| Autor: |
Kim Y; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.; Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, USA., Gautam S; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Aseer KR; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Kim J; Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Chandrasekaran P; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Mazucanti CH; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Ghosh P; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., O'Connell JF; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Doyle ME; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Appleton A; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Lehrmann E; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Liu QR; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Egan JM; Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. eganj@grc.nia.nih.gov. |
| Abstrakt: |
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. |
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