Chronic Intermittent Hypoxia Causes Hepatic Fibrosis in a Mouse Model of Diet-Induced Fatty Liver

Abstract

SESSION TITLE: Obstructive Sleep Apnea: Insights & Management SESSION TYPE: Original Investigation Slide PRESENTED ON: Sunday, October 29, 2017 at 01:30 PM - 03:00 PM PURPOSE: Obstructive sleep apnea (OSA) is known to be associated with nonalcoholic fatty liver disease (NAFLD). OSA causes chronic intermittent hypoxia (CIH) during sleep. Experimental evidence suggests that CIH may trigger liver injury, inflammation, and fibrogenesis. The purpose of this study was to examine whether CIH induces fibrotic changes in the liver in mice with diet-induced hepatic steatosis. METHODS: Male C57BL/6J mice were fed a high fat or regular diet for 12 weeks and then exposed to CIH or room air for 4 weeks. We assessed the level of inflammation and fibrosis in the liver tissue by western blotting, real time polymerase chain reaction (PCR) and collagen assay. RESULTS: In CIH with diet-induced obesity (DIO) mice, there were significant increase in α1(I)-collagen mRNA, compared to the room air groups; trends toward increases in platelet-derived growth factor receptor-beta (PDGFRß), transforming growth factor beta 1 (TGFß1), and caspase 3 by real time PCR. CIH mice showed hepatic fibrosis by Masson’s trichrome staining and hydroxyproline assay. CIH caused increases in protein expression of Interleukin 1 ß (IL-lß), toll like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), phospho I kappa B (I-κB), phospho-ERK, vascular endothelial growth factor (VEGF), and the p65 subunit of nuclear factor kappa B (NF-κB), in liver, which was augmented in DIO mice. CONCLUSIONS: CIH induces fibrosis in the livers of mice on a high-fat diet via TLR4/MAPK/NF-κB pathways. CLINICAL IMPLICATIONS: These results suggest a new aspect of TLR4 potentially related to the pathogenesis of liver fibrosis in CIH. Thus, TLR4 inhibition consider to be a strategy for the prevention of hepatic fibrosis in patients with OSA. DISCLOSURE: The following authors have nothing to disclose: Hyeon Hui Kang, In Kyoung Kim, Hye In Lee, Sang Haak Lee, Hwa Sik Moon No Product/Research Disclosure Information