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Fatty Liver Disease and Multi-System Complications | EK28


Sleep fragmentation in a mouse model of NASH exacerbates fibrosis and induces phenotypic changes in liver macrophages in an age-dependent manner


Mar 22, 2021 12:00am ‐ Mar 22, 2021 12:00am

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Sleep fragmentation in a mouse model of NASH exacerbates fibrosis and induces phenotypic changes in liver macrophages in an age-dependent manner Ravin Fisher, Sezgi Arpag-McIntosh, Manasa Vallabhaneni, Larry Sanford and Anca Dobrian Department of Physiological Sciences, Eastern Virginia Medical School Sleep dysregulation is known to impact on metabolism, immunity and inflammation. NASH is a chronic metabolic condition characterized by liver fibrosis, steatosis and inflammation and with high risk of progression to hepatocellular carcinoma. The goal of our study was to determine the effect of 2-week sleep fragmentation (SF) on liver fibrosis and inflammatory milieu at different stages of disease progression using DIAMOND (diet-induced animal model for NASH disease) mice that closely recapitulate human disease history and histopathology. The DIAMOND mice are a stable isogenic cross between C57Bl/6J and 129SI/Sylm strains. When fed a 40% kcal fat diet and 4% fructose water (HFD), starting at 8 weeks of age, male mice develop progressively fatty liver and NASH. We examined 3 time points in the disease development, after 18, 26 and 40 weeks of diet that correspond to steatosis and early fibrosis, advanced fibrosis and necrosis and, bridging fibrosis and occasional hepatocellular carcinoma, respectively. We characterized the liver macrophage (LMF) spatial and phenotypic profile in SF and control (no SF intervention) mice using F4/80 and galectin-3 markers to differentiate between macrophages of different functional phenotypes and Clec4 as a marker for Kupfer resident macrophages. Recent studies showed that F4/80+ Gal3+ MF have a pro-fibrotic phenotype, while F4/80+Gal3- MF are more pro-inflammatory. LMF that surrounded lipid droplets (lipid crown-like structures, LCS) were quantitated separately from the isolated parenchymal LMF. Fibrosis was determined using SiriusRed staining. Gene expression was measured in livers of SF and control mice at different time points using the NanoString platform and a myeloid gene expression panel. Data was analyzed using t-test between SF and control groups (n=5-6mice/group) for each time point and null hypothesis was rejected for a p-value

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