Restraint stress exacerbates carbon tetrachloride-induced liver injury in rats: A role of endogenous corticotropin-releasing factor (CRF) in the brain

Central neuropeptides play important roles in many instances of physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Stressors and sympathetic nerve activation are reported to exacerbate experimental liver injury. Some stressors are known to stimulate corticotropin-releasing factor (CRF) synthesis in the central nervous system and induce activation of sympathetic nerves in animal models. The effect of intracisternal CRF on carbon tetrachloride (CCl4)-induced acute liver injury was examined in rats. Intracisternal injection of CRF dose dependently enhanced elevation of the serum alanine aminotransferase (ALT) level induced by CCl4. Elevations of serum aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels by CCl4were also enhanced by intracisternal CRF injection. Intracisternal injection of CRF also aggravated CCl4-induced hepatic histological changes. Intracisternal CRF injection alone did not modify the serum ALT level. Intravenous administration of CRF did not influence CCl4-induced acute liver injury. The aggravating effect of central CRF on CCl4-induced acute liver injury was abolished by denervation of hepatic plexus with phenol and by denervation of noradrenergic fibers with 6-hydroxydopamine treatment but not by hepatic branch vagotomy or atropine treatment. These results suggest that CRF acts in the brain to exacerbate acute liver injury through the sympathetic-noradrenergic pathways.

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Involvement of endogenous CRF in carbon tetrachloride-induced acute liver injury in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00514.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. R1782-R1788 ◽

Cited By ~ 8

Author(s):

Yukiomi Nakade ◽

Masashi Yoneda ◽

Kimihide Nakamura ◽

Isao Makino ◽

Akira Terano

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Receptor Antagonist ◽

Acute Liver Injury ◽

Bile Secretion ◽

Liver Sample ◽

Histological Changes ◽

6 Hydroxydopamine ◽

The Brain

Central neuropeptides play important roles in many physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Central injection of corticotropin-releasing factor (CRF) aggravates carbon tetrachloride (CCl4)-induced acute liver injury through the sympathetic nervous pathway in rats. However, still nothing is known about a role of endogenous neuropeptides in the brain in hepatic pathophysiological regulations. Involvement of endogenous CRF in the brain in CCl4-induced acute liver injury was investigated by centrally injecting a CRF receptor antagonist in rats. Male fasted Wistar rats were injected with CRF receptor antagonist α-helical CRF-(9–41) (0.125–5 μg) intracisternally just before and 6 h after CCl4 (2 ml/kg) administration, and blood samples were obtained before and 24 h after CCl4 injection for measurement of hepatic enzymes. The liver sample was removed 24 h after CCl4 injection, and histological changes were examined. Intracisternal α-helical CRF-(9–41) dose dependently (0.25–2 μg) reduced the elevation of alanine aminotransferase and aspartate aminotransferase levels induced by CCl4. Intracisternal α-helical CRF-(9–41) reduced CCl4-induced liver histological changes, such as centrilobular necrosis. The effect of central CRF receptor antagonist on CCl4-induced liver injury was abolished by sympathectomy and 6-hydroxydopamine pretreatment but not by hepatic branch vagotomy or atropine pretreatment. These findings suggest the regulatory role of endogenous CRF in the brain in experimental liver injury in rats.

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Protective Role of Estrogen-induced miRNA-29 Expression in Carbon Tetrachloride-induced Mouse Liver Injury

Journal of Biological Chemistry ◽

10.1074/jbc.m111.314922 ◽

2012 ◽

Vol 287 (18) ◽

pp. 14851-14862 ◽

Cited By ~ 71

Author(s):

Yaqin Zhang ◽

Linping Wu ◽

Yang Wang ◽

Mingcao Zhang ◽

Limin Li ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Mouse Liver ◽

Protective Role

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The protective role of Hepatopoietin Cn on liver injury induced by carbon tetrachloride in rats

Hepatology Research ◽

10.1111/j.1872-034x.2008.00447.x ◽

2009 ◽

Vol 39 (2) ◽

pp. 200-206 ◽

Cited By ~ 11

Author(s):

Chun-Ping Cui ◽

Ping Wei ◽

Yang Liu ◽

Da-Jin Zhang ◽

Li-Sheng Wang ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Protective Role

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Assessment of the Potential Role of Silymarin Alone or in Combination with Vitamin E and/ or Curcumin on the Carbon Tetrachloride Induced Liver Injury in Rat

Brazilian Archives of Biology and Technology ◽

10.1590/s1516-891320150232 ◽

2015 ◽

Vol 58 (6) ◽

pp. 833-842 ◽

Cited By ~ 4

Author(s):

Nouf Al-Rasheed ◽

Laila Faddah ◽

Iman A Sharaf ◽

Azza M Mohamed ◽

Nawal Al-Rasheed ◽

...

