Hepatocyte cannabinoid 1 receptor nullification alleviates toxin-induced liver damage via NF-\u03baB signaling

Yoo Kim,Ashley Appleton,Qing-Rong Liu,Kanikkai Raja Aseer,Sudeep Gautam,Jaekwan Kim,Paritosh Ghosh,Elin Lehrmann,Prabha Chandrasekaran,Caio Henrique Mazucanti,Jennifer F O’Connell,Josephine M Egan,Máire E Doyle

doi:10.1038/s41419-020-03261-8

Abstract

Cannabinoid 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.

Highlights

Inflammatory liver diseases, an increasing health problem worldwide, are caused by diverse agents such as toxins, viruses, various drugs and alcohol ingestion, fatty liver disease (FLD), and immune dysfunction[1]
Our findings show that lack of Cannabinoid 1 receptor (CB1R) exerts a hepatoprotective effect and raises the possibility of using CB1R-specific antagonists or inverse agonists to mitigate against hepatitis during acute toxin injury
The genes controlled by inflammatory cytokines such as interleukin 1 receptor 1 (Il1r1), interleukin 1β (Il1b), interleukin 6 (Il6), and tumor necrosis factor (Tnf) were substantially downregulated (Fig. 1F)

Summary

Introduction

Inflammatory liver diseases, an increasing health problem worldwide, are caused by diverse agents such as toxins, viruses, various drugs and alcohol ingestion, fatty liver disease (FLD), and immune dysfunction[1]. The first insult leads to hepatocyte injury that is reflected in increased circulating levels of liver enzymes, and, if left unchecked, progressive liver inflammation, hepatocyte apoptosis, necrosis, and fibrosis results in. Kim et al Cell Death and Disease (2020)11:1044 coupled (GPCRs). While the expression levels of EC receptors are low in the liver under normal physiological conditions, marked increases in their levels occur upon injury and disease[7,8]. Pharmacological or genetic inhibition of CB1R, but not CB2R, has been proposed to be a therapeutic strategy to treat liver pathology due to alcohol- and high fat diet-induced FLD11

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Results

Conclusion