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Kudo J, Hirono H, Ohkoshi S. Low-frequency, mild-gradient chronic intermittent hypoxia still induces liver fibrogenesis in mice on a high-fat diet. Biochem Biophys Res Commun 2025; 761:151744. [PMID: 40184789 DOI: 10.1016/j.bbrc.2025.151744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/03/2025] [Accepted: 03/31/2025] [Indexed: 04/07/2025]
Abstract
The fibrogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) may progress when complicated by obstructive sleep apnea (OSA). Studies using animal models have shown that high-frequency intermittent hypoxia (IH) exposure, which resembles human OSA, accelerates liver fibrosis in fatty liver. This study highlights that low-frequency, mild-gradient intermittent hypoxia (IH) can exacerbate fibrogenesis in fatty liver disease, even without significantly raising markers of liver injury or insulin resistance. Using a mice model on a high-fat diet (HFD), we found that while routine liver tests (e.g., ALT, AST) and cholesterol levels remained comparable between HFD mice exposed to room air (RA) versus those exposed to chronic intermittent hypoxia (CIH), indicators of liver fibrosis and oxidative stress were elevated in the latter group. This suggests that even low-frequency, mild-gradient IH can increase oxidative stress and fibrotic activity within the liver, primarily through the upregulation of specific markers like ICAM-1 and osteopontin (OPN), which may play a role CIH-induced liver inflammation and fibrosis in fatty liver. In conclusion. Our study further notes that these hypoxia-related changes occurred without significantly worsening systemic insulin resistance, focusing attention on localized liver impacts rather than global metabolic disruptions. The findings underscore the potential role of oxidative stress and specific cytokines in the progression of liver fibrosis in MASLD, especially when complicated by conditions that introduce IH.
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Affiliation(s)
- Junpei Kudo
- Clinical Examination, Graduate School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan
| | - Haruka Hirono
- Clinical Examination, Graduate School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan
| | - Shogo Ohkoshi
- Clinical Examination, Graduate School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan.
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Zhang H, Lei S, Zhuo H, Xu Y, Ye Y, Luo Y. TRIM24 Up-Regulates ORM2 to Alleviate Abnormal Lipid Metabolism, Inflammation, and Oxidative Stress in Mice with Obstructive Sleep Apnea Syndrome and Metabolic Dysfunction-Associated Steatotic Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:2091-2105. [PMID: 39168366 DOI: 10.1016/j.ajpath.2024.07.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 06/29/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024]
Abstract
Obstructive sleep apnea syndrome (OSAS) is associated with the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Tripartite motif containing 24 (TRIM24) deficiency causes hepatic lipid accumulation and hepatitis. However, the expression, function, and mechanism of TRIM24 in OSAS and MASLD remain unclear. Herein, an OSAS and MASLD mouse model was established by intermittent hypoxia (IH) and high-fat diet. IH- and 1% free fatty acid-induced mouse liver cells served as an in vitro model. TRIM24 and HIF1A were up-regulated under the IH condition. HIF1A enhanced the transcriptional activity of TRIM24. Overexpression of TRIM24 reduced hepatic lipid accumulation, decreased serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and increased serum levels of high-density lipoprotein cholesterol in OSAS and MASLD mice. Additionally, overexpression of TRIM24 alleviated inflammation and oxidative stress, and modulated aberrant lipid metabolism. Mechanically, TRIM24 up-regulated the expression of ORM2, a key regulator of hepatic lipogenesis, by binding to H3K27ac and recruiting retinoic acid receptor-α to ORM2 promoter. The cell rescue model was used to verify that ORM2 mediated the hepatoprotective effects of TRIM24. The current study reveals the important role of TRIM24 as an epigenetic coregulator of transcription in OSAS and MASLD, providing additional insights into understanding the pathogenesis and preventing the development of OSAS and MASLD.
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Affiliation(s)
- Hui Zhang
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Si Lei
- Department of General Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hui Zhuo
- Department of General Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yan Xu
- Department of General Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yun Ye
- Department of General Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yingquan Luo
- Department of General Medicine, The Second Xiangya Hospital of Central South University, Changsha, China.
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Zhao ZW, Huang WS, Li L, Chen LD, Lin L, Zeng HX. Association between sleep apnea and ultrasound-defined liver fibrosis: Results from NHANES 2017 to 2020. Medicine (Baltimore) 2024; 103:e37949. [PMID: 38669359 PMCID: PMC11049750 DOI: 10.1097/md.0000000000037949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Liver fibrosis is a critical factor in the advancement of nonalcoholic fatty liver disease towards cirrhosis. There is limited research exploring the association between obstructive sleep apnea (OSA) and liver fibrosis among community populations. The present study aimed to assess the association between sleep apnea (SA) and liver fibrosis based on the National Health and Nutrition Examination Survey (NHANES). Data were acquired from NHANES survey cycle 2017 to 2020. We assessed liver fibrosis by the median values of liver stiffness measurement (LSM). The diagnosis of SA was based on participants' response to sleep questionnaire. Univariate and multivariate logistic regression were used to validate the association of SA and liver fibrosis. A total of 7615 participants were included in this study. The LSM level of SA group was significantly higher than non-SA group. The proportion of liver fibrosis in SA group was markedly higher than that in non-SA group (14.0% vs 7.3%, P < .001). Univariate logistic analysis showed that SA was positively associated with liver fibrosis (OR = 2.068, 95%CI = 1.715-2.494, P < .001). Further multivariate logistic analysis revealed that SA was independently associated with increased risk of liver fibrosis after adjusting for confounding factors (OR = 1.277, 95%CI = 1.003-1.625, P = .048). The current study demonstrated an independent association between self-reported SA and increased risk of ultrasound-defined liver fibrosis in community-based sample.
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Affiliation(s)
- Zhi-Wei Zhao
- Department of Otolaryngology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China
| | - Wen-Sen Huang
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China
| | - Ling Li
- Department of Ultrasound, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China
| | - Li-Da Chen
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China
| | - Li Lin
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China
| | - Hui-Xue Zeng
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China
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Yang L, He Y, Liu S, Gan L, Ni Q, Dai A, Mu C, Liu Q, Chen H, Lu H, Sun R. Adipocyte-derived exosomes from obstructive sleep apnoea rats aggravate MASLD by TCONS_00039830/miR-455-3p/Smad2 axis. Commun Biol 2024; 7:492. [PMID: 38654054 PMCID: PMC11039760 DOI: 10.1038/s42003-024-06171-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 04/10/2024] [Indexed: 04/25/2024] Open
Abstract
A correlation exists between obstructive sleep apnoea (OSA) and the severity of metabolic dysfunction-associated steatotic liver disease (MASLD), OSA can induce more severe MASLD. However, the underlying regulatory mechanism between the two is unclear. To this end, this study explored the role and possible molecular mechanisms of adipocyte-derived exosomes under OSA in aggravating MASLD. Through sequencing technology, miR-455-3p was identified as a co-differentially expressed miRNA between the MASLD + OSA and Control groups and between the MASLD + OSA and MASLD groups. Upregulation of TCONS-00039830 and Smad2 and downregulation of miR-455-3p in the MASLD and MASLD + OSA groups were validated in vivo and in vitro. TCONS-00039830, as a differentially expressed LncRNA in exosomes found in the sequencing results, transfection notably downregulated miR-455-3p and upregulated Smad2 in hepatocytes. TCONS_00039830 overexpression increased fat, triglyceride and cholesterol levels, while miR-455-3p overexpression decreased these levels. Furthermore, exosome administration promoted the accumulation of fat, triglyceride and cholesterol, upregulated TCONS_00039830 and Smad2, and downregulated miR-455-3p. Overexpression of miR-455-3p reversed the increased fat accumulation and upregulated TCONS_00039830 and Smad2. In conclusion, OSA-derived exosomes promoted hepatocyte steatosis by regulating TCONS_00039830/miR-455-3p/Smad2 axis, thereby aggravating liver damage in MASLD.
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Affiliation(s)
- Li Yang
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China.
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China.
| | - Yan He
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Shijie Liu
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Lulu Gan
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Qing Ni
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Anni Dai
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Changhuan Mu
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Qian Liu
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Hongyan Chen
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Hongying Lu
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
| | - Ruixue Sun
- Hypertension Center, Yan 'an Hospital of Kunming, Kunming, China
- Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming, China
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Read N, Jennings C, Hare A. Obstructive sleep apnoea-hypopnoea syndrome. Emerg Top Life Sci 2023; 7:467-476. [PMID: 38130167 DOI: 10.1042/etls20180939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/25/2023] [Accepted: 11/18/2023] [Indexed: 12/23/2023]
Abstract
Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is a common disorder characterised by repetitive episodes of the complete or partial collapse of the pharyngeal airway during sleep. This results in cessation (apnoea) or reduction (hypopnoea) of airflow, leading to oxygen desaturation and sleep fragmentation. An individual's disposition to develop OSAHS depends on the collapsibility of a segment of the upper airway. The degree of collapsibility can be quantified by the balance between occluding or extraluminal pressures of the surrounding tissues. Patients can experience snoring, unrefreshing sleep, witnessed apnoeas, waking with a choking sensation and excessive daytime sleepiness. OSAHS has a broad range of consequences, including cardiovascular, metabolic, and neurocognitive sequelae. Treatment options include lifestyle measures, in particular weight loss, and strategies to maintain upper airway patency overnight, including continuous positive airway pressure, mandibular advancement devices and positional modifiers.
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Affiliation(s)
- Nicola Read
- Royal Brompton Hospital, Kings Health Partnership, London, U.K
| | - Callum Jennings
- Royal Brompton Hospital, Kings Health Partnership, London, U.K
| | - Alanna Hare
- Royal Brompton Hospital, Kings Health Partnership, London, U.K
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Ji Y, Liang Y, Chu PH, Ge M, Yeung SC, Ip MSM, Mak JCW. The effects of intermittent hypoxia on hepatic expression of fatty acid translocase CD36 in lean and diet-induced obese mice. Biomed J 2023; 46:100566. [PMID: 36244649 PMCID: PMC10498409 DOI: 10.1016/j.bj.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 09/01/2022] [Accepted: 10/11/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Both obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) are prevalent within obese individuals. We aimed to investigate the effects of intermittent hypoxia (IH), a clinical feature of OSA, on hepatic expression of fatty acid translocase (CD36) in relation to liver injury in lean and diet-induced obese mice. METHODS Four-week-old male C57BL/6J mice were randomized to standard diet (SD) or high fat (HF) diet groups. At 13-week-old, all mice were exposed to either air or IH (IH30; thirty hypoxic episodes per hour) for four weeks. We assessed liver injury through lipid profile, oxidative and inflammatory stress, histological scoring and hepatic CD36 expression. RESULTS In lean mice, IH elevated serum and hepatic triglyceride and free fatty acid (FFA) levels, in line with upregulation of hepatic CD36 expression and myeloperoxidase (MPO)-positive cells in support of inflammatory infiltrates along with increase in serum malondialdehyde (MDA), C-X-C motif chemokine ligand 1(CXCL-1) and monocyte chemoattractant protein-1 (MCP-1). In diet-induced obese mice, an increase in hepatic alanine transaminase (ALT) activity, serum and hepatic levels of lipid parameters and inflammatory markers, serum MDA level, hepatic expressions of CD36 and α-smooth muscle actin (α-SMA), and MPO-positive cells was observed. IH potentiated hepatic ALT activity, serum CXCL-1 and hepatic interleukin-6 (IL-6), in line with inflammatory infiltrates, but paradoxically, reduced hepatic FFA level and hepatic CD36 expression, compared to obese mice without IH exposure. However, IH further augmented diet-induced liver steatosis and fibrosis as shown by histological scores. CONCLUSION This study contributes to support that IH featuring OSA may lead to liver injury via differential regulation of hepatic CD36 expression in lean and diet-induced obese mice.
