Hepatocyte cannabinoid 1 receptor nullification alleviates toxin-induced liver damage via NF-κB signaling

AbstractCannabinoid 1 receptor (CB1R) expression is upregulated in the liver with viral hepatitis, cirrhosis, and both alcoholic and non-alcoholic fatty liver disease (FLD), whereas its expression is muted under usual physiological conditions. Inhibiting CB1R has been shown to be beneficial in preserving hepatic function in FLD but it is unclear if inhibiting CB1R during an inflammatory response to an acute hepatic injury, such as toxin-induced injury, would also be beneficial. We found that intrinsic CB1R in hepatocytes regulated liver inflammation-related gene transcription. We tested if nullification of hepatocyte-specific CB1R (hCNR1−/−) in mice protects against concanavalin A (Con A)-induced liver injury. We looked for evidence of liver damage and markers of inflammation in response to Con A by measuring liver enzyme levels and proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-17) in serum collected from hCNR1−/− and control mice. We observed a shift to the right in the dose-response curve for liver injury and inflammation in hCNR1−/− mice. We also found less inflammatory cell infiltration and focal necrosis in livers of hCNR1−/− mice compared to controls, resulting from downregulated apoptotic markers. This anti-apoptotic mechanism results from increased activation of nuclear factor kappa B (NF-κB), especially cAMP-dependent cannabinoid signaling and membrane-bound TNF-α, via downregulated TNF-α receptor 2 (TNFR2) transcription levels. Collectively, these findings provide insight into involvement of CB1R in the pathogenesis of acute liver injury.

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Streptococcus, the Predominant Bacterium to Predict the Severity of Liver Injury in Alcoholic Liver Disease

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.649060 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaodan Zhong ◽

Ping Cui ◽

Junjun Jiang ◽

Chuanyi Ning ◽

Bingyu Liang ◽

...

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Gut Microbiota ◽

Alcoholic Liver Disease ◽

Early Stage ◽

Characteristic Curve ◽

Hepatic Function ◽

Rrna Gene ◽

Alcoholic Fatty Liver ◽

Predominant Bacterium

BackgroundNew evidence implies that the imbalance of gut microbiota is associated with the progression of alcoholic liver disease (ALD) and that the composition of gut microbiota is altered in ALD patients. However, the predominant bacterium in patients involved in the progress of ALD has not been identified. The purpose of this study is to investigate the predominant bacterium in the early and end-stages of ALD as well as the relationship between the bacterium and the degree of liver injury.MethodsWe enrolled 21 alcoholic fatty liver (AFL) patients, 17 alcoholic liver cirrhosis (ALC) patients and 27 healthy controls, and sequenced the 16S rRNA gene of their fecal microbiota. The gut microbiota composition and its relationship with the indicators of clinical hepatic function were assessed using canonical correspondence analysis (CCA), spearman correlation heatmap and multivariate association with linear (MaAsLin) Models.ResultsThe composition and structure of gut microbiota changed greatly in different stages of ALD, and the degree of disorder was aggravated with the progression of ALD, even in the early stage. Moreover, the relative abundance of Streptococcus was highly enriched only in patients with ALC (P <0.001), and positively correlated with AST level (P = 0.029). The abundance of Streptococcus distinguished the liver injury of ALC patients from the controls with an area under the receiver-operating characteristic curve (AUC) of 0.877 (P < 0.001).ConclusionsThese findings indicate that the imbalance of gut microbiota exists at the early and end-stages of ALD, and the degree of disorder is aggravated with the progression of ALD. Streptococcus, as the predominant bacterium, may be a microbiological marker to evaluate the severity of liver injury in ALD patients.

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The Effects of L-Arginine on Liver Damage in Experimental Acute Cholestasis an Immunohistochemical Study

HPB Surgery ◽

10.1155/2011/306069 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 11

Author(s):

Yucel Ozsoy ◽

Mustafa Ozsoy ◽

Teoman Coskun ◽

Kemal Namlı ◽

Ahmet Var ◽

...

Keyword(s):

Liver Injury ◽

Liver Damage ◽

Biliary Obstruction ◽

Hepatic Tissue ◽

Control Group ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Duct Ligation ◽

And Control ◽

Acute Cholestasis

Obstructive jaundice damages critical functions in the liver. Nitric oxide modulation would influence liver damage induced by biliary obstruction, and little is known about it Acute cholestasis was induced by bile duct ligation (BDL) in two groups of male Sprague-Dawley rats. L-Arginine or serum physiologic was administered to treatment and control group. Histopathological and immunohistochemical iNOS expression was investigated in hepatic tissue. Plasma enzyme activities were increased in acute cholestasis, and that L-arginine treatment partially but significantly prevented the elevation of these markers of liver damage (P< .05). Also histopathology scoring showed that the liver injury was prevented and immunohistochemical iNOS activity was increased significantly in L-arginine group (P< .05). This study shows that, after 7 days of biliary obstruction, liver damage is well established and exogenous L-arginine treatment partially but significantly prevented the liver injury in acute cholestasis.

