International Session（Workshop）1(JSH・JSGE)
Thu. November 5th   9:40 - 12:00   Room 11: Portopia Hotel South Wing Topaz
IS-W1-6_H
 Macrophage autophagy suppression promotes NASH pathology with increased secretion of inflammatory cytokines
Kenji Fukumoto1, Hayato Hikita1, Tetsuo Takehara1
1Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
【Objective】
Macrophages play an important role in the pathogenesis of hepatitis. We reported that autophagy suppression of hepatocytes is involved in pathogenesis of NAFLD/NASH. However, its relation with macrophage autophagy remains unclear and we addresses it.
【Methods and Results】
When palmitic acid (PA) was administered to macrophages derived from THP-1 cells, the LC3-II flux index by Western Blotting decreased, suggesting suppression of autophagy. PA administration under LPS stimulation also increased the expression levels of inflammatory cytokines, including IL-1β, IL-6 and, TNFα, and the concentrations of these cytokines in the culture supernatant.
LPS-stimulated macrophages derived from Atg7-deficient THP-1 cells created with CRISPR-Cas9 system showed significantly higher expression levels of IL-1β, IL-6, and TNFα than those from control cells.
Upon administration of a high fat diet for 12 weeks, inflammatory cytokines and macrophage-related genes expressions in liver tissue of bone marrow-derived cell-specific Atg7-deficient (LysM-Cre Atg7 fl/fl) mice were higher than those of wild-type mice . Their serum ALT level and serum caspase-3/7 activity also higher than those of wild-type mice. Upon administration of streptozotocin followed by high fat diet feeding for 12 weeks, the number of macroscopic liver tumors in LysM-Cre Atg7 fl/fl mice tended to increase compared to wild type mice.
【Conclusion】
PA suppressed macrophage autophagy leading to increasing inflammatory cytokine secretion, which may contribute to progression of NAFLD/NASH pathology.
Index Term 1: NASH
Index Term 2: Macrophage
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