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Affiliation(s)
- Yang Ji
- Respiratory Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yingmin Liang
- Respiratory Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Pak Hin Chu
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Mengqin Ge
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Sze Chun Yeung
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Mary Sau Man Ip
- Respiratory Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Judith Choi Wo Mak
- Respiratory Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong SAR, China.
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Zhang B, Lu S, Guo H, Xu J, Zhang X, Zhao H, Tang J. The effect of obstructive sleep apnea on fatty liver disease may be obscured by alcohol consumption: An ordinal logistic regression analysis. Sleep Med 2023; 109:82-89. [PMID: 37423023 DOI: 10.1016/j.sleep.2023.06.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/10/2023] [Accepted: 06/27/2023] [Indexed: 07/11/2023]
Abstract
BACKGROUND Obstructive sleep apnea (OSA) is closely associated with non-alcoholic fatty liver disease (NAFLD). The current definition of NAFLD cannot exclude the involvement of alcohol consumption in the development of fatty liver disease (FLD), but alcohol can aggravate OSA and participate in steatosis. There is limited evidence on the relationship between OSA and alcohol and its effect on FLD severity. OBJECTIVE To determine the effect of OSA on FLD severity based on ordinal responses, and its relationship with alcohol consumption, in order to develop strategies for the prevention and treatment of FLD. METHODS Patients with chief complaints of "snoring" who underwent polysomnography and abdominal ultrasound between January 2015 and October 2022 were selected. A total of 325 cases were divided into three groups according to abdominal ultrasound results: no FLD (n = 66), mild FLD (n = 116), and moderately severe FLD (n = 143) group. Patients were also categorized into alcoholic and nonalcoholic groups. Univariate analysis was used to examine the correlation between OSA and FLD severity. Multivariate ordinal logistic regression analysis was further used to identify the determinants of FLD severity and differences between the alcoholic and nonalcoholic groups. RESULTS A higher proportion of moderately severe FLD was observed in the group with an apnea/hypopnea index (AHI) > 30 compared to the AHI<15 group in all participants and in the nonalcoholic population (all p < 0.05). There was no significant difference among these groups in the alcoholic population. Ordinal logistic regression analysis found that in all participants, age [OR = 0.966(0.947-0.986)], BMI [OR = 1.293 (1.205-1.394)], diabetes mellitus [OR = 1.932(1.132-3.343)], hyperlipidemia [OR = 2.432(1.355-4.464)], severe OSA [OR = 2.36(1.315-4.259)] (all p < 0.05) were the independent risk factors for more severe FLD. However, different risk factors applied according to alcohol consumption. In addition to age and BMI, the independent risk factors for the alcoholic group also included diabetes mellitus [OR = 3.323(1.494-7.834)] while in the non-alcoholic group risk factors included hyperlipidemia [OR = 4.094(1.639-11.137)], and severe OSA[OR = 2.956(1.334-6.664)] (all p < 0.05). CONCLUSION Severe OSA is an independent determinant for developing more severe NAFLD in nonalcoholic population, and alcohol consumption may obscure the effect of OSA on the progression of FLD.
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Affiliation(s)
- Baokun Zhang
- Department of Neurology, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shanshan Lu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, China
| | - Huiying Guo
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, China
| | - Juanjuan Xu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, China
| | - Xiao Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, China
| | - Hongyao Zhao
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, China
| | - Jiyou Tang
- Department of Neurology, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Department of Neurology, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, China.
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Badal BD, Bajaj JS. Whoop there it is: decoding sleep, cirrhosis, and HE. Hepatol Commun 2023; 7:e0071. [PMID: 36790341 PMCID: PMC9931030 DOI: 10.1097/hc9.0000000000000071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 11/28/2022] [Indexed: 02/16/2023] Open
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Huang X, Huang X, Guo H, Li J, Zhou C, Huang Y, Lai C, Zeng W, Tan X, Niu L, Li H, Qi J, Xie C. Intermittent hypoxia-induced METTL3 downregulation facilitates MGLL-mediated lipolysis of adipocytes in OSAS. Cell Death Dis 2022; 8:352. [PMID: 35933406 PMCID: PMC9357002 DOI: 10.1038/s41420-022-01149-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/21/2022] [Accepted: 07/25/2022] [Indexed: 11/30/2022]
Abstract
Intermittent hypoxia (IH) is the core pathological feature of obstructive sleep apnea syndrome (OSAS), and insulin resistance (IR) is the most common metabolic complication of OSAS. Studies have shown that the levels of free fatty acids (FFAs), which are mainly released from adipocytes by lipolysis, are elevated in OSAS and play an important role in the development of IR. However, whether and how IH regulates adipocyte lipolysis in OSAS is not clear. Here, we revealed that the apnea hypopnea index was positively correlated with the serum levels of FFAs and FFA release from adipocytes in OSAS. In addition, IH facilitated lipolysis and FFA release from adipocytes by downregulating the level of METTL3. METTL3 downregulation impaired N6-methyladenosine (m6A) levels in MGLL mRNA and reduced MGLL expression, thereby promoting lipolysis. In addition, we identified YTHDF2 as the m6A reader that interacts with MGLL mRNA, accelerating its degradation. Furthermore, our data showed reduced levels of METTL3 and elevated levels of MGLL in the adipose tissues of OSAS patients and indicated an effect of METTL3 on lowering FFA levels and improving IR in rats with chronic IH. In conclusion, our study provides new insights into the development and treatment of IR in OSAS.
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Affiliation(s)
- Xiuji Huang
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Xuming Huang
- Department of Thyroid and Vascular Surgery, Maoming People's Hospital, Southern Medical University, Maoming, 525000, P.R. China
| | - Haiyan Guo
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Jin Li
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Chunxia Zhou
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Yuanli Huang
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Chunliu Lai
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Wan Zeng
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Xiaozhen Tan
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Lihong Niu
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China
| | - Hui Li
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China.
| | - Jian Qi
- Department of Gastroenterology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China.
| | - Canmao Xie
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P.R. China.
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Zhang H, Wang Y, Chen C, Wang B, Chen J, Tan X, Xia F, Zhang J, Lu Y, Wang N. Non-alcoholic fatty liver disease, sleep behaviors, and incident type 2 diabetes. J Gastroenterol Hepatol 2022; 37:1633-1640. [PMID: 35499342 DOI: 10.1111/jgh.15877] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/19/2022] [Accepted: 04/24/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Non-alcoholic fatty liver disease (NAFLD) is associated with incident type 2 diabetes; however, the extent to which NAFLD may confer its risk remains uncertain, especially in Europeans. Emerging evidence suggests that sleep behaviors are linked to NAFLD and diabetes. We aimed to measure whether sleep behaviors modified the association between NAFLD and incident type 2 diabetes. METHODS This prospective cohort study included 365 339 participants without type 2 diabetes at baseline in UK Biobank data. Five sleep behaviors, including sleep duration, insomnia, snoring, chronotype, and daytime sleepiness, were collected from the questionnaire. Overall sleep patterns were created by summing the five scores. Liver steatosis was based on the fatty liver index. RESULTS During a median follow up of 11.0 years, we documented 8774 patients with incident type 2 diabetes. NAFLD was significantly associated with increased diabetes risk. Sleeping 7-8 h/day, no insomnia, no self-reported snoring, and no frequent daytime sleepiness were independently associated with incident type 2 diabetes, with a 20%, 18%, 16%, and 31% lower risk, respectively. About 33.8% and 33.5% of type 2 diabetes events in this cohort could be attributed to NAFLD and poor sleep pattern, respectively. Participants with NAFLD and poor sleep pattern showed the highest risk of type 2 diabetes (relative risk 3.17, 95% confidence interval 2.80, 3.59). Sleep pattern (healthy, intermediate, and poor) did not significantly modify the association between NAFLD and type 2 diabetes. However, when studying separately, we found a significant interaction between NAFLD and insomnia on the risk of incident type 2 diabetes (P for interaction = 0.003). CONCLUSION In this large prospective study, both NAFLD and some sleep behaviors were risk factors for type 2 diabetes. Although overall sleep pattern did not modify the association between NAFLD and type 2 diabetes, certain sleep behavior, especially insomnia, showed the modification effect.
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Affiliation(s)
- Haojie Zhang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yuying Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Chi Chen
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Bin Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jie Chen
- Sleep Assessment Unit, Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiao Tan
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
- Department of Clinical Neuroscience, Karolinska Institute, Solna, Sweden
| | - Fangzhen Xia
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jihui Zhang
- Guangdong Mental Health Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yingli Lu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Ningjian Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
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11
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T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms222212190. [PMID: 34830072 PMCID: PMC8623596 DOI: 10.3390/ijms222212190] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/06/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.
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12
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Qin Y, Li B, Arumugam S, Lu Q, Mankash SM, Li J, Sun B, Li J, Flavell RA, Li HB, Ouyang X. m 6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity. Cell Rep 2021; 37:109968. [PMID: 34758326 PMCID: PMC8667589 DOI: 10.1016/j.celrep.2021.109968] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 08/02/2021] [Accepted: 10/19/2021] [Indexed: 12/23/2022] Open
Abstract
N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism, but its role in innate immunity-driven non-alcoholic fatty liver disease (NAFLD) and obesity is not known. Here, we show that myeloid lineage-restricted deletion of the m6A "writer" protein Methyltransferase Like 3 (METTL3) prevents age-related and diet-induced development of NAFLD and obesity in mice with improved inflammatory and metabolic phenotypes. Mechanistically, loss of METTL3 results in the differential expression of multiple mRNA transcripts marked with m6A, with a notable increase of DNA Damage Inducible Transcript 4 (DDIT4) mRNA level. In METTL3-deficient macrophages, there is a significant downregulation of mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4. Taken together, our findings identify the contribution of METTL3-mediated m6A modification of Ddit4 mRNA to macrophage metabolic reprogramming in NAFLD and obesity.