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The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00460.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. G1261-G1268 ◽

Cited By ~ 50

Author(s):

Allan Tsung ◽

Michael T. Stang ◽

Atsushi Ikeda ◽

Nathan D. Critchlow ◽

Kunihiko Izuishi ◽

...

Keyword(s):

Transcription Factor ◽

Liver Injury ◽

Liver Damage ◽

Knockout Mice ◽

Ischemia Reperfusion ◽

Wild Type ◽

Regulatory Factor ◽

Hepatic Ischemia ◽

Adenoviral Delivery ◽

Tnf Α

Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH2-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-α, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-γ and IFN-β were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-α and IL-1β also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.

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SHED ameliorated concanavalin A-induced autoimmune hepatitis by protecting hepatocytes from apoptosis

10.21203/rs.3.rs-17847/v1 ◽

2020 ◽

Author(s):

Yikun Zhou ◽

Ruili Yang ◽

Lingsu Zhu ◽

Huaming Huang ◽

Shengjie Cui ◽

...

Keyword(s):

Liver Injury ◽

Autoimmune Hepatitis ◽

Concanavalin A ◽

Acute Liver Injury ◽

Deciduous Teeth ◽

Protective Effects ◽

Hepatocyte Apoptosis ◽

Con A ◽

Tnf Α ◽

Ifn Γ

Abstract Background：Autoimmune hepatitis (AIH) is serious autoimmune liver diseases that threaten people’s health worldwide, emphasizing the need to identify novel treatment. Stem cells from human exfoliated deciduous teeth (SHED), which is easy to obtain and non-invasive, showed pronounced proliferation and immunomodulation capacity. This study aims to investigate the effect of SHED on ConA-induced AIH and the potential underlying mechanisms.Methods: We used a concanavalin A (ConA) induced acute hepatitis mouse model and in vitro co-culture system to study the protective effects of SHED on ConA-induced autoimmune hepatitis and the underlying mechanisms.Results: SHED infusion could prevent aberrant histopathological architecture of liver with infiltration of abundant of CD3+, CD4+, TNF-α+ and IFN-γ+ inflammatory cells induced by ConA. The expression of ALT and AST which indicated the liver function significantly elevated in hepatitis mice. While SHED infusion could block the elevation of ALT and AST induced by ConA. Mechanistically, Con-A upregulated TNF-α and IFN-γ expression activated NF-κB pathways to induced hepatocyte apoptosis, resulting in acute liver injury. SHED administration protected hepatocytes from Con-A-induced apoptosis. Conclusions: These results demonstrated that SHED alleviated ConA-induced acute liver injury via inhibition of hepatocyte apoptosis mediated by the NF-κB pathways. Our findings could provide a potential prevention and therapeutic strategy for hepatitis and acute hepatic injury.

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Thioacetamide-induced liver damage and thrombocytopenia is associated with induction of antiplatelet autoantibody in mice

Scientific Reports ◽

10.1038/s41598-019-53977-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

You-Yen Lin ◽

Chi-Tan Hu ◽

Der-Shan Sun ◽

Te-Sheng Lien ◽

Hsin-Hou Chang

Keyword(s):

Liver Injury ◽

Liver Damage ◽

Critical Role ◽

Rodent Models ◽

Wild Type ◽

Antiplatelet Antibody ◽

Pathogenic Factors ◽

Tnf Α ◽

Acute Liver Disease ◽

Rats And Mice

AbstractThrombocytopenia is usually associated with liver injury, elevated plasma aspartate aminotransferase and alanine aminotransferase levels, and high antiplatelet immunoglobulin (Ig) titers, although the mechanism behind these effects remains elusive. Deciphering the mechanism behind acute liver disease–associated thrombocytopenia may help solve difficulties in routine patient care, such as liver biopsy, antiviral therapy, and surgery. To determine whether liver damage is sufficient per se to elicit thrombocytopenia, thioacetamide (TAA)-induced hepatitis rodent models were employed. The analysis results indicated that TAA treatment transiently induced an elevation of antiplatelet antibody titer in both rats and mice. B-cell-deficient (BCD) mice, which have loss of antibody expression, exhibited markedly less thrombocytopenia and liver damage than wild-type controls. Because TAA still induces liver damage in BCD mice, this suggests that antiplatelet Ig is one of the pathogenic factors, which play exacerbating role in the acute phase of TAA-induced hepatitis. TNF-α was differentially regulated in wild-type versus BCD mice during TAA treatment, and anti-TNF treatment drastically ameliorated antiplatelet Ig induction, thrombocytopenia, and liver injury, suggesting that the TNF pathway plays a critical role in the disease progression.

