Obstructive Sleep Apnea–Hypopnea Syndrome and Nonalcoholic Fatty Liver Disease: Emerging Evidence and Mechanisms

Abstract

Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are common conditions, frequently encountered in patients with metabolic disorders. OSAS has been associated with an increased risk of cardiovascular and metabolic complications. It has been recently suggested that the chronic intermittent hypoxia of OSAS may also affect the presence and severity of NAFLD. We will critically review experimental and human evidence connecting OSAS to NAFLD pathogenesis, trying to dissect the effect of intermittent hypoxia from that of obesity and associated comorbidities, and examine molecular mechanisms connecting OSAS to liver and metabolic disease in NAFLD, including hypoxia inducible factor (HIF), nuclear factor-kappa B, unfolded protein response, hypoxic adipose tissue inflammation, and their therapeutic potential for NAFLD and its complications, including cirrhosis and hepatocellular carcinoma. Finally, we will provide suggestions for the management of NAFLD patients with suspected OSAS and recommendations for future research.

Keywords

Sleep apnea - chronic intermittent hypoxia - hypoxia inducible factor - fatty liver

• References

• 1 Younossi ZM, Stepanova M, Afendy M , et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011; 9 (6) 524-530 , e1, quiz e60
• 2 Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43 (8) 617-649
• 3 Ghouri N, Preiss D, Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. Hepatology 2010; 52 (3) 1156-1161
• 4 Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328 (17) 1230-1235
• 5 Lindberg E, Gislason T. Epidemiology of sleep-related obstructive breathing. Sleep Med Rev 2000; 4 (5) 411-433
• 6 West SD, Nicoll DJ, Stradling JR. Prevalence of obstructive sleep apnoea in men with type 2 diabetes. Thorax 2006; 61 (11) 945-950
• 7 Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 2004; 25 (9) 735-741
• 8 Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365 (9464) 1046-1053
• 9 Drager LF, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: an emerging risk factor for atherosclerosis. Chest 2011; 140 (2) 534-542
• 10 Sharma SK, Agrawal S, Damodaran D , et al. CPAP for the metabolic syndrome in patients with obstructive sleep apnea. N Engl J Med 2011; 365 (24) 2277-2286
• 11 Abe H, Takahashi M, Yaegashi H , et al. Efficacy of continuous positive airway pressure on arrhythmias in obstructive sleep apnea patients. Heart Vessels 2010; 25 (1) 63-69
• 12 Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007; 176 (7) 706-712
• 13 Shaw JE, Punjabi NM, Wilding JP, Alberti KG, Zimmet PZ ; International Diabetes Federation Taskforce on Epidemiology and Prevention. Sleep-disordered breathing and type 2 diabetes: a report from the International Diabetes Federation Taskforce on Epidemiology and Prevention. Diabetes Res Clin Pract 2008; 81 (1) 2-12
• 14 Iber C, Ancoli-Israel S, Chesson A , et al. The AASM manual for snoring of sleep and associated events: rules, terminology and technical specifications. 1st ed. Westchester, IL: American Academy of Sleep Medicine; 2007
• 15 Dancey DR, Hanly PJ, Soong C, Lee B, Shepard Jr J, Hoffstein V. Gender differences in sleep apnea: the role of neck circumference. Chest 2003; 123 (5) 1544-1550
• 16 Strauss RS, Browner WS. Risk for obstructive sleep apnea. Ann Intern Med 2000; 132 (9) 758-759
• 17 Rowley JA, Aboussouan LS, Badr MS. The use of clinical prediction formulas in the evaluation of obstructive sleep apnea. Sleep 2000; 23 (7) 929-938
• 18 Mulgrew AT, Fox N, Ayas NT, Ryan CF. Diagnosis and initial management of obstructive sleep apnea without polysomnography: a randomized validation study. Ann Intern Med 2007; 146 (3) 157-166
• 19 Magalang UJ, Dmochowski J, Veeramachaneni S , et al. Prediction of the apnea-hypopnea index from overnight pulse oximetry. Chest 2003; 124 (5) 1694-1701
• 20 Cheliout-Heraut F, Senny F, Djouadi F, Ouayoun M, Bour F. Obstructive sleep apnoea syndrome: comparison between polysomnography and portable sleep monitoring based on jaw recordings. Neurophysiol Clin 2011; 41 (4) 191-198
• 21 Jungermann K, Kietzmann T. Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology 2000; 31 (2) 255-260
• 22 Fandrey J, Gassmann M. Oxygen sensing and the activation of the hypoxia inducible factor 1 (HIF-1)—invited article. Adv Exp Med Biol 2009; 648: 197-206
• 23 Broughan TA, Naukam R, Tan C, Van De Wiele CJ, Refai H, Teague TK. Effects of hepatic zonal oxygen levels on hepatocyte stress responses. J Surg Res 2008; 145 (1) 150-160
• 24 Baze MM, Schlauch K, Hayes JP. Gene expression of the liver in response to chronic hypoxia. Physiol Genomics 2010; 41: 275-288
• 25 Piguet AC, Stroka D, Zimmermann A, Dufour JF. Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN. Clin Sci (Lond) 2010; 118 (6) 401-410
• 26 Reinke C, Bevans-Fonti S, Drager LF, Shin MK, Polotsky VY. Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes. J Appl Physiol 2011; 111 (3) 881-890
• 27 Choi JH, Park MJ, Kim KW , et al. Molecular mechanism of hypoxia-mediated hepatic gluconeogenesis by transcriptional regulation. FEBS Lett 2005; 579 (13) 2795-2801
• 28 Kietzmann T, Cornesse Y, Brechtel K, Modaressi S, Jungermann K. Perivenous expression of the mRNA of the three hypoxia-inducible factor alpha-subunits, HIF1alpha, HIF2alpha and HIF3alpha, in rat liver. Biochem J 2001; 354 (Pt 3) 531-537
• 29 Kenneth NS, Rocha S. Regulation of gene expression by hypoxia. Biochem J 2008; 414 (1) 19-29
• 30 Dimova EY, Kietzmann T. Hypoxia-inducible factors: post-translational crosstalk of signaling pathways. Methods Mol Biol 2010; 647: 215-236
• 31 Jaakkola P, Mole DR, Tian YM , et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292 (5516) 468-472
• 32 Benita Y, Kikuchi H, Smith AD, Zhang MQ, Chung DC, Xavier RJ. An integrative genomics approach identifies hypoxia inducible factor-1 (HIF-1)-target genes that form the core response to hypoxia. Nucleic Acids Res 2009; 37 (14) 4587-4602
• 33 Rankin EB, Rha J, Selak MA , et al. Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Mol Cell Biol 2009; 29 (16) 4527-4538
• 34 Qu A, Taylor M, Xue X , et al. Hypoxia-inducible transcription factor 2α promotes steatohepatitis through augmenting lipid accumulation, inflammation, and fibrosis. Hepatology 2011; 54 (2) 472-483
• 35 Nath B, Levin I, Csak T , et al. Hepatocyte-specific hypoxia-inducible factor-1α is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology 2011; 53 (5) 1526-1537
• 36 Li J, Savransky V, Nanayakkara A, Smith PL, O'Donnell CP, Polotsky VY. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol 2007; 102 (2) 557-563
• 37 Drager LF, Li J, Shin MK , et al. Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. Eur Heart J 2011;
• 38 Kucejova B, Sunny NE, Nguyen AD , et al. Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death. Oncogene 2011; 30 (18) 2147-2160
• 39 Marín-Hernández A, Gallardo-Pérez JC, Ralph SJ, Rodríguez-Enríquez S, Moreno-Sánchez R. HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem 2009; 9 (9) 1084-1101
• 40 Copple BL, Bai S, Moon JO. Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic Kupffer cells. Hepatol Res 2010; 40 (5) 530-539
• 41 Moon JO, Welch TP, Gonzalez FJ, Copple BL. Reduced liver fibrosis in hypoxia-inducible factor-1alpha-deficient mice. Am J Physiol Gastrointest Liver Physiol 2009; 296 (3) G582-G592
• 42 Copple BL, Bai S, Burgoon LD, Moon JO. Hypoxia-inducible factor-1α regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis. Liver Int 2011; 31 (2) 230-244
• 43 Shi YF, Fong CC, Zhang Q , et al. Hypoxia induces the activation of human hepatic stellate cells LX-2 through TGF-beta signaling pathway. FEBS Lett 2007; 581 (2) 203-210
• 44 Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 2009; 48 (1) 1-26
• 45 Imtiyaz HZ, Williams EP, Hickey MM , et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 2010; 120 (8) 2699-2714
• 46 Gambino R, Musso G, Cassader M. Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities. Antioxid Redox Signal 2011; 15 (5) 1325-1365
• 47 Coulon S, Heindryckx F, Geerts A, Van Steenkiste C, Colle I, Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int 2011; 31 (2) 146-162
• 48 Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51 (5) 1820-1832
• 49 Bangoura G, Liu ZS, Qian Q, Jiang CQ, Yang GF, Jing S. Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol 2007; 13 (23) 3176-3182
• 50 Dai CX, Gao Q, Qiu SJ , et al. Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery. BMC Cancer 2009; 9: 418
• 51 Daskalow K, Rohwer N, Raskopf E , et al. Role of hypoxia-inducible transcription factor 1alpha for progression and chemosensitivity of murine hepatocellular carcinoma. J Mol Med (Berl) 2010; 88 (8) 817-827
• 52 Sun X, Jiang H, Jiang X , et al. Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats. Hum Gene Ther 2009; 20 (4) 314-324
• 53 Greenberger LM, Horak ID, Filpula D , et al. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 2008; 7 (11) 3598-3608
• 54 Liu F, Wang P, Jiang X , et al. Antisense hypoxia-inducible factor 1alpha gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma. Cancer Sci 2008; 99 (10) 2055-2061
• 55 Clément S, Juge-Aubry C, Sgroi A , et al. Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes. Hepatology 2008; 48 (3) 799-807
• 56 Alisi A, Panera N, Balsano C, Nobili V. Activation of the endotoxin/toll-like receptor 4 pathway: the way to go from nonalcoholic steatohepatitis up to hepatocellular carcinoma. Hepatology 2011; 53 (3) 1069
• 57 Musso G, Gambino R, Cassader M. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded?. Diabetes Care 2010; 33 (10) 2277-2284
• 58 Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 2011; 54 (1) 133-144
• 59 Musso G, Gambino R, Cassader M. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med 2011; 62: 361-380
• 60 Scharte M, Han X, Uchiyama T, Tawadrous Z, Delude RL, Fink MP. LPS increases hepatic HIF-1alpha protein and expression of the HIF-1-dependent gene aldolase A in rats. J Surg Res 2006; 135 (2) 262-267
• 61 Rius J, Guma M, Schachtrup C , et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 2008; 453 (7196) 807-811
• 62 Mauro C, Leow SC, Anso E , et al. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol 2011; 13 (10) 1272-1279
• 63 Nácher M, Farré R, Montserrat JM , et al. Biological consequences of oxygen desaturation and respiratory effort in an acute animal model of obstructive sleep apnea (OSA). Sleep Med 2009; 10 (8) 892-897
• 64 Jelic S, Lederer DJ, Adams T , et al. Vascular inflammation in obesity and sleep apnea. Circulation 2010; 121 (8) 1014-1021
• 65 Lam JC, Mak JC, Ip MS. Obesity, obstructive sleep apnea and metabolic syndrome. Respirology 2012; 17 (2) 223-236
• 66 Beraza N, Malato Y, Vander Borght S , et al. Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut 2008; 57 (5) 655-663
• 67 Videla LA, Tapia G, Rodrigo R , et al. Liver NF-kappaB and AP-1 DNA binding in obese patients. Obesity (Silver Spring) 2009; 17 (5) 973-979
• 68 Luedde T, Schwabe RFNF. NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8 (2) 108-118
• 69 He G, Karin MNF. NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res 2011; 21 (1) 159-168
• 70 Robinson SM, Mann DA. Role of nuclear factor kappaB in liver health and disease. Clin Sci (Lond) 2010; 118 (12) 691-705
• 71 Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S. Mechanism of hypoxia-induced NF-kappaB. Mol Cell Biol 2010; 30 (20) 4901-4921
• 72 Melvin A, Mudie S, Rocha S. Further insights into the mechanism of hypoxia-induced NFκB. [corrected]. Cell Cycle 2011; 10 (6) 879-882
• 73 Li J, Fan R, Zhao S , et al. Reactive oxygen species released from hypoxic hepatocytes regulates MMP-2 expression in hepatic stellate cells. Int J Mol Sci 2011; 12 (4) 2434-2447
• 74 Snapp E, Endoplasmic reticulum biogenesis proliferation and differentiation. In: Mullins C. , ed. The Biogenesis of Cellular Organelles. New York: Kluwer Academic/Plenum; 2005: 63-95
• 75 Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol 2011; 54 (4) 795-809
• 76 Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334 (6059) 1081-1086
• 77 Hetz C, Martinon F, Rodriguez D, Glimcher LH. The unfolded protein response: integrating stress signals through the stress sensor IRE1α. Physiol Rev 2011; 91 (4) 1219-1243
• 78 Diehl JA, Fuchs SY, Koumenis C. The cell biology of the unfolded protein response. Gastroenterology 2011; 141 (1) 38-41 , 41, e1–e2
• 79 Rahman SM, Schroeder-Gloeckler JM, Janssen RC , et al. CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology 2007; 45 (5) 1108-1117
• 80 Kammoun HL, Chabanon H, Hainault I , et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 2009; 119 (5) 1201-1215
• 81 Rinella ME, Siddiqui MS, Gardikiotes K, Gottstein J, Elias M, Green RM. Dysregulation of the unfolded protein response in db/db mice with diet-induced steatohepatitis. Hepatology 2011; 54 (5) 1600-1609
• 82 Glimcher LH, Lee AH. From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis. Ann N Y Acad Sci 2009; 1173 (Suppl 1) E2-E9
• 83 Ning J, Hong T, Ward A , et al. Constitutive role for IRE1α-XBP1 signaling pathway in the insulin-mediated hepatic lipogenic program. Endocrinology 2011; 152 (6) 2247-2255
• 84 Gentile CL, Frye M, Pagliassotti MJ. Endoplasmic reticulum stress and the unfolded protein response in nonalcoholic fatty liver disease. Antioxid Redox Signal 2011; 15 (2) 505-521
• 85 Gregor MF, Yang L, Fabbrini E , et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009; 58 (3) 693-700
• 86 Puri P, Mirshahi F, Cheung O , et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134 (2) 568-576
• 87 Al-Rawashdeh FY, Scriven P, Cameron IC, Vergani PV, Wyld L. Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2010; 22 (9) 1099-1105
• 88 Blais JD, Addison CL, Edge R , et al. Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol Cell Biol 2006; 26 (24) 9517-9532
• 89 van den Beucken T, Magagnin MG, Jutten B , et al. Translational control is a major contributor to hypoxia induced gene expression. Radiother Oncol 2011; 99 (3) 379-384
• 90 Zhu Y, Fenik P, Zhan G, Sanfillipo-Cohn B, Naidoo N, Veasey SC. Eif-2a protects brainstem motoneurons in a murine model of sleep apnea. J Neurosci 2008; 28 (9) 2168-2178
• 91 Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002; 165 (5) 670-676
• 92 Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med 2002; 165 (5) 677-682
• 93 Makino S, Handa H, Suzukawa K , et al. Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance. Clin Endocrinol (Oxf) 2006; 64 (1) 12-19
• 94 Polotsky VY, Li J, Punjabi NM , et al. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 2003; 552 (Pt 1) 253-264
• 95 Iiyori N, Alonso LC, Li J , et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med 2007; 175 (8) 851-857
• 96 Oltmanns KM, Gehring H, Rudolf S , et al. Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med 2004; 169 (11) 1231-1237
• 97 Schahin SP, Nechanitzky T, Dittel C , et al. Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome. Med Sci Monit 2008; 14 (3) CR117-CR121
• 98 Harsch IA, Schahin SP, Radespiel-Tröger M , et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2004; 169 (2) 156-162
• 99 Lam JC, Lam B, Yao TJ , et al. A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea. Eur Respir J 2010; 35 (1) 138-145
• 100 Musso G, Gambