Intermittent hypoxia induces hepatic senescence through promoting oxidative stress in a mouse model.

PURPOSE: Metabolic-associated fatty liver disease (MAFLD) is an aging-related disease. Obstructive sleep apnea (OSA) may cause MAFLD. This study aimed to explore whether or not intermittent hypoxia (IH), the hallmark of OSA, induces liver aging through oxidative stress. METHODS: C57BL/6J male mice were administered normal air (control), IH, or antioxidant tempol + IH daily for 6 weeks before the collection of serum and liver tissue samples. A histological examination was conducted to assess liver aging. ELISA was performed to measure liver function indicator levels in the serum and oxidative stress indicator activities in the liver. Western blot analysis was carried out to determine the protein expression of the markers related to oxidative stress, inflammation, and senescence. RESULTS: Compared with control, IH resulted in significant increases in serum ALT, AST, and TG levels in mice (all P < 0.001), along with lobular inflammation and accumulation of collagen and fat in the liver. The protein levels of inflammatory factors and senescent markers were significantly increased in the IH mouse liver compared with those in the control mouse liver. Meanwhile, IH significantly reduced SOD and CAT activities while enhancing p22phox and Nrf2 protein expression in mouse liver compared with control. Importantly, antioxidant therapy with tempol effectively abrogated the effects of IH on oxidative stress response and aging-related liver injury. CONCLUSIONS: Our findings suggest that IH induces liver inflammation and aging through oxidative stress. OSA may exacerbate target organ aging and participate in target organ damage. Strategies targeting oxidative stress may prevent and treat OSA-related MAFLD.

Effect of information-motivation-behavior skills on adherence of continuous positive airway pressure therapy in patients with obstructive sleep apnea hypopnea syndrome. / 信息-动机-è¡Œä¸ºæŠ€å·§å¯¹é˜»å¡žæ€§ç¡çœ å‘¼å¸æš‚åœä½Žé€šæ°”ç»¼åˆå¾æ‚£è€ æŒç»­æ°”é“æ­£åŽ‹é€šæ°”æ²»ç–—ä¾ä»Žæ€§çš„å½±å“.

OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a common disease that seriously affects health. Continuous positive airway pressure (CPAP) therapy is the preferred treatment for moderate-to-severe OSAHS patients. However, poor adherence to CPAP is a major obstacle in the treatment of OSAHS. Information-motivation-behavioral (IMB) skills, as a kind of mature technology to change the behavior, has been used in various health areas to improve treatment adherence. This study aims to explore the effects of the IMB skills intervention on CPAP adherence in OSAHS patients. METHODS: Patients who were primary diagnosed with moderate-to-severe OSAHS were randomly divided into the IMB group (n=62) and the control group (n=58). The patients in the IMB group received CPAP therapy and the IMB skills intervention for 4 weeks. The patients in the control group received CPAP therapy and a usual health care provided by a registered nurse. We collected the baseline data of the general information, including age, sex, body mass index (BMI), the Epworth Sleepiness Scale (ESS) score, the Hospital Anxiety and Depression Scale (HADS) score, and indicators about disease severity [apnea-hypopnea index (AHI), percentage of time with arterial oxygen saturation SaO2<90% (T90), average SaO2, lowest SaO2, arousal index]. After CPAP titration, we collected CPAP therapy-relevant parameters (optimal pressure, maximum leakage, average leakage, 95% leakage, and residual AHI), score of satisfaction and acceptance of CPAP therapy, and score of willingness to continue CPAP therapy. After 4 weeks treatment, we collected the ESS score, HADS score, CPAP therapy-relevant parameters, effective CPAP therapy time per night, CPAP therapy days within 4 weeks, CPAP adherence rate, score of satisfaction and acceptance of CPAP therapy, and score of willingness to continue CPAP therapy. Visual analog scale (VAS) of 0-5 was used to evaluate the satisfaction and acceptance of IMB intervention measures in the IMB group. RESULTS: There were no significant differences in the baseline level of demographic parameters, ESS score, HADS score, disease severity, and CPAP therapy related parameters between the IMB group and the control group (all P>0.05). There were no significant differences in score of willingness to continue CPAP therapy, as well as score of satisfaction and acceptance of CPAP therapy after CPAP titration between the IMB group and the control group (both P>0.05). After 4 weeks treatment, the ESS score, HADS score, maximum leakage, average leakage, and 95% leakage of the IMB group were significantly decreased, while the score of satisfaction and acceptance of CPAP therapy and willingness to continue CPAP therapy of the IMB group were significantly increased (all P<0.05); while the above indexes in the control group were not different before and after 4 weeks treatment (all P<0.05). Compared with the control group, the ESS score, HADS score, maximum leakage, average leakage, and 95% leakage of the IMB group after 4 weeks treatment were significantly lower (all P<0.05); the effective CPAP therapy time, CPAP therapy days within 4 weeks, score of satisfaction and acceptance of CPAP therapy, score of willingness to continue CPAP therapy of the IMB group were significantly higher (all P<0.05). The rate of CPAP therapy adherence in 4 weeks of the IMB group was significantly higher than that of the control group (90.3% vs 62.1%, P<0.05). The VAS of overall satisfaction with IMB skills intervention measures was 4.46±0.35. CONCLUSIONS: IMB skills intervention measures can effectively improve the adherence of CPAP therapy in OSAHS patients, and is suitable for clinical promotion.

HRD1-mediated ubiquitination of HDAC2 regulates PPARα-mediated autophagy and alleviates metabolic-associated fatty liver disease.

BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease worldwide. Autophagy plays a pivotal role in lipid metabolism; however, the mechanism underlying the reduced autophagic activity in MAFLD remains elusive. METHODS: Autophagy was monitored by TUNEL assay and immunofluorescence staining of LC3. The expression of autophagy-related proteins, PPARα, HDAC2, and HRD1 was detected by Western blot. The association between HDAC2 and PPARα promoter was assessed by chromatin immunoprecipitation (ChIP) and dual-luciferase assays, and the HRD1-mediated ubiquitin-proteasomal degradation of HDAC2 was detected by co-immunoprecipitation (co-IP). The in vitro findings were validated in a hypoxia-induced MAFLD mouse model. Histological changes, fibrosis, and apoptosis in liver tissues were detected by hematoxylin and eosin staining, Masson's trichrome staining, and TUNEL assay. The immunoreactivities of key molecules were examined by IHC analysis. RESULTS: Hypoxia-suppressed autophagy in hepatocytes. Hypoxic exposure downregulated HRD1 and PPARα, while upregulating HDAC2 in hepatocytes. Overexpression of PPARα promoted hepatic autophagy, while knocking down HDAC2 or overexpressing HRD1 reduced hypoxia-suppressed autophagy in hepatocytes. Mechanistically, HDAC2 acted as a transcriptional repressor of PPARα, and HRD1 mediated the degradation of HDAC2 through the ubiquitin-proteasome pathway. Functional studies further showed that hypoxia-suppressed hepatic autophagy via the HRD1/HDAC2/PPARα axis in vitro and in vivo. CONCLUSION: HRD1-mediated ubiquitination of HDAC2 regulates PPARα-mediated autophagy and ameliorates hypoxia-induced MAFLD.

CX3CL1 represses autophagy via CX3CR1/ CaMKIIδ/HDAC4/Rubicon axis and exacerbates chronic intermittent hypoxia induced Kupffer cell apoptosis.

BACKGROUND: Nocturnal hypoxemia is an established factor in the pathogenesis and exacerbation of term metabolic (dysfunction) associated fatty liver disease (MAFLD). Kupffer cells (KCs) are resident macrophages in the liver, and their activity is closely related to the progress of MAFLD. KC insufficient autophagy is involved in MAFLD pathogenesis. Herein, the regulatory mechanism of KC autophagy under chronic intermittent hypoxia (CIH) condition was investigated. METHODS: Primary KCs and hepatic stellate cells (HSCs) were isolated from mouse liver. Immunofluorescence was employed to detect immunofluorescence intensity of LC3 protein and HDAC4 distribution. KC apoptosis was measured by TUNEL staining. Dual-luciferase reporter and ChIP assays were performed to analyze the interactions between HDAC4, MEF2C and RUBCN. RESULTS: Herein, our results revealed that CIH-induced increased CX3CL1 in HSCs inhibited KC autophagy and promoted cell apoptosis by interacting with CX3CR1. Meanwhile, CX3CL1 treatment inhibited KC autophagy (p < 0.001, fold change: 0.059) and promoted cell apoptosis (p < 0.001, fold change: 8.18). Rubicon knockdown promoted KC autophagy (p < 0.001, fold change: 2.90) and inhibited cell apoptosis (p < 0.05, fold change: 0.23), while these effects were reversed by CX3CL1 treatment (p < 0.01, fold change: 6.59; p < 0.001, fold change: 0.35). Our mechanistic experiments demonstrated that HDAC4 overexpression transcriptionally inhibited RUBCN expression by interacting with MEF2C, thereby promoting KC autophagy and inhibiting cell apoptosis. Moreover, CaMKIIδ inhibition promoted the translocation of HDAC4 from the cytosol to the nucleus to promote KC autophagy and inhibit the apoptosis. CONCLUSION: Taken together, CIH-induced increased CX3CL1 expression in HSCs inhibited KC autophagy and promoted apoptosis by regulating the CX3CR1/ CaMKIIδ/HDAC4/Rubicon axis.