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Affiliation(s)
- Yanqin Qin
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA; Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China
| | - Binghua Li
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China
| | - Suyavaran Arumugam
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Qiuxia Lu
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Salah M Mankash
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Junzi Li
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA; Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China
| | - Jiansheng Li
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
| | - Hua-Bing Li
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Xinshou Ouyang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
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13
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Carotenuto M, Di Sessa A, Esposito M, Grandone A, Marzuillo P, Bitetti I, Umano GR, Precenzano F, Miraglia del Giudice E, Santoro N. Association between Hepatic Steatosis and Obstructive Sleep Apnea in Children and Adolescents with Obesity. CHILDREN (BASEL, SWITZERLAND) 2021; 8:984. [PMID: 34828697 PMCID: PMC8624374 DOI: 10.3390/children8110984] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 04/09/2023]
Abstract
BACKGROUND Owing to the increasing rate of pediatric obesity, its complications such as non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) have become prevalent already in childhood. We aimed to assess the relationship between these two diseases in a cohort of children with obesity. METHODS We enrolled 153 children with obesity (mean age 10.5 ± 2.66, mean BMI 30.9 ± 5.1) showing OSA. Subjects underwent a laboratory evaluation, a cardio-respiratory polysomnography (PSG), and a liver ultrasound. RESULTS All subjects had a clinical diagnosis of OSA based on the AHI > 1/h (mean AHI 8.0 ± 5.9; range 2.21-19.0). Of these, 69 showed hepatic steatosis (62.3% as mild, 20.3% as moderate, and 17.4% as severe degree). A strong association between ALT and apnea/hypopnea index (AHI) was observed (p = 0.0003). This association was not confirmed after adjusting for hepatic steatosis (p = 0.53). By subdividing our population according to the presence/absence of steatosis, this association was found only in the steatosis group (p = 0.009). As the severity of steatosis increased, the significance of its association with AHI compared to the absence of steatosis became progressively stronger (all p < 0.0001). CONCLUSIONS Hepatic steatosis seems to drive the association between OSA and ALT levels, suggesting a potential pathogenic role of OSA in NAFLD.
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Affiliation(s)
- Marco Carotenuto
- Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy; (M.C.); (M.E.); (I.B.); (F.P.)
| | - Anna Di Sessa
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.G.); (P.M.); (G.R.U.); (E.M.d.G.)
| | - Maria Esposito
- Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy; (M.C.); (M.E.); (I.B.); (F.P.)
| | - Anna Grandone
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.G.); (P.M.); (G.R.U.); (E.M.d.G.)
| | - Pierluigi Marzuillo
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.G.); (P.M.); (G.R.U.); (E.M.d.G.)
| | - Ilaria Bitetti
- Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy; (M.C.); (M.E.); (I.B.); (F.P.)
| | - Giuseppina Rosaria Umano
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.G.); (P.M.); (G.R.U.); (E.M.d.G.)
| | - Francesco Precenzano
- Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy; (M.C.); (M.E.); (I.B.); (F.P.)
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.G.); (P.M.); (G.R.U.); (E.M.d.G.)
| | - Nicola Santoro
- Department of Pediatrics, Yale University, New Haven, CT 06510, USA;
- Department of Medicine and Health Sciences, “V.Tiberio” University of Molise, 86100 Campobasso, Italy
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14
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Lopez-Pascual A, Trayhurn P, Martínez JA, González-Muniesa P. Oxygen in Metabolic Dysfunction and Its Therapeutic Relevance. Antioxid Redox Signal 2021; 35:642-687. [PMID: 34036800 DOI: 10.1089/ars.2019.7901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Significance: In recent years, a number of studies have shown altered oxygen partial pressure at a tissue level in metabolic disorders, and some researchers have considered oxygen to be a (macro) nutrient. Oxygen availability may be compromised in obesity and several other metabolism-related pathological conditions, including sleep apnea-hypopnea syndrome, the metabolic syndrome (which is a set of conditions), type 2 diabetes, cardiovascular disease, and cancer. Recent Advances: Strategies designed to reduce adiposity and its accompanying disorders have been mainly centered on nutritional interventions and physical activity programs. However, novel therapies are needed since these approaches have not been sufficient to counteract the worldwide increasing rates of metabolic disorders. In this regard, intermittent hypoxia training and hyperoxia could be potential treatments through oxygen-related adaptations. Moreover, living at a high altitude may have a protective effect against the development of abnormal metabolic conditions. In addition, oxygen delivery systems may be of therapeutic value for supplying the tissue-specific oxygen requirements. Critical Issues: Precise in vivo methods to measure oxygenation are vital to disentangle some of the controversies related to this research area. Further, it is evident that there is a growing need for novel in vitro models to study the potential pathways involved in metabolic dysfunction to find appropriate therapeutic targets. Future Directions: Based on the existing evidence, it is suggested that oxygen availability has a key role in obesity and its related comorbidities. Oxygen should be considered in relation to potential therapeutic strategies in the treatment and prevention of metabolic disorders. Antioxid. Redox Signal. 35, 642-687.
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Affiliation(s)
- Amaya Lopez-Pascual
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Neuroendocrine Cell Biology, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Paul Trayhurn
- Obesity Biology Unit, University of Liverpool, Liverpool, United Kingdom.,Clore Laboratory, The University of Buckingham, Buckingham, United Kingdom
| | - J Alfredo Martínez
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.,CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, ISCIII, Madrid, Spain.,Precision Nutrition and Cardiometabolic Health, IMDEA Food, Madrid Institute for Advanced Studies, Madrid, Spain
| | - Pedro González-Muniesa
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.,CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, ISCIII, Madrid, Spain
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15
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Bhatt SP, Guleria R. Association of IRS1 (Gly972Arg) and IRS2 (Gly1057Asp) genes polymorphisms with OSA and NAFLD in Asian Indians. PLoS One 2021; 16:e0245408. [PMID: 34449768 PMCID: PMC8396739 DOI: 10.1371/journal.pone.0245408] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 07/31/2021] [Indexed: 12/12/2022] Open
Abstract
AIM AND OBJECTIVE The aim of the study was to investigate the relationships between insulin receptor substrate (IRS) 1 (Gly972Arg) and IRS2 (Gly1057Asp) genes with obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in Asian Indians. METHOD A total of 410 overweight/obese subjects (130 with OSA with NAFLD, 100 with OSA without NAFLD, 95 without OSA and with NAFLD and 85 without OSA and without NAFLD) were recruited. Degree of NAFLD was based on liver ultrasound and of OSA on overnight polysomnography. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by gene sequencing. RESULT Mean values of blood pressure, body fat markers, blood glucose, lipids, liver function, and markers of insulin resistance were significantly increased in OSA and NAFLD subjects (p<0.05). In addition, according to age (years) categories, blood pressure, blood glucose, lipids, obesity markers, and markers of insulin resistance were significantly higher in 45-60 years group as compared to 20-45 years group (p<0.05). In IRS1 gene, the genotype frequency (%) of Arg/Arg was significantly higher in NAFLD and OSA subjects. In addition, Gly/Arg genotype of IRS1 gene was associated with significantly higher body mass index, fat mass, %body fat, triglycerides, cholesterol, alkaline phosphate, aspartate transaminase, fasting insulin and HOMA-IR levels in OSA and NAFLD subjects. No significant difference in genotype frequencies of IRS2 was observed between four groups. Further we found that subjects carrying IRS1 Gly/Arg (OR 4.49, 95% C.I. 1.06-12.52, p = 0.002) genotype possess a much higher risk of OSA and NAFLD compared to IRS2 Gly/Asp (OR 1.01, 95% C.I. 0.8-2.56, p = 0.05). In sub group analysis of IRS1 Gly/Arg have significant differences between the mild, moderate and severe group (P<0.05). In addition, patients with the 'Gly' allele were inclined to develop more severe OSA. CONCLUSION We concluded that Asian Indian subject carrying the allele Gly972Arg polymorphism of IRS1 is predisposed to develop OSA and NAFLD.
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Affiliation(s)
- Surya Prakash Bhatt
- Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
- * E-mail:
| | - Randeep Guleria
- Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
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16
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Chen LD, Huang ZW, Huang YZ, Huang JF, Zhang ZP, Lin XJ. Untargeted Metabolomic Profiling of Liver in a Chronic Intermittent Hypoxia Mouse Model. Front Physiol 2021; 12:701035. [PMID: 34305653 PMCID: PMC8298499 DOI: 10.3389/fphys.2021.701035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/14/2021] [Indexed: 12/13/2022] Open
Abstract
Obstructive sleep apnea (OSA) has been demonstrated to be associated with liver injury. Nevertheless, the mechanisms linking the two disorders remain largely unexplored to date. Based on UHPLC/Q-TOF MS platform, the present study aimed to study the hepatic metabolomic profiling in a chronic intermittent hypoxia (CIH) mouse model to identify altered metabolites and related metabolic pathways. C57BL/6 Mice (n = 12 each group) were exposed to intermittent hypoxia or control conditions (room air) for 12 weeks. At the end of the exposure, liver enzymes and histological changes were assessed. Untargeted metabolomics approach by UHPLC/Q-TOF MS and orthogonal partial least squares-discriminant analysis (OPLS-DA) were applied to screen altered metabolites in mice liver. Bioinformatics analyses were applied to identify the related metabolic pathways. CIH treatment caused a remarkable liver injury in mice. A total of 27 differential metabolites in negative ion mode and 44 in positive ion mode were identified between the two groups. These metabolites were correlated to multiple biological and metabolic processes, including various amino acid metabolism, membrane transport, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, ferroptosis, etc. three differential metabolites including glutathione, glutathione disulfide, arachidonic acid (peroxide free) were identified in the ferroptosis pathway. CIH was associated with a significant metabolic profiling change in mice liver. The metabolites in amino acid metabolism, membrane transport, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and ferroptosis played an important role in CIH-induced liver injury. These findings contribute to a better understanding of the mechanisms linking OSA and liver injury and help identify potential therapeutic targets.
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Affiliation(s)
- Li-Da Chen
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Zhi-Wei Huang
- Department of Otolaryngology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China
| | - Yu-Zhen Huang
- Department of Pathology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Jie-Feng Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Zhong-Ping Zhang
- Department of Pathology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Xue-Jun Lin
- Department of Laboratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
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17
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Kim LJ, Pham LV, Polotsky VY. Sleep Apnea, Hypoxia Inducible Factor, and Fatty Liver: More Questions than Answers? Am J Respir Cell Mol Biol 2021; 65:337-338. [PMID: 34101539 PMCID: PMC8525207 DOI: 10.1165/rcmb.2021-0204ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Lenise J Kim
- Johns Hopkins Medicine, 1501, Pulmonary and Critical Care Medicine, Baltimore, Maryland, United States
| | - Luu V Pham
- Johns Hopkins Medicine School of Medicine, 1500, Pulmonary and Critical Care Medicine, Baltimore, Maryland, United States
| | - Vsevolod Y Polotsky
- Johns Hopkins University, 1466, Pulmonary and Critical Care Medicine, Baltimore, Maryland, United States;
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18
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Ng SSS, Wong VWS, Wong GLH, Chu WCW, Chan TO, To KW, Ko FWS, Chan KP, Hui DS. Continuous Positive Airway Pressure Does Not Improve Nonalcoholic Fatty Liver Disease in Patients with Obstructive Sleep Apnea. A Randomized Clinical Trial. Am J Respir Crit Care Med 2021; 203:493-501. [PMID: 32926803 DOI: 10.1164/rccm.202005-1868oc] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Rationale: Obstructive sleep apnea (OSA) is associated with development of nonalcoholic fatty liver disease (NAFLD). The effects of continuous positive airway pressure (CPAP) on NAFLD in patients with concomitant OSA are unknown.Objectives: To investigate the effects of autoadjusting CPAP versus subtherapeutic CPAP treatment over 6 months on NAFLD activities.Methods: Patients with NAFLD and OSA, as defined by respiratory event index ≥5/h diagnosed by a validated level 3 Embletta device, were randomized into group A) autoadjusting CPAP (4-20 cm H2O) or group B) subtherapeutic CPAP (pressure fixed at 4 cm H2O). The primary endpoint was the difference in changes in intrahepatic triglyceride as measured by proton magnetic resonance spectroscopy after 6 months of therapy. Key secondary endpoints included changes in controlled attenuation parameter (CAP) and liver stiffness measurement measured with transient elastography, and serum cytokeratin-18 fragment.Measurements and Main Results: A total of 120 patients were randomized equally into two groups. There were significant correlations between CAP and respiratory event index (r = 0.203, P = 0.026), percentage of total recording time with SaO2 < 90% (r = 0.265, P = 0.003), and oxygen desaturation index (r = 0.214, P = 0.019). After 6 months of treatment, there were no significant differences of changes in primary and secondary endpoints between the two treatment groups. Regression analysis showed that weight change over 6 months correlated with changes in both intrahepatic triglyceride and CAP (P < 0.001).Conclusions: Despite significant correlations between hepatic steatosis and markers of severity of OSA, CPAP alone did not improve hepatic steatosis and fibrosis. However, the additional role of weight reduction through lifestyle modification deserves further investigation.
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Affiliation(s)
- Susanna S S Ng
- SH Ho Sleep Apnea Management Center, Department of Medicine and Therapeutics
| | | | | | - Winnie C W Chu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Tat-On Chan
- SH Ho Sleep Apnea Management Center, Department of Medicine and Therapeutics
| | - Kin-Wang To
- SH Ho Sleep Apnea Management Center, Department of Medicine and Therapeutics
| | - Fanny W S Ko
- SH Ho Sleep Apnea Management Center, Department of Medicine and Therapeutics
| | - Ka-Pang Chan
- SH Ho Sleep Apnea Management Center, Department of Medicine and Therapeutics
| | - David S Hui
- SH Ho Sleep Apnea Management Center, Department of Medicine and Therapeutics
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19
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Chen LD, Chen MX, Chen GP, Lin XJ, Huang JF, Zeng AM, Huang YP, Lin QC. Association between obstructive sleep apnea and non-alcoholic fatty liver disease in pediatric patients: a meta-analysis. Pediatr Obes 2021; 16:e12718. [PMID: 32881371 DOI: 10.1111/ijpo.12718] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/02/2020] [Accepted: 08/07/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Some studies have reported a relationship between obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in pediatric population. However, this issue remains controversial. OBJECTIVES The purpose of the present study was to investigate the association between OSA and NAFLD in pediatric population. METHODS We systematically searched PubMed, Web of Science, Embase for eligible studies. The data involving markers of NAFLD including alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic inflammation, hepatic fibrosis of both OSA group and control group were extracted. Pooled standardised mean difference (SMD) and weighted mean difference (WMD) were appropriately calculated through a fixed or random-effect model. RESULTS Nine cross-sectional studies with 1133 children and adolescents were included. OSA was significantly associated with ALT, AST, and NAFLD fibrosis stage, but not NAFLD inflammation grade. Subgroup analysis indicated that both mild OSA and severe OSA were significantly associated with elevated ALT and AST. Furthermore, in the studies with all main confounding factors (age, gender, and BMI) matched, OSA group had higher ALT and AST levels than control group. CONCLUSIONS This meta-analysis suggested that OSA was associated with NAFLD evidenced by elevated liver enzymes and progressive hepatic fibrosis in pediatric population. Screening and monitoring of NAFLD in pediatric patients with obesity-related OSA are necessary.
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Affiliation(s)
- Li-Da Chen
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Meng-Xue Chen
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Gong-Ping Chen
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xue-Jun Lin
- Department of Laboratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Jie-Feng Huang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ai-Ming Zeng
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ya-Ping Huang
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Qi-Chang Lin
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Provincial Sleep-disordered Breathing Clinic Center, Fuzhou, China.,Laboratory of Respiratory Disease of the Fujian Medical University, Fuzhou, China
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20
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Chen LD, Wu RH, Huang YZ, Chen MX, Zeng AM, Zhuo GF, Xu FS, Liao R, Lin QC. The role of ferroptosis in chronic intermittent hypoxia-induced liver injury in rats. Sleep Breath 2020; 24:1767-1773. [PMID: 32361960 DOI: 10.1007/s11325-020-02091-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 11/26/2022]
Abstract
PURPOSE Obstructive sleep apnea (OSA) has been related to an increased risk of liver injury. Ferroptosis is a form of programmed cell death implicated in multiple physiological and pathological processes. This study aimed to explore the role of ferroptosis in chronic intermittent hypoxia (CIH)-induced liver injury as well as to uncover the underlying mechanisms using a CIH rat model. METHODS Fourteen male Sprague-Dawley rats were randomly allocated to either the normal control (NC) (n = 7) or the CIH group (n = 7). Rats were exposed to intermittent hypoxia for 8 weeks in CIH group. Liver function, histological changes, and markers of oxidative stress were evaluated. The protein levels of hypoxia-inducible factor-1α, nuclear factor E2-related factor 2 (Nrf2), Acyl-CoA synthetase long-chain family member 4 (ACSL4), and glutathione peroxidase 4 (GPX4) in liver were examined by Western blot analysis. RESULTS CIH treatment caused significant increase of serum alanine aminotransferase, aspartate aminotransferase, and malondialdehyde (MDA). Liver MDA was significantly higher in CIH group than that in NC group. Histology showed that CIH treatment induced discernible swelled, disordered hepatocytes, necrosis, and infiltrated inflammatory cells. CIH treatment significantly reduced the expression of GPX4, while markedly up-regulated expression of ACSL4, indicating elevation in hepatic ferroptosis. In addition, the protein expression of Nrf2 in CIH group was significantly lower than that in NC group. CONCLUSIONS Ferroptosis played a crucial role in CIH-induced liver injury. The hepatic ferroptosis in CIH rat model might be mediated by the dysregulation of Nrf2. This highlights a potential therapeutic target for the treatment of OSA-related liver injury.
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Affiliation(s)
- Li-Da Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, No 20, Chazhong road, Taijiang district, Fuzhou, Fujian Province, 350005, People's Republic of China
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People's Republic of China
| | - Run-Hua Wu
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People's Republic of China
| | - Yu-Zhen Huang
- Department of Pathology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People's Republic of China
| | - Meng-Xue Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, No 20, Chazhong road, Taijiang district, Fuzhou, Fujian Province, 350005, People's Republic of China
| | - Ai-Ming Zeng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, No 20, Chazhong road, Taijiang district, Fuzhou, Fujian Province, 350005, People's Republic of China
| | - Gui-Feng Zhuo
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People's Republic of China
| | - Feng-Sheng Xu
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People's Republic of China
| | - Ran Liao
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People's Republic of China
| | - Qi-Chang Lin
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, No 20, Chazhong road, Taijiang district, Fuzhou, Fujian Province, 350005, People's Republic of China.
- Fujian Provincial Sleep-Disordered Breathing Clinic Center, Fuzhou, Fujian Province, People's Republic of China.
- Laboratory of Respiratory Disease of the Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
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21
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Velarde-Ruiz Velasco J, García-Jiménez E, García-Zermeño K, Morel-Cerda E, Aldana-Ledesma J, Castro-Narro G, Cerpa-Cruz S, Tapia-Calderón D, Mercado-Jauregui L, Contreras-Omaña R. Extrahepatic complications of non-alcoholic fatty liver disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2019. [DOI: 10.1016/j.rgmxen.2019.05.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Velarde-Ruiz Velasco JA, García-Jiménez ES, García-Zermeño KR, Morel-Cerda EC, Aldana-Ledesma JM, Castro-Narro GE, Cerpa-Cruz S, Tapia-Calderón DK, Mercado-Jauregui LA, Contreras-Omaña R. Extrahepatic complications of non-alcoholic fatty liver disease: Its impact beyond the liver. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2019; 84:472-481. [PMID: 31488310 DOI: 10.1016/j.rgmx.2019.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 04/20/2019] [Accepted: 05/02/2019] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently one of the main causes of chronic liver disease in Western countries, with a 25% prevalence reported in the general population worldwide. Visceral adiposity and liver fat promote a state of systemic inflammation, predisposing individuals with NAFLD to the extrahepatic pathologies of cardiovascular disease (the most common cause of death in patients with NAFLD), diabetes mellitus, chronic kidney disease, hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea, and an increased risk for presenting with gastrointestinal and extraintestinal neoplasias. Different mechanisms between NAFLD and its association with extrahepatic diseases have been reported, and lipotoxicity is the main cause of inflammatory pathway activation that results in extrahepatic tissue damage.
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Affiliation(s)
- J A Velarde-Ruiz Velasco
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México.
| | - E S García-Jiménez
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - K R García-Zermeño
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - E C Morel-Cerda
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - J M Aldana-Ledesma
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - S Cerpa-Cruz
- Servicio de Reumatología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - D K Tapia-Calderón
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - L A Mercado-Jauregui
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - R Contreras-Omaña
- Centro de Investigación en Enfermedades Hepáticas y Gastroenterología (CIEHG), Pachuca, Hidalgo, México
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Farabi SS, Barbour LA, Heiss K, Hirsch NM, Dunn E, Hernandez TL. Obstructive Sleep Apnea Is Associated With Altered Glycemic Patterns in Pregnant Women With Obesity. J Clin Endocrinol Metab 2019; 104:2569-2579. [PMID: 30794722 PMCID: PMC6701202 DOI: 10.1210/jc.2019-00159] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 02/19/2019] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Often unrecognized, obstructive sleep apnea (OSA) worsens over pregnancy and is associated with poorer perinatal outcomes. The association between OSA in late pregnancy and metabolic biomarkers remains poorly understood. We tested the hypothesis that OSA in pregnant women with obesity is positively correlated with 24-hour patterns of glycemia and IR despite controlling for diet. DESIGN Pregnant women (32 to 34 weeks' gestation; body mass index, 30 to 40 kg/m2) wore a continuous glucose monitor for 3 days. OSA was measured in-home by WatchPAT 200™ [apnea hypopnea index (AHI), oxygen desaturation index (ODI; number per hour)]. Fasting blood was collected followed by a 2-hour, 75-g, oral glucose tolerance test to measure IR. Association between AHI and 24-hour glucose area under the curve (AUC) was the powered outcome. RESULTS Of 18 women (29.4 ± 1.4 years of age [mean ± SEM]), 12 (67%) had an AHI ≥5 (mild OSA). AHI and ODI were correlated with 24-hour glucose AUC (r = 0.50 to 0.54; P ≤ 0.03) and mean 24-hour glucose (r = 0.55 to 0.59; P ≤ 0.02). AHI and ODI were correlated with estimated hepatic IR (r = 0.59 to 0.74; P < 0.01), fasting free fatty acids (fFFAs; r = 0.53 to 0.56; P < 0.05), and waking cortisol (r = 0.49 to 0.64; P < 0.05). CONCLUSIONS Mild OSA is common in pregnant women with obesity and correlated with increased glycemic profiles, fFFAs, and estimates of hepatic IR. OSA is a potentially treatable target to optimize maternal glycemia and metabolism, fetal fuel supply, and pregnancy outcomes.
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Affiliation(s)
- Sarah S Farabi
- Office of Nursing Research, Goldfarb School of Nursing, St. Louis, Missouri
- Correspondence and Reprint Requests: Sarah S. Farabi, PhD, Goldfarb School of Nursing, Office of Nursing Research, Mailstop 90-36-697, 4483 Duncan Avenue, St. Louis, Missouri 63110. E-mail:
| | - Linda A Barbour
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kristy Heiss
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Nicole M Hirsch
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Emily Dunn
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Teri L Hernandez
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- College of Nursing, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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24
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Morsy NE, Farrag NS, Zaki NFW, Badawy AY, Abdelhafez SA, El-Gilany AH, El Shafey MM, Pandi-Perumal SR, Spence DW, BaHammam AS. Obstructive sleep apnea: personal, societal, public health, and legal implications. REVIEWS ON ENVIRONMENTAL HEALTH 2019; 34:153-169. [PMID: 31085749 DOI: 10.1515/reveh-2018-0068] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 02/22/2019] [Indexed: 06/09/2023]
Abstract
Introduction Obstructive sleep apnea (OSA) is a widely prevalent sleep-related breathing disorder, which leads to several life-threatening diseases. OSA has systemic effects on various organ systems. Untreated OSA is associated with long-term health consequences including hypertension, heart disease, diabetes, depression, metabolic disorders, and stroke. In addition, untreated OSA is reported to be associated with cognitive dysfunction, impaired productivity at the workplace and in an increased risk of motor vehicle accidents (MVAs) resulting in injury and fatality. Other consequences of OSA include, but are not limited to, impaired vigilance, daytime somnolence, performance deficits, morning headaches, mood disturbances, neurobehavioral impairments, and general malaise. Additionally, OSA has become an economic burden on most health systems all over the world. Many driving license regulations have been developed to reduce MVAs among OSA patients. Methods Studies of the personal, societal, public health, and legal aspects of OSA are reviewed. Data were collected through the following databases: MEDLINE, Google Scholar, Scopus, SAGE Research Methods, and ScienceDirect. Conclusion OSA leads to worsening of patients' personal relationships, decreasing work productivity, and increasing occupational accidents as well as MVAs. The costs of undiagnosed and untreated OSA to healthcare organizations are excessive. Thus, proper management of OSA will benefit not only the patient but will also provide widespread benefits to the society as a whole.
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Affiliation(s)
- Nesreen E Morsy
- Department of Pulmonary Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Mansoura University Sleep Center, Mansoura, Egypt
| | - Nesrine S Farrag
- Public Health and Preventive Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nevin F W Zaki
- Assistant Professor of Psychiatry, Department of Psychiatry, Faculty of Medicine, Mansoura University, P.O. Box 36551, Gomhoria Street, Mansoura 35511, Egypt
- Mansoura University Sleep Center, Mansoura, Egypt, E-mail:
| | - Ahmad Y Badawy
- Department of Pulmonary Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Sayed A Abdelhafez
- Department of Pulmonary Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Abdel-Hady El-Gilany
- Public Health and Preventive Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | | | | | | | - Ahmed S BaHammam
- The University Sleep Disorders Center, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Strategic Technologies Program of the National Plan for Sciences, Technology, and Innovation, Riyadh, Saudi Arabia
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25
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Bos MM, Noordam R, van den Berg R, de Mutsert R, Rosendaal FR, Blauw GJ, Rensen PCN, Biermasz NR, van Heemst D. Associations of sleep duration and quality with serum and hepatic lipids: The Netherlands Epidemiology of Obesity Study. J Sleep Res 2018; 28:e12776. [PMID: 30324729 PMCID: PMC7379241 DOI: 10.1111/jsr.12776] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 08/09/2018] [Accepted: 08/29/2018] [Indexed: 11/26/2022]
Abstract
Short and long sleep duration and poor sleep quality may affect serum and hepatic lipid content, but available evidence is inconsistent. Therefore, we aimed to investigate the associations of sleep duration and quality with serum and hepatic lipid content in a large population‐based cohort of middle‐aged individuals. The present cross‐sectional study was embedded in the Netherlands Epidemiology of Obesity (NEO) study and consisted of 4260 participants (mean age, 55 years; proportion men, 46%) not using lipid‐lowering agents. Self‐reported sleep duration and quality were assessed using the Pittsburgh Sleep Quality Index questionnaire (PSQI). Outcomes of this study were fasting lipid profile (total cholesterol, low‐density lipoprotein [LDL]‐cholesterol, high‐density lipoprotein [HDL]‐cholesterol and triglycerides), postprandial triglyceride (response) levels, and hepatic triglyceride content (HTGC) as measured with magnetic resonance spectroscopy. We performed multivariable linear regression analyses, adjusted for confounders and additionally for measures that link to adiposity (e.g. body mass index [BMI] and sleep apnea). We observed that relative to the group with median sleep duration (≈7.0 hr of sleep), the group with shortest sleep (≈5.0 hr of sleep) had 1.5‐fold higher HTGC (95% confidence interval [CI]: 1.0‐2.2). The group with PSQI score ≥ 10 had a 1.1‐fold (95% CI: 1.0‐1.2) higher serum triglyceride level compared with the group with PSQI ≤ 5. However, these associations disappeared after adjustment for BMI and sleep apnea. Therefore, we concluded that previously observed associations of shorter sleep duration and poorer sleep quality with an adverse lipid profile, may be explained by BMI and sleep apnea, rather than by a direct effect of sleep on the lipid profile.
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Affiliation(s)
- Maxime M Bos
- Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Raymond Noordam
- Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Rosa van den Berg
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Renée de Mutsert
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Frits R Rosendaal
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.,Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Gerard Jan Blauw
- Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Patrick C N Rensen
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Nienke R Biermasz
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Diana van Heemst
- Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Prussick RB, Miele L. Nonalcoholic fatty liver disease in patients with psoriasis: a consequence of systemic inflammatory burden? Br J Dermatol 2018; 179:16-29. [PMID: 29235656 DOI: 10.1111/bjd.16239] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2017] [Indexed: 02/06/2023]
Abstract
Patients with psoriasis are at an increased risk for nonalcoholic fatty liver disease (NAFLD) compared with the general population. However, the pathophysiology underlying this comorbidity and elucidation of effective treatment strategies are unclear. This review provides insights into the possible role of chronic, low-grade inflammation in the pathogenesis of NAFLD in patients with psoriasis. Both conditions are associated with increased levels of proinflammatory adipokines (such as tumour necrosis factor-α and interleukin-6) and hepatokines, and decreased levels of adiponectin, an anti-inflammatory adipokine. This imbalance in inflammatory mediators could result in insulin resistance and, thereby, facilitate the occurrence and progression of NAFLD in a multistep manner. All patients with psoriasis should, therefore, be considered candidates for NAFLD screening and managed accordingly. Given the common aetiology of inflammation between these conditions, it is hypothesized that biological therapies for psoriasis may attenuate the systemic inflammatory process and progression of NAFLD in patients with psoriasis.
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Affiliation(s)
- R B Prussick
- Washington Dermatology Center, Rockville, MD, U.S.A.,Department of Dermatology, George Washington University, Washington, DC, U.S.A
| | - L Miele
- Institute of Internal Medicine, Catholic University of Sacred Heart of Rome, Rome, Italy.,Gastroenterological Area, Gastroenterology and Endocrine-Metabolic Sciences Department, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
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27
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Chen LD, Zhang LJ, Lin XJ, Qi JC, Li H, Wu Z, Xu QZ, Huang YP, Lin L. Association between continuous positive airway pressure and serum aminotransferases in patients with obstructive sleep apnea. Eur Arch Otorhinolaryngol 2017; 275:587-594. [PMID: 29224042 DOI: 10.1007/s00405-017-4840-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 12/04/2017] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Obstructive sleep apnea (OSA) has been suggested to be a potential contributing factor for nonalcoholic fatty liver disease (NAFLD). Studies on the association between continuous positive airway pressure (CPAP) and NAFLD in OSA patients are limited and controversial. OBJECTIVES The aim of this study was to assess the relationship between OSA and NAFLD and the effect of CPAP therapy on serum aminotransferase levels in OSA patients. METHODS A total of 160 consecutive patients who underwent standard polysomnography were enrolled. Blood samples were obtained in the morning after sleep for biological profile measurements. Non-invasive ultrasound techniques were used to assess liver steatosis and fibrosis. Within the OSA group, serum aminotransferases were detected before and after CPAP treatment. RESULTS Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase, and liver steatosis score increased significantly with an increase in OSA severity. Stepwise multiple regression with liver steatosis score, ALT, AST as dependent variable, respectively, apnea-hypopnea index (β = 0.447, p = 0.020; β = 0.266, p = 0.001; β = 0.351, p = 0.020, respectively) significantly predicted the liver steatosis score, ALT, AST after adjustment for confounders. After 3 months of CPAP treatment, there was a significant decrease in both ALT (54.20 ± 24.34 vs. 46.52 ± 24.95, p = 0.000) and AST (31.82 ± 8.91 vs. 29.00 ± 8.34, p = 0.039). CONCLUSIONS OSA severity was independently associated with liver steatosis and elevation of serum aminotransferases. 3 months of CPAP therapy were associated with a statistically significant improvement on liver injury in OSA patients.
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Affiliation(s)
- Li-Da Chen
- Department of Respiratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, No 59, Shenglixi road, Xiangcheng district, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Liang-Ji Zhang
- Department of Respiratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, No 59, Shenglixi road, Xiangcheng district, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Xue-Jun Lin
- Department of Laboratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, People's Republic of China
| | - Jia-Chao Qi
- Department of Respiratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, No 59, Shenglixi road, Xiangcheng district, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Hao Li
- Department of Respiratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, No 59, Shenglixi road, Xiangcheng district, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Zhi Wu
- Department of Respiratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, No 59, Shenglixi road, Xiangcheng district, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Qiao-Zhen Xu
- Department of Respiratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, No 59, Shenglixi road, Xiangcheng district, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Ya-Ping Huang
- Department of Respiratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, No 59, Shenglixi road, Xiangcheng district, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Li Lin
- Department of Respiratory Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, No 59, Shenglixi road, Xiangcheng district, Zhangzhou, 363000, Fujian, People's Republic of China.
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Abstract
BACKGROUND AND AIM The association between obstructive sleep apnea (OSA) and abnormal liver enzymes has been reported in multiple studies. The existing literature regarding the relationship between OSA and nonalcoholic steatohepatitis (NASH) is conflicting. Thus we aimed to determine the relationship between OSA and NASH from a large database. PATIENTS AND METHODS A cross-sectional study was performed using the 2012 Nationwide Inpatient Sample. We identified adult patients (18-90 years) who had a diagnosis of OSA using the International Classification of Diseases 9th version codes. The control group was comprised of adult individuals with no discharge records of OSA. NASH diagnosis was also identified using the International Classification of Diseases 9th version codes. The association between OSA and NASH was calculated using univariable and multivariable logistic regression. RESULTS A total of 30 712 524 hospitalizations were included. The OSA group included 1 490 150 patients versus 29 222 374 in the control non-OSA group. The OSA group average age was 61.8±0.07 years (44.2% females) compared with 57.0±0.11 years (60.1% females) in the non-OSA group. NASH prevalence was significantly higher in the OSA group compared with the non-OSA group [2% (95% confidence interval (CI): 1.9, 2.1) vs. 0.65% (95% CI: 0.63, 0.66), P<0.001]. After adjusting for obesity, diabetes, hypertension, dyslipidemia, the metabolic syndrome and Charlson comorbidity index, OSA patients were three times more likely to have NASH [adjusted odds ratio: 3.1 (95% CI: 3.0-3.3), P<0.001]. CONCLUSION Patients with OSA are three times more likely to have NASH compared with patients without OSA after controlling for other confounders. These data indicate that OSA should be considered as an independent risk factor for developing NASH.
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Gu C, Younas H, Jun JC. Sleep apnea: An overlooked cause of lipotoxicity? Med Hypotheses 2017; 108:161-165. [PMID: 29055392 DOI: 10.1016/j.mehy.2017.09.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023]
Abstract
Obstructive sleep apnea (OSA) is a common sleep disorder associated with diabetes and cardiovascular disease. However, the mechanisms by which OSA causes cardiometabolic dysfunction are not fully elucidated. OSA increases plasma free fatty acids (FFA) during sleep, reflecting excessive adipose tissue lipolysis. In animal studies, intermittent hypoxia simulating OSA also increases FFA, and the increase is attenuated by beta-adrenergic blockade. In other contexts, excessive plasma FFA can lead to ectopic fat accumulation, insulin resistance, vascular dysfunction, and dyslipidemia. Herein, we propose that OSA is a cause of excessive adipose tissue lipolysis contributing towards systemic "lipotoxicity". Since visceral and upper-body obesity contributes to OSA pathogenesis, OSA-induced lipolysis may further aggravate the consequences of this metabolically harmful state. If this hypothesis is correct, then OSA may represent a reversible risk factor for cardio-metabolic dysfunction, and this risk might be mitigated by preventing OSA-induced lipolysis during sleep.
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Affiliation(s)
- Chenjuan Gu
- Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haris Younas
- Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Jonathan C Jun
- Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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30
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Li D, Du Y, Yuan X, Han X, Dong Z, Chen X, Wu H, Zhang J, Xu L, Han C, Zhang M, Xia Q. Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity. Free Radic Biol Med 2017; 110:102-116. [PMID: 28583670 DOI: 10.1016/j.freeradbiomed.2017.06.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 05/31/2017] [Accepted: 06/01/2017] [Indexed: 01/25/2023]
Abstract
Oxidative stress has a critical role in the pathogenesis of acetaminophen (APAP) induced hepatocellular necrosis, and the identification of novel approaches to attenuate oxidative stress is essential to prevent/revert the disease. This study investigated the role of both HIF-1 and HIF-2 in the pathogenesis of APAP-induced oxidative stress, as well as the underlying mechanisms. In the present study, we initially found that knockout of HIF-1α or HIF-2α reduced APAP toxicity, and double knockout afforded the best protection. APAP treatment led to stabilization of both HIF-1α and HIF-2α in mouse livers. Moreover, the protective effects of HIF deficiency were related to the attenuated oxidative stress. Further experiments proved that PPARα, a master regulator in cellular metabolism accounted for the HIF deficiency-caused protective impact on APAP toxicity. Inactivation of HIFs promoted the expression of peroxisome proliferator-activated receptor α (PPARα) in the liver, which in turn activated nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of PPARα or Nrf2 negated the hepatoprotection afforded by HIF deficiency. At last，examination of the PPARα promoter identified a HIF-binding site and HIF-dependent repression of PPARα in hepatocytes by luciferase reporter and EMSA study. Taken together， Our results demonstrate that HIFs are key suppressors of PPARα in the liver, thereby compromising the adaptive defense mechanisms against oxidative stress when confronted with APAP. These findings are important to the etiology and therapeutics of APAP hepatotoxicity. The functional link between HIFs and PPARα may have more implications in liver physiology and other pathologic conditions than APAP injury.
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Affiliation(s)
- Dawei Li
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yingdong Du
- Department of Hepatic Surgery, PLA No.107 hospital, Yantai, China
| | - Xiaodong Yuan
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoxiao Han
- Department of Biomaterials, School of Material, University of Manchester, United Kingdom
| | - Zhen Dong
- Transplantation Center of the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaosong Chen
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haoyu Wu
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Zhang
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Longmei Xu
- The Central Laboratory of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Conghui Han
- Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China
| | - Ming Zhang
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Qiang Xia
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Anavi S, Madar Z, Tirosh O. Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers. Redox Biol 2017; 13:386-392. [PMID: 28667907 PMCID: PMC5493836 DOI: 10.1016/j.redox.2017.06.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 06/18/2017] [Accepted: 06/20/2017] [Indexed: 12/29/2022] Open
Abstract
Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver.
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Affiliation(s)
- Sarit Anavi
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel; Peres Academic Center, Rehovot, Israel
| | - Zecharia Madar
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel
| | - Oren Tirosh
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel.
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Cholankeril G, Patel R, Khurana S, Satapathy SK. Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management. World J Hepatol 2017; 9:533-543. [PMID: 28469809 PMCID: PMC5395802 DOI: 10.4254/wjh.v9.i11.533] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 02/25/2017] [Accepted: 03/14/2017] [Indexed: 02/06/2023] Open
Abstract
With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASH-related HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.
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Affiliation(s)
- George Cholankeril
- George Cholankeril, Sanjaya K Satapathy, Division of Gastroenterology and Hepatology, Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN 38104, United States
| | - Ronak Patel
- George Cholankeril, Sanjaya K Satapathy, Division of Gastroenterology and Hepatology, Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN 38104, United States
| | - Sandeep Khurana
- George Cholankeril, Sanjaya K Satapathy, Division of Gastroenterology and Hepatology, Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN 38104, United States
| | - Sanjaya K Satapathy
- George Cholankeril, Sanjaya K Satapathy, Division of Gastroenterology and Hepatology, Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN 38104, United States
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Zhan Y, Xie P, Li D, Li L, Chen J, An W, Zhang L, Zhang C. Deficiency of CKIP-1 aggravates high-fat diet-induced fatty liver in mice. Exp Cell Res 2017; 355:40-46. [PMID: 28351752 DOI: 10.1016/j.yexcr.2017.03.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 03/08/2017] [Accepted: 03/16/2017] [Indexed: 01/07/2023]
Abstract
Casein kinase 2 interacting protein-1(CKIP-1) is widely expressed in a variety of tissues and cells, and plays an important role in various critical cellular and physiological processes including cell growth, apoptosis, differentiation, cytoskeleton and bone formation. Here, we found: (1) CKIP-1 deficient mice exhibited increased body weight, liver weight, number and size of lipid droplets, and TG content comparing with WT mice after being exposed to high fat diet (HFD); (2) the levels of serum insulin, liver glycogen, phosphorylated C-Jun-N-terminal kinase-1 (pJNK1) and phosphorylated insulin receptor substrate -1(pIRS1) in CKIP-1-/- mice were higher than those of WT mice; (3) CKIP-1 interacted with JNK1 in vitro. Our results indicate that CKIP-1 deficiency in mice aggravates HFD-induced fatty liver by upregulating JNK1 phosphorylation and further upregulating IRS-1 phosphorylation and RI.
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Affiliation(s)
- Yutao Zhan
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Ping Xie
- Physical Examination Centre, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Dongnian Li
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China
| | - Li Li
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Jing Chen
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Wei An
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
| | - Lingqiang Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China
| | - Chuan Zhang
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
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The association between continuous positive airway pressure therapy and liver disease development in obstructive sleep apnea/hypopnea syndrome patients: a nationwide population-based cohort study in Taiwan. Sleep Breath 2016; 21:461-467. [PMID: 27957696 DOI: 10.1007/s11325-016-1439-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Revised: 10/29/2016] [Accepted: 11/17/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE Studies on the association between continuous positive airway pressure (CPAP) treatment and liver diseases such as non-alcoholic fatty liver disease (NAFLD) and cirrhosis in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) are limited. To the best of our knowledge, none exists that makes use of a national database in an Asian population. This study aims to evaluate the effects of CPAP treatment on patients with these two disorders in a retrospective, population-based study in Taiwan. METHODS Using the Taiwan National Health Insurance claims database, this study collected the data of OSAHS patients diagnosed between 2000 and 2008 and divided them into CPAP treatment and non-CPAP treatment groups. All subjects were followed up until 2010. Liver disease incidence and risk were calculated. RESULTS The CPAP group had a lower cumulative incidence rate of developing liver disease than the non-CPAP group within the observation periods (p < 0.001). After adjusting for age, gender, urbanization level, and comorbidities, the CPAP treatment group showed a lower risk of developing liver disease compared with the non-CPAP treatment group (sub-aHR of 0.66 (95% CI 0.55-0.80), p < 0.001). CONCLUSIONS Our observations suggest that CPAP treatment may play an important role to delay the progression of liver disease in OSAHS patients and decreases the incidence of liver disease among OSAHS patients. Thus, CPAP therapy may be a feasible way to decrease the risk of liver disease among patients with OSAHS.
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Gileles-Hillel A, Kheirandish-Gozal L, Gozal D. Biological plausibility linking sleep apnoea and metabolic dysfunction. Nat Rev Endocrinol 2016; 12:290-8. [PMID: 26939978 DOI: 10.1038/nrendo.2016.22] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Obstructive sleep apnoea (OSA) is a very common disorder that affects 10-25% of the general population. In the past two decades, OSA has emerged as a cardiometabolic risk factor in both paediatric and adult populations. OSA-induced metabolic perturbations include dyslipidaemia, atherogenesis, liver dysfunction and abnormal glucose metabolism. The mainstay of treatment for OSA is adenotonsillectomy in children and continuous positive airway pressure therapy in adults. Although these therapies are effective at resolving the sleep-disordered breathing component of OSA, they do not always produce beneficial effects on metabolic function. Thus, a deeper understanding of the underlying mechanisms by which OSA influences metabolic dysfunction might yield improved therapeutic approaches and outcomes. In this Review, we summarize the evidence obtained from animal models and studies of patients with OSA of potential mechanistic pathways linking the hallmarks of OSA (intermittent hypoxia and sleep fragmentation) with metabolic dysfunction. Special emphasis is given to adipose tissue dysfunction induced by sleep apnoea, which bears a striking resemblance to adipose dysfunction resulting from obesity. In addition, important gaps in current knowledge and promising lines of future investigation are identified.
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Affiliation(s)
- Alex Gileles-Hillel
- Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Knapp Center for Biomedical Discovery, Room 4100, 900 East 57th Street, Mailbox 4, Chicago, Illinois 60637-1470, USA
| | - Leila Kheirandish-Gozal
- Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Knapp Center for Biomedical Discovery, Room 4100, 900 East 57th Street, Mailbox 4, Chicago, Illinois 60637-1470, USA
| | - David Gozal
- Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Knapp Center for Biomedical Discovery, Room 4100, 900 East 57th Street, Mailbox 4, Chicago, Illinois 60637-1470, USA
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Kohler M, Stradling JR. Does continuous positive airway pressure therapy improve non‐alcoholic fatty liver disease? Respirology 2016; 21:209-10. [DOI: 10.1111/resp.12720] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Malcolm Kohler
- Department of PulmonologyUniversity Hospital of Zurich Zurich Switzerland
- Center for Integrative Human PhysiologyUniversity of Zurich Zurich Switzerland
- Center for Interdisciplinary Sleep ResearchUniversity of Zurich Zurich Switzerland
| | - John R. Stradling
- Oxford Centre for Respiratory MedicineOxford NIHR Biomedical Research CentreUniversity of Oxford Oxford UK
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Cakmak E, Duksal F, Altinkaya E, Acibucu F, Dogan OT, Yonem O, Yilmaz A. Association Between the Severity of Nocturnal Hypoxia in Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Damage. HEPATITIS MONTHLY 2015; 15:e32655. [PMID: 26834793 PMCID: PMC4719120 DOI: 10.5812/hepatmon.32655] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 09/20/2015] [Accepted: 09/22/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Obstructive sleep apnea (OSA) is a major disease that can cause significant mortality and morbidity. Chronic intermittent hypoxia is a potential causal factor in the progression from fatty liver to nonalcoholic steatohepatitis. OBJECTIVES This study evaluated the association between the degree of liver steatosis and severity of nocturnal hypoxia. PATIENTS AND METHODS In this study, between December 2011 and December 2013, patients with ultrasound-diagnosed NAFLD evaluated by standart polysomnography were subsequentally recorded. Patients with alcohol use, viral hepatitis and other chronic liver diseases were excluded. We analyzed polysomnographic parameters, steatosis level and severity of obstructive sleep apnea (OSA) in consideration of body mass index (BMI), biochemical tests and ultrasonographic liver data of 137 subjects. Patients with sleep apnea and AHI scores of < 5, 5 - 14, 15 - 29 and ≥30 are categorized as control, mild, moderate and severe, respectively. RESULTS One hundred and thirty-seven patients (76 women, 61 men) with a mean age of 55.75 ± 10.13 years who underwent polysomnography were included in the study. Of 118 patients diagnosed with OSA, 19 (16.1%) had mild OSA, 39 (33.1%) moderate OSA and 60 (50.8%) severe OSA. Nineteen cases formed the control group. Apnea/hypopnea index and oxygen desaturation index (ODI) values were significantly higher in moderate and severe non-alcoholic fatty liver disease (NAFLD) compared to the non-NAFLD group. Mean nocturnal SpO2 values were significantly lower in mild NAFLD and severe NAFLD compared to the non-NAFLD group. Lowest O2 saturation (LaSO2) was found low in mild, moderate and severe NAFLD compared to the non-NAFLD group in a statistically significant manner. CONCLUSIONS We assessed polysomnographic parameters of AHI, ODI, LaSO2 and mean nocturnal SpO2 levels, which are especially important in the association between NAFLD and OSAS. We think that it is necessary to be attentive regarding NAFLD development and progression in patients with OSA whose nocturnal hypoxia is severe.
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Affiliation(s)
- Erol Cakmak
- Department of Gastroenterology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
- Corresponding Author: Erol Cakmak, Department of Gastroenterology, Cumhuriyet University Faculty of Medicine, P. O. Box: 58140, Sivas, Turkey. Tel: +90-3464444458, Fax: +90-3462239530, E-mail:
| | - Faysal Duksal
- Department of Chest Diseases, Sivas Numune Hospital, Sivas, Turkey
| | - Engin Altinkaya
- Department of Gastroenterology, Kayseri Training and Research Hospital, Kayseri, Turkey
| | - Fettah Acibucu
- Department of Endocrinology, Sivas Numune Hospital, Sivas, Turkey
| | - Omer Tamer Dogan
- Department of Chest Diseases, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
| | - Ozlem Yonem
- Department of Gastroenterology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
| | - Abdulkerim Yilmaz
- Department of Gastroenterology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
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Giordano C, Lemaire C, Li T, Kimoff RJ, Petrof BJ. Autophagy-associated atrophy and metabolic remodeling of the mouse diaphragm after short-term intermittent hypoxia. PLoS One 2015; 10:e0131068. [PMID: 26107816 PMCID: PMC4480857 DOI: 10.1371/journal.pone.0131068] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 05/28/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Short-term intermittent hypoxia (IH) is common in patients with acute respiratory disorders. Although prolonged exposure to hypoxia induces atrophy and increased fatigability of skeletal muscle, the response to short-term IH is less well known. We hypothesized that the diaphragm and limb muscles would adapt differently to short-term IH given that hypoxia stimulates ventilation and triggers a superimposed exercise stimulus in the diaphragm. METHODS We determined the structural, metabolic, and contractile properties of the mouse diaphragm after 4 days of IH (8 hours per day, 30 episodes per hour to a FiO2 nadir=6%), and compared responses in the diaphragm to a commonly studied reference limb muscle, the tibialis anterior. Outcome measures included muscle fiber size, assays of muscle proteolysis (calpain, ubiquitin-proteasome, and autophagy pathways), markers of oxidative stress and mitochondrial function, quantification of intramyocellular lipid and lipid metabolism genes, type I myosin heavy chain (MyHC) expression, and in vitro contractile properties. RESULTS After 4 days of IH, the diaphragm alone demonstrated significant atrophy (30% decrease of myofiber size) together with increased LC3B-II protein (2.4-fold) and mRNA markers of the autophagy pathway (LC3B, Gabarapl1, Bnip3), whereas active calpain and E3 ubiquitin ligases (MuRF1, atrogin-1) were unaffected in both muscles. Succinate dehydrogenase activity was significantly reduced by IH in both muscles. However, only the diaphragm exhibited increased intramyocellular lipid droplets (2.5-fold) after IH, along with upregulation of genes linked to activated lipid metabolism. In addition, although the diaphragm showed evidence for acute fatigue immediately following IH, it underwent an adaptive fiber type switch toward slow type I MyHC-expressing fibers, associated with greater intrinsic endurance of the muscle during repetitive stimulation in vitro. CONCLUSIONS Short-term IH induces preferential atrophy in the mouse diaphragm together with increased autophagy and a rapid compensatory metabolic adaptation associated with enhanced fatigue resistance.
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Affiliation(s)
- Christian Giordano
- Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada
- Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada
| | - Christian Lemaire
- Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada
- Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada
| | - Tong Li
- Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada
- Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada
| | - R. John Kimoff
- Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada
- Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada
| | - Basil J. Petrof
- Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada
- Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada
- * E-mail:
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Moon Y, Choi SM, Chang S, Park B, Lee S, Lee MO, Choi HS, Park H. Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes. PLoS One 2015; 10:e0130911. [PMID: 26098428 PMCID: PMC4476666 DOI: 10.1371/journal.pone.0130911] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 05/25/2015] [Indexed: 12/28/2022] Open
Abstract
This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O2) and severe hypoxia (0.1% O2). We found that chenodeoxy cholic acid (CDCA) reduced the amount of HIF-1α protein only under physiological hypoxia but not under severe hypoxia without decreasing its mRNA level. By using a proteasome inhibitor MG132 and a translation inhibitor cyclohexamide, we showed that CDCA reduced HIF-1α protein by decreasing its translation but not by enhancing its degradation. The following findings indicated that farnesoid X receptor (FXR), a CDCA receptor and its target gene, Small heterodimer partner (SHP) are not involved in this effect of CDCA. Distinctly from CDCA, MG132 prevented SHP and an exogenous FXR agonist, GW4064 from reducing HIF-1α protein. Furthermore a FXR antagonist, guggulsterone failed to prevent CDCA from decreasing HIF-1α protein. Furthermore, guggulsterone by itself reduced HIF-1α protein even in the presence of MG132. These findings suggested that CDCA and guggulsterone reduced the translation of HIF-1α in a mechanism which FXR and SHP are not involved. This study reveals novel therapeutic functions of traditional nontoxic drugs, CDCA and guggulsterone, as inhibitors of HIF-1α protein.
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Affiliation(s)
- Yunwon Moon
- Department of Life Science, University of Seoul, Seoul, Korea
| | - Su Mi Choi
- Department of Life Science, University of Seoul, Seoul, Korea
| | - Soojeong Chang
- Department of Life Science, University of Seoul, Seoul, Korea
| | - Bongju Park
- Department of Life Science, University of Seoul, Seoul, Korea
| | - Seongyeol Lee
- Department of Life Science, University of Seoul, Seoul, Korea
| | - Mi-Ock Lee
- College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hueng-Sik Choi
- National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Korea
| | - Hyunsung Park
- Department of Life Science, University of Seoul, Seoul, Korea
- * E-mail:
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Azzam H, Malnick S. Non-alcoholic fatty liver disease - the heart of the matter. World J Hepatol 2015; 7:1369-1376. [PMID: 26052382 PMCID: PMC4450200 DOI: 10.4254/wjh.v7.i10.1369] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 03/02/2015] [Accepted: 03/30/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease in the Western world. There is a close association with the metabolic syndrome and NAFLD is considered to be the hepatic manifestation of the metabolic syndrome. The components of the metabolic syndrome include hypertension, obesity and insulin resistance which are well established cardiovascular risk factors. The mortality rate of NAFLD patients from myocardial infarction is higher than that in the general United States population and there is also an increased risk of non-fatal cardiovascular events. This article reviews the cardiovascular complications associated with NAFLD. In order to provide comprehensive care of NAFLD patients, physicians need to be aware of, and search for, the cardiac morbidity associated with NAFLD.
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Affiliation(s)
- Haneen Azzam
- Haneen Azzam, Stephen Malnick, Department of Internal Medicine C, Kaplan Medical Center, Rehovot 76100, Israel
| | - Stephen Malnick
- Haneen Azzam, Stephen Malnick, Department of Internal Medicine C, Kaplan Medical Center, Rehovot 76100, Israel
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Lückhoff HK, Kruger FC, Kotze MJ. Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries. World J Hepatol 2015; 7:1192-1208. [PMID: 26019735 PMCID: PMC4438494 DOI: 10.4254/wjh.v7.i9.1192] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/18/2014] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
Heterogeneity in clinical presentation, histological severity, prognosis and therapeutic outcomes characteristic of non-alcoholic fatty liver disease (NAFLD) necessitates the development of scientifically sound classification schemes to assist clinicians in stratifying patients into meaningful prognostic subgroups. The need for replacement of invasive liver biopsies as the standard method whereby NAFLD is diagnosed, graded and staged with biomarkers of histological severity injury led to the development of composite prognostic models as potentially viable surrogate alternatives. In the present article, we review existing scoring systems used to (1) confirm the presence of undiagnosed hepatosteatosis; (2) distinguish between simple steatosis and NASH; and (3) predict advanced hepatic fibrosis, with particular emphasis on the role of NAFLD as an independent cardio-metabolic risk factor. In addition, the incorporation of functional genomic markers and application of emerging imaging technologies are discussed as a means to improve the diagnostic accuracy and predictive performance of promising composite models found to be most appropriate for widespread clinical adoption.
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Prussick R, Prussick L, Nussbaum D. Nonalcoholic Fatty liver disease and psoriasis: what a dermatologist needs to know. THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY 2015; 8:43-45. [PMID: 25852814 PMCID: PMC4382145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Psoriasis is a systemic inflammatory disease associated with a variety of comorbidities. It has been shown that psoriasis patients have an increased incidence of nonalcoholic fatty liver disease over controls. Patients with nonalcoholic fatty liver disease and psoriasis have more severe skin disease and are at higher risk of severe liver fibrosis than patients without psoriasis. The authors will review the diagnosis of nonalcoholic fatty liver disease and also discuss lifestyle changes and treatments for psoriasis that may benefit or worsen nonalcoholic fatty liver disease.
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Affiliation(s)
- Ronald Prussick
- Washington Dermatology Center, Rockville, Maryland
- Department of Dermatology, George Washington University, Washington, DC
| | - Lisa Prussick
- Washington Dermatology Center, Rockville, Maryland
- Tufts University School of Medicine, Boston, Massachusetts
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Mutskov V, Khalyfa A, Wang Y, Carreras A, Nobrega MA, Gozal D. Early-life physical activity reverses metabolic and Foxo1 epigenetic misregulation induced by gestational sleep disturbance. Am J Physiol Regul Integr Comp Physiol 2015; 308:R419-30. [PMID: 25568076 DOI: 10.1152/ajpregu.00426.2014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Sleep disorders are highly prevalent during late pregnancy and can impose adverse effects, such as preeclampsia and diabetes. However, the consequences of sleep fragmentation (SF) on offspring metabolism and epigenomic signatures are unclear. We report that physical activity during early life, but not later, reversed the increased body weight, altered glucose and lipid homeostasis, and increased visceral adipose tissue in offspring of mice subjected to gestational SF (SFo). The reversibility of this phenotype may reflect epigenetic mechanisms induced by SF during gestation. Accordingly, we found that the metabolic master switch Foxo1 was epigenetically misregulated in SFo livers in a temporally regulated fashion. Temporal Foxo1 analysis and its gluconeogenetic targets revealed that the epigenetic abnormalities of Foxo1 precede the metabolic syndrome phenotype. Importantly, regular physical activity early, but not later in life, reversed Foxo1 epigenetic misregulation and altered the metabolic phenotype in gestationally SF-exposed offspring. Thus, we have identified a restricted postnatal period during which lifestyle interventions may reverse the Foxo1 epigenetically mediated risk for metabolic dysfunction later in the life, as induced by gestational sleep disorders.
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Affiliation(s)
- Vesco Mutskov
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois; and
| | - Abdelnaby Khalyfa
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois; and
| | - Yang Wang
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois; and
| | - Alba Carreras
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois; and
| | - Marcelo A Nobrega
- Department of Human Genetics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois
| | - David Gozal
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois; and
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Fargion S, Porzio M, Fracanzani AL. Nonalcoholic fatty liver disease and vascular disease: State-of-the-art. World J Gastroenterol 2014; 20:13306-13324. [PMID: 25309067 PMCID: PMC4188888 DOI: 10.3748/wjg.v20.i37.13306] [Citation(s) in RCA: 165] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 05/02/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis (increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific life-style modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.
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Xu H, Yi H, Guan J, Yin S. Effect of continuous positive airway pressure on lipid profile in patients with obstructive sleep apnea syndrome: a meta-analysis of randomized controlled trials. Atherosclerosis 2014; 234:446-53. [PMID: 24769714 DOI: 10.1016/j.atherosclerosis.2014.03.034] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 03/27/2014] [Accepted: 03/27/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for development of dyslipidemia. Continuous positive airway pressure (CPAP) is the first-line treatment for OSAS. However, it is unclear whether CPAP improves lipid metabolism. OBJECTIVES To review the effect of CPAP on lipid profile of patients with OSAS. METHODS We searched PubMed, Embase, and the Cochrane Library to identify eligible articles published prior to October 30, 2013. Six randomized controlled trials (RCTs) were subjected to meta-analysis using Comprehensive Meta-Analysis software. RESULTS Six RCTs meeting the inclusion criteria were enrolled. The total numbers of measurements of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol, in CPAP intervention patients and sham/control groups, were 370 and 371, 330 and 328, 276 and 274, and 269 and 266 respectively. The pooled estimate of the difference in the mean TC level between the CPAP and sham CPAP/control groups was significantly different (-0.15 [95% confidence interval, -0.27 to -0.03]; p = 0.01). Subgroup analysis revealed that OSAS patients of younger age, who were more obese, and who had been treated via CPAP for a longer duration, showed a significant decrease in TC levels (the differences in the means were -0.27, -0.24, and -0.20; and the p values 0.001, 0.01, and 0.04, respectively). CONCLUSION We confirmed that CPAP decreases the TC level, especially in OSAS patients who are younger, more obese, and who use CPAP for a longer period. CPAP did not alter TG, LDL, or HDL levels, suggesting that CPAP may have no clinically important effect on lipid metabolism.
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Affiliation(s)
- Huajun Xu
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Otolaryngology Institute of Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China
| | - Hongliang Yi
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Otolaryngology Institute of Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China
| | - Jian Guan
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Otolaryngology Institute of Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China.
| | - Shankai Yin
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Otolaryngology Institute of Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China.
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Mirrakhimov AE. Nonalcoholic fatty pancreatic disease and cardio-metabolic risk: is there is a place for obstructive sleep apnea? Cardiovasc Diabetol 2014; 13:29. [PMID: 24475948 PMCID: PMC3909423 DOI: 10.1186/1475-2840-13-29] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 01/29/2014] [Indexed: 02/07/2023] Open
Abstract
Background Obstructive sleep apnea is a common disorder acting as a risk factor for the development and progression of cardiometabolic derangements including non-alcoholic fatty liver disease. Recent research data suggest that non-alcoholic fatty pancreatic disease may be a more sensitive marker than non-alcoholic fatty liver disease for early subclinical metabolic risk and may contribute to the progression of subclinical disease to overt type 2 diabetes mellitus. Presentation of the hypothesis We postulate that obstructive sleep apnea may be a risk factor for non-alcoholic fatty pancreatic disease. It is well known that intermittent hypoxia related to obstructive sleep apnea leads to hormonal derangements. Excessive lipolysis, enhanced lipid synthesis and systemic and local inflammation may favor ectopic fat deposition similarly to non-alcoholic fatty liver disease. Furthermore, it is possible that obstructive sleep apnea can lead to pancreatic beta cell damage via intermittent hypoxia. Testing of the hypothesis Future research should focus on the following: first, whether non-alcoholic fatty pancreatic disease is an independent risk factor for the development of metabolic disease including diabetes mellitus or is a simple consequence of obesity; second, the prevalence of non-alcoholic fatty pancreatic disease among people with obstructive sleep apnea and vice versa, which should be compared to the prevalence of these diseases in general population; third, whether coexistence of these conditions is related to greater cardiometabolic risk than either disease alone; and fourth, whether the treatment of obstructive sleep apnea will translate into the resolution of non-alcoholic fatty pancreatic disease. Implications of the hypothesis If proven, this hypothesis will provide new knowledge on the complex interplay between various metabolic insults. Second, screening for NAFPD may identify individuals at risk for developing type 2 diabetes mellitus for targeted prevention. Third, screening for the presence of non-alcoholic fatty pancreatic disease in patients with obstructive sleep apnea may help to decrease the incidence of diabetes mellitus through a targeted prevention.
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Affiliation(s)
- Aibek E Mirrakhimov
- Kyrgyz State Medical Academy named by I,K, Akhunbaev, Akhunbaev street 92, Bishkek 720020, Kyrgyzstan.
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Gerhard GS, Benotti P, Wood GC, Chu X, Argyropoulos G, Petrick A, Strodel WE, Gabrielsen JD, Ibele A, Still CD, Kingsley C, DiStefano J. Identification of novel clinical factors associated with hepatic fat accumulation in extreme obesity. J Obes 2014; 2014:368210. [PMID: 25610640 PMCID: PMC4290025 DOI: 10.1155/2014/368210] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 10/16/2014] [Accepted: 10/17/2014] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES The accumulation of lipids stored as excess triglycerides in the liver (steatosis) is highly prevalent in obesity and has been associated with several clinical characteristics, but most studies have been based on relatively small sample sizes using a limited set of variables. We sought to identify clinical factors associated with liver fat accumulation in a large cohort of patients with extreme obesity. METHODS We analyzed 2929 patients undergoing intraoperative liver biopsy during a primary bariatric surgery. Univariate and multivariate regression modeling was used to identify associations with over 200 clinical variables with the presence of any fat in the liver and with moderate to severe versus mild fat accumulation. RESULTS A total of 19 data elements were associated with the presence of liver fat and 11 with severity of liver fat including ALT and AST, plasma lipid, glucose, and iron metabolism variables, several medications and laboratory measures, and sleep apnea. The accuracy of a multiple logistic regression model for presence of liver fat was 81% and for severity of liver fat accumulation was 77%. CONCLUSIONS A limited set of clinical factors can be used to model hepatic fat accumulation with moderate accuracy and may provide potential mechanistic insights in the setting of extreme obesity.
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Affiliation(s)
- Glenn S. Gerhard
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA 19140, USA
- *Glenn S. Gerhard:
| | - Peter Benotti
- Geisinger Obesity Research Institute, Danville, PA 17822, USA
| | - G. Craig Wood
- Geisinger Obesity Research Institute, Danville, PA 17822, USA
| | - Xin Chu
- Geisinger Obesity Research Institute, Danville, PA 17822, USA
| | | | - Anthony Petrick
- Geisinger Obesity Research Institute, Danville, PA 17822, USA
| | | | | | - Anna Ibele
- Geisinger Obesity Research Institute, Danville, PA 17822, USA
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Mirrakhimov AE, Barbaryan A. Obstructive sleep apnea and cancer: is it time to study organ-specific cancers? Am J Respir Crit Care Med 2013; 188:399. [PMID: 23905531 DOI: 10.1164/rccm.201301-0046le] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Abstract
Despite skeletal muscle being considered by many as the source of insulin resistance, physiology tells us that the liver is a central and cardinal regulator of glucose homeostasis. This is sometimes underestimated because, in contrast with muscle, investigations of liver function are technically very difficult. Nevertheless, recent experimental and clinical research has demonstrated clearly that, due in part to its anatomic position, the liver is exquisitely sensitive to insulin and other hormonal and neural factors, either by direct intrahepatic mechanisms or indirectly by organ cross-talk with muscle or adipose tissue. Because the liver receives absorbed nutrients, these have a direct impact on liver function, whether via a caloric excess or via the nature of food components (eg, fructose, many lipids, and trans fatty acids). An emerging observation with a possibly great future is the increase in intestinal permeability observed as a consequence of high fat intake or bacterial modifications in microbiota, whereby substances normally not crossing the gut gain access to the liver, where inflammation, oxidative stress, and lipid accumulation leads to fatty liver, a situation observed very early in the development of diabetes. The visceral adipose tissue located nearby is another main source of inflammatory substances and oxidative stress, and also acts on hepatocytes and Kupffer cells, resulting in stimulation of macrophages. Liberation of these substances, in particular triglycerides and inflammation factors, into the circulation leads to ectopic fat deposition and vascular damage. Therefore, the liver is directly involved in the development of the prediabetic cardiometabolic syndrome. Treatments are mainly metformin, and possibly statins and vitamin D. A very promising avenue is treatment of the leaky gut, which appears increasingly to be an important causal factor in hepatic insulin resistance and steatosis.
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Affiliation(s)
- Nicolas Wiernsperger
- INSERM French Institute of Health and Medical Research, U1060, National Institute of Applied Sciences, Lyon, University of Lyon, Villeurbanne, France
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Reply to Mirrakhimov and Mirrakhimov–Nonalcoholic Fatty Liver Disease and Cardiovascular Risk in Obese Children and Adolescents. Can J Cardiol 2013; 29:1139.e9. [DOI: 10.1016/j.cjca.2012.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 11/14/2012] [Indexed: 11/23/2022] Open
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