Chronic Intermittent Hypoxia Is Related to the Hepatic Injury Through TLR4 Signaling in Diet Induced Obesity

SESSION TITLE: Sleep Disorders Posters I: Diagnosis SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM PURPOSE: Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. Inflammatory processes and oxidative stress are known to play a key role in the development of metabolic complications induced by CIH. Several evidences suggest that innate immune defense mechanisms might interact with proinflammatory pathways in OSA. The purpose of this study was to investigate the activity of toll like receptor 4 (TLR4) in lean mice and mice with diet-induced obesity (DIO) under CIH condition. METHODS: Eight-week old C57BL/6J mice were randomly divided into 4 groups. Two groups of mice were fed a high fat diet for 12 weeks and then exposed to CIH or control conditions (room air) for 4 weeks. Two groups of age-matched mice were fed a regular chow diet for 12 weeks and then exposed to CIH or room air also for 4 weeks. At the end of the exposure, we examined several genes including myeloid differentiation primary response protein 88 (MyD88), Toll/interleukin-1-receptor-domain-containing adaptor-inducing interferon-α (TRIF), I kappa B (I-κB), nuclear factor kappa B (NF-κB), and Toll-like receptor 4(TLR4) in liver. RESULTS: There was a significant reduction in body weight in DIO mice exposed to CIH steadily through 4 weeks compared with DIO group exposed to room air (P<0.05). In DIO mice, CIH led to increase the activation of NF-κB in the nuclear fraction of hepatocytes and mRNA levels of TLR4, which was not observed in lean mice. The protein level of TLR4, phospho I-κB and MyD88 were significantly elevated in CIH + DIO group compared to the normoxic group, while there was no significant change in the level of TRIF in all groups. CONCLUSIONS: CIH is associated with enhanced expression and signaling events downstream of TLR4 in liver of DIO mice. We suggest that CIH causes significant hepatic injury in DIO mice mediated by TLR4-MyD88-dependent pathway. CLINICAL IMPLICATIONS: These results suggest that TLR4 may play a critical role in CIH-induced hepatic inflammation. DISCLOSURE: The following authors have nothing to disclose: Hyeon Hui Kang, Jin Woo Kim, Sung-Kyoung Kim, Ki Hoon Park, Sang Haak Lee, Ji Young Kang, Hwasik Moon No Product/Research Disclosure Information