Keyword(s):

Vitamin E ◽

Carbon Tetrachloride ◽

Liver Injury ◽

Potential Role

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Pathological role of CD44 on NKT cells in carbon tetrachloride-mediated liver injury

Hepatology Research ◽

10.1111/j.1872-034x.2008.00409.x ◽

2009 ◽

Vol 39 (1) ◽

pp. 93-105 ◽

Cited By ~ 5

Author(s):

Kiminori Kimura ◽

Masahito Nagaki ◽

Tomokazu Matsuura ◽

Hisataka Moriwaki ◽

Kazuhiro Kakimi

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Nkt Cells

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Central injection of a novel corticotropin-releasing factor(CRF)antagonist, astressin, protects carbon tetrachloride (CC14)-induced acute liver injury in rats

Gastroenterology ◽

10.1016/s0016-5085(00)83835-4 ◽

2000 ◽

Vol 118 (4) ◽

pp. A430

Author(s):

Yukiomi Nakade ◽

Masashi Yoneda ◽

Shuujirou Takamoto ◽

Shirou Yokohama ◽

Mitsuyoshi Okada ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Acute Liver Injury ◽

Corticotropin Releasing Factor

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The Role of Alpha-1 and Alpha-2 Adrenoceptors in Restraint Stress-Induced Liver Injury in Mice

PLoS ONE ◽

10.1371/journal.pone.0092125 ◽

2014 ◽

Vol 9 (3) ◽

pp. e92125 ◽

Cited By ~ 10

Author(s):

Qing Zhu ◽

Liwei Gu ◽

Yimei Wang ◽

Li Jia ◽

Zengming Zhao ◽

...

Keyword(s):

Liver Injury ◽

Restraint Stress

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Caveolin-1 Deficiency Protects Mice Against Carbon Tetrachloride-Induced Acute Liver Injury Through Regulating Polarization of Hepatic Macrophages

Frontiers in Immunology ◽

10.3389/fimmu.2021.713808 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ziheng Yang ◽

Jie Zhang ◽

Yan Wang ◽

Jing Lu ◽

Quan Sun

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Liver Diseases ◽

Acute Liver Injury ◽

Mrna Levels ◽

Alcoholic Fatty Liver ◽

Caveolin 1 ◽

Hepatic Macrophages ◽

M1 Phenotype

Polarization of hepatic macrophages plays a crucial role in the injury and repair processes of acute and chronic liver diseases. However, the underlying molecular mechanisms remain elusive. Caveolin-1 (Cav1) is the structural protein of caveolae, the invaginations of the plasma membrane. It has distinct functions in regulating hepatitis, cirrhosis, and hepatocarcinogenesis. Given the increasing number of cases of liver cancer, nonalcoholic steatohepatitis, and non-alcoholic fatty liver disease worldwide, investigations on the role of Cav1 in liver diseases are warranted. In this study, we aimed to investigate the role of Cav1 in the pathogenesis of acute liver injury. Wild-type (WT) and Cav1 knockout (KO) mice (Cav1tm1Mls) were injected with carbon tetrachloride (CCl4). Cav1 KO mice showed significantly reduced degeneration, necrosis, and apoptosis of hepatocytes and decreased level of alanine transaminase (ALT) compared to WT mice. Moreover, Cav1 was required for the recruitment of hepatic macrophages. The analysis of the mRNA levels of CD86, tumor necrosis factor (TNF), and interleukin (IL)-6, as well as the protein expression of inducible nitric oxide synthase (iNOS), indicated that Cav1 deficiency inhibited the polarization of hepatic macrophages towards the M1 phenotype in the injured liver. Consistent with in vivo results, the expressions of CD86, TNF, IL-6, and iNOS were significantly downregulated in Cav1 KO macrophages. Also, fluorescence-activated cell sorting (FACS) analysis showed that the proportion of M1 macrophages was significantly decreased in the liver tissues obtained from Cav1 KO mice following CCl4 treatment. In summary, our results showed that Cav1 deficiency protected mice against CCl4-induced acute liver injury by regulating polarization of hepatic macrophages. We provided direct genetic evidence that Cav1 expressed in hepatic macrophages contributed to the pathogenesis of acute liver injury by regulating the polarization of hepatic macrophages towards the M1 phenotype. These findings suggest that Cav1 expressed in macrophages may represent a potential therapeutic target for acute liver injury.

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