia and oval cell expansion. Oval cell reaction correlated robustly with liver fibrosis. No liver injury was observed in scopolamine-treated and Chrm3(Ϫ/Ϫ) mice that were not treated with AOM. Only AOMtreated Chrm3(Ϫ/Ϫ) mice developed ascites and had reduced survival compared with AOM-treated wild-type controls. In AOMinduced liver injury, inhibiting postneuronal cholinergic muscarinic receptor activation with either scopolamine treatment or Chrm3 gene ablation results in prominent oval cell reaction. We conclude that Chrm3 plays a critical role in the liver injury response by modulating hepatocyte proliferation and apoptosis.Acetylcholine activates two classes of cholinergic receptors: nicotinic, which function as cation channels, and muscarinic (CHRM), which mediate G protein-coupled signaling. Five mammalian CHRM subtypes (CHRM1-5) are described; oddnumbered CHRM (CHRM1, 3, and 5) preferentially activate G q/11 proteins, whereas even-numbered CHRM (CHRM2 and 4) activate G i/o proteins. Cell type-specific expression of CHRM subtypes mediates diverse signaling events. In the nervous system, muscarinic receptors play a major role in synaptic transmission and regulate sensory, motor, and autonomic functions. In non-neuronal tissue, muscarinic receptor activation regulates cell function (Shah et al., 2009). For example, muscarinic receptors mediate proliferation of lung and colon cancer cells (Raufman et al., 2008;Shah et al., 2009).In the liver, stimulation of the vagus nerve induces proliferation of oval cells (designated intermediate hepatobiliary Article, publication date, and citation information can be found at

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“…The identity of the relevant tissue that mediates JNK1-dependent hepatic regeneration has not been established. One possibility is represented by the hypothalamus, a region of the brain that strongly influences liver regeneration (Kiba 2002). This possibility is consistent with the discovery that the major metabolic phenotypes of Jnk1 À/À mice are largely accounted for by the effects of JNK1 deficiency in the hypothalamus, rather than in peripheral tissues (Belgardt et al 2010;Sabio et al 2010).…”

Section: The Role Of Jnk In Liver Regenerationmentioning

confidence: 99%

The role of JNK in the development of hepatocellular carcinoma

Das¹,

Garlick²,

Greiner³

et al. 2011

Genes Dev.

179

161

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The cJun NH 2 -terminal kinase (JNK) signal transduction pathway has been implicated in the growth of carcinogen-induced hepatocellular carcinoma. However, the mechanism that accounts for JNK-regulated tumor growth is unclear. Here we demonstrate that compound deficiency of the two ubiquitously expressed JNK isoforms (JNK1 and JNK2) in hepatocytes does not prevent hepatocellular carcinoma development. Indeed, JNK deficiency in hepatocytes increased the tumor burden. In contrast, compound JNK deficiency in hepatocytes and nonparenchymal cells reduced both hepatic inflammation and tumorigenesis. These data indicate that JNK plays a dual role in the development of hepatocellular carcinoma. JNK promotes an inflammatory hepatic environment that supports tumor development, but also functions in hepatocytes to reduce tumor development.

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The Role of the Autonomic Nervous System in Liver Regeneration and Apoptosis – Recent Developments

Cited by 57 publications

References 64 publications

HMGB1 Protein Does Not Mediate the Inflammatory Response in Spontaneous Spinal Cord Regeneration

HMGB1 Protein Does Not Mediate the Inflammatory Response in Spontaneous Spinal Cord Regeneration

Scopolamine Treatment and Muscarinic Receptor Subtype-3 Gene Ablation Augment Azoxymethane-Induced Murine Liver Injury

The role of JNK in the development of hepatocellular carcinoma

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