Abstract
ABSTRACTAlcoholic hepatitis (AH) is the dramatic acute presentation of alcoholic liver disease, with a 15% mortality rate within 28 days in severe cases. Research into AH has been hampered by the lack of effective and reproducible murine models that can be operated under different regulatory frameworks internationally. The liquid Lieber-deCarli (LdC) diet has been used as a means of ad libitum delivery of alcohol but without any additional insult, and is associated with relatively mild liver injury. The transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) protects against oxidative stress, and mice deficient in this molecule are suggested to be more sensitive to alcohol-induced injury. We have established a novel model of AH in mice and compared the nature of liver injury in C57/BL6 wild-type (WT) versus Nrf2−/− mice. Our data showed that both WT and Nrf2−/− mice demonstrate robust weight loss, and an increase in serum transaminase, steatosis and hepatic inflammation when exposed to diet and ethanol. This is accompanied by an increase in peripheral blood and hepatic myeloid cell populations, fibrogenic response and compensatory hepatocyte regeneration. We also noted characteristic disturbances in hepatic carbohydrate and lipid metabolism. Importantly, use of Nrf2−/− mice did not increase hepatic injury responses in our hands, and female WT mice exhibited a more-reproducible response. Thus, we have demonstrated that this simple murine model of AH can be used to induce an injury that recreates many of the key human features of AH – without the need for challenging surgical procedures to administer ethanol. This will be valuable for understanding of the pathogenesis of AH, for testing new therapeutic treatments or devising metabolic approaches to manage patients whilst in medical care.This article has an associated First Person interview with the joint first authors of the paper.
Highlights
Alcoholic liver disease (ALD) places an enormous burden on patients, their carers and society as a whole
The mean weight of the experimental and control groups was similar at baseline, both WT and nuclear factor-erythroid 2-related factor 2 (Nrf2)−/− mice lost a significant amount of weight after introduction of EtOH, with weight loss approaching 20% by day 15 (Fig. 1A)
A mix of micro and macrovesicular steatosis was evident in mice that had been exposed to ethanol plus diet
Summary
Alcoholic liver disease (ALD) places an enormous burden on patients, their carers and society as a whole. In the past 30 years, mortality from ALD has risen by 450% (https://acmedsci.ac.uk/filedownload/34760-CallingT.pdf ), and in part this relates to the more dramatic, acute form of disease, alcoholic hepatitis (AH). There is no approved therapy for AH and, drugs, including immune modulators and monoclonal antibodies, have been tested for management of severe AH, only glucocorticoids and pentoxyfylline are currently licensed for use (European Association for the Study of the Liver, 2012). The large randomised, controlled STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial showed that corticosteroids can improve short-term survival (28 days) in patients with severe AH, 40% of patients were considered ‘nonresponders’ (Mathurin, 2005). No significant mortality benefit was seen following the application of steroids at 90 days or one year in the STOPAH trial (Thursz et al, 2015). The UK NIHR James Lind Alliance has identified AH as a priority translational research area owing to the lack of licensed therapies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