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Acute liver injury following acetaminophen administration does not activate atrophic pathways in the mouse diaphragm

Scientific Reports ◽

10.1038/s41598-021-85859-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

C. S. Bruells ◽

P. Duschner ◽

G. Marx ◽

G. Gayan-Ramirez ◽

N. Frank ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Liver Injury ◽

Liver Damage ◽

Acute Liver Injury ◽

Serum Levels ◽

Acute Liver Damage ◽

Markers Of Inflammation ◽

Amino Phenol ◽

And Oxidative Stress

AbstractN-acetyl-para-amino phenol (APAP, usually named paracetamol), which is commonly used for its analgesic and antipyretic properties may lead to hepatotoxicity and acute liver damage in case of overdoses. Released cytokines and oxidative stress following acute liver damage may affect other organs’ function notably the diaphragm, which is particularly sensitive to oxidative stress and circulating cytokines. We addressed this issue in a mouse model of acute liver injury induced by administration of APAP. C57BL/6J mice (each n = 8) were treated with N-acetyl-para-amino phenol (APAP) to induce acute drug caused liver injury and sacrificed 12 or 24 h afterwards. An untreated group served as controls. Key markers of inflammation, proteolysis, autophagy and oxidative stress were measured in diaphragm samples. In APAP treated animals, liver damage was proven by the enhanced serum levels of alanine aminotransferase and aspartate aminotransferase. In the diaphragm, besides a significant increase in IL 6 and lipid peroxidation, no changes were observed in key markers of the proteolytic, and autophagy signaling pathways, other inflammatory markers and fiber dimensions. The first 24 h of acute liver damage did not impair diaphragm atrophic pathways although it slightly enhanced IL-6 and lipid peroxidation. Whether longer exposure might affect the diaphragm needs to be addressed in future experiments.

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Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to Lps/Galactosamine Liver Injury and Protection by Betaine Administration

Biology ◽

10.3390/biology10010019 ◽

2020 ◽

Vol 10 (1) ◽

pp. 19

Author(s):

Karuna Rasineni ◽

Serene M. L. Lee ◽

Benita L. McVicker ◽

Natalia A. Osna ◽

Carol A. Casey ◽

...

Keyword(s):

Liver Injury ◽

Liver Failure ◽

Liver Damage ◽

Asialoglycoprotein Receptor ◽

Fulminant Liver Failure ◽

Wild Type ◽

Tissue Samples ◽

Tnf Α ◽

Deficient Mice

Background: Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. Methods: Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. Results: LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. Conclusion: Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.

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6-O-galloylsalidroside, an active ingredient from Acer tegmentosum, ameliorates alcoholic steatosis and liver injury in a mouse model of chronic ethanol consumption

10.1101/821397 ◽

2019 ◽

Author(s):

Young Han Kim ◽

Dong-Cheol Woo ◽

Moonjin Ra ◽

Sangmi Jung ◽

Su Jung Ham ◽

...

Keyword(s):

Liver Disease ◽

Magnetic Resonance ◽

Alcohol Consumption ◽

Liver Injury ◽

Fatty Liver ◽

Liver Damage ◽

Active Ingredient ◽

Alcoholic Fatty Liver ◽

Fat Accumulation ◽

Hepatocellular Damage

AbstractWe previously reported that Acer tegmentosum extract, which is traditionally used to treat liver disease in Korea, may help reduce fat accumulation, improve liver metabolism, and suppress inflammation in alcoholic liver disease. The active ingredient was found to be 6-O-galloylsalidroside, which was isolated from the methanol extract of A. tegmentosum. We hypothesized that 6-O-galloylsalidroside extracted from A. tegmentosum may help protect from liver damage and attenuate hepatic fat accumulation associated with chronic alcohol consumption. In the present study, we aimed to investigate whether 6-O-galloylsalidroside can regulate alcoholic fatty liver and liver injury in mice. For this purpose, mice were fed with Lieber-DeCarli 5% ethanol diet for 11 days to induce steatosis and liver injury. Oral 6-O-galloylsalidroside was administered once a day for 11 days. Intrahepatic lipid accumulation caused by alcohol consumption was measured using in vivo 1H magnetic resonance imaging. Hepatic steatosis was observed histologically in tissue samples stained with hematoxylin and eosin, as well as Oil Red O. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, as well as the triglyceride content in liver homogenates. On magnetic resonance spectroscopy, 6-O-galloylsalidroside appeared to alleviate alcohol-induced steatosis, which was reflected in decreased hepatic and serum triglyceride levels despite ethanol feeding. Furthermore, 6-O-galloylsalidroside treatment was associated with decreased RNA expression of Cd36, which plays an important role in the development of alcoholic steatosis through the hepatic de novo lipogenesis pathway. Furthermore, treatment with 6-O-galloylsalidroside inhibited the expression of cytochrome P4502E1 and attenuated hepatocellular damage, reflected in reduced ALT and AST levels. These findings suggest that 6-O-galloylsalidroside extracted from A. tegmentosum might serve as a bioactive agent for treating alcoholic fatty liver and liver damage.

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Hepatic Response of Magnesium-Restricted Wild Type Mice

Metabolites ◽

10.3390/metabo11110762 ◽

2021 ◽

Vol 11 (11) ◽

pp. 762

Author(s):

Vera H. Fengler ◽

Tanja Macheiner ◽

Walter Goessler ◽

Maria Ratzer ◽

Johannes Haybaeck ◽

...

Keyword(s):

High Fat Diet ◽

Magnesium Deficiency ◽

Serum Magnesium ◽

Cholesterol Content ◽

High Fat ◽

Deficient Diet ◽

Metabolic Markers ◽

Alcoholic Fatty Liver ◽

Markers Of Inflammation ◽

And Control

Magnesium-deficiency is implicated in many metabolic disorders, e.g., type 2 diabetes and metabolic syndrome, representing risk factors for non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the contribution of magnesium-restriction to the development of NAFLD. Magnesium-deficiency was induced in C57BL/6 mice by feeding a magnesium-deficient-diet. Metabolic markers as well as markers of inflammation and liver function were assessed. Furthermore, liver tissue was examined histopathologically and compared with specimens from high-fat-diet fed and control mice. Finally, the hepatic inflammatory response was quantified by determining hepatic IL-6, TNFα, and MCP-1. Magnesium-restriction resulted in at least a 2-fold significant reduction of serum magnesium levels compared to the high-fat-diet fed and control mice, whereas the hepatic magnesium content was decreased due to high-fat-diet feeding. No changes in metabolic markers in magnesium-restricted mice were observed, while the cholesterol content was elevated in high-fat-diet fed mice. Magnesium-restricted mice additionally featured inflammation and enlarged hepatocytes in liver histology. Furthermore, magnesium-restricted and high-fat-diet fed mice exhibited elevated hepatic TNFα levels compared to control mice. Accordingly, our data suggest that magnesium is involved in hepatic inflammatory processes and hepatocyte enlargement, key histological features of human NAFLD, and may therefore contribute to development and progression of the disease.

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Monascin and Ankaflavin of Monascus purpureus Prevent Alcoholic Liver Disease through Regulating AMPK-Mediated Lipid Metabolism and Enhancing Both Anti-Inflammatory and Anti-Oxidative Systems

Molecules ◽

10.3390/molecules26206301 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6301

Author(s):

Jhao-Ru Lai ◽

Ya-Wen Hsu ◽

Tzu-Ming Pan ◽

Chun-Lin Lee

Keyword(s):

Liver Injury ◽

Fatty Liver ◽

Liver Damage ◽

Monascus Purpureus ◽

Liver Cholesterol ◽

Alcoholic Liver Injury ◽

Ppar Γ ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory

Alcohol metabolism causes an excessive accumulation of liver lipids and inflammation, resulting in liver damage. The yellow pigments monascin (MS) and ankaflavin (AK) of Monascus purpureus-fermented rice were proven to regulate ethanol-induced damage in HepG2 cells, but the complete anti-inflammatory and anti-fatty liver mechanisms in the animal model are still unclear. This study explored the roles of MS and AK in improving alcoholic liver injury. MS and AK were simultaneously fed to evaluate their effects and mechanisms in C57BL/6J mice fed the Lieber–DeCarli liquid alcohol diet for 6 weeks. The results indicated that MS and AK significantly reduced the serum aspartate aminotransferase and alanine aminotransferase activity, as well as the total liver cholesterol and triglyceride levels. The histopathological results indicated that MS and AK prevented lipid accumulation in the liver. MS and AK effectively enhanced the activity of antioxidant enzymes and reduced the degree of lipid peroxidation; AK was particularly effective and exhibited a superior preventive effect against alcoholic liver injury and fatty liver. In addition to inhibiting the phosphorylation of the MAPK family, MS and AK directly reduced TNF-α, IL-6, and IL-1β levels, thereby reducing NF-κB and its downstream iNOS and COX-2 expressions, as well as increasing PPAR-γ, Nrf-2, and HO-1 expressions to prevent liver damage. MS and AK also directly reduced TNF-α, IL-6, and IL-1β expression, thereby reducing the production of NF-κB and its downstream iNOS and COX-2, and increasing PPAR-γ, Nrf-2, and HO-1 expressions, preventing alcohol damage to the liver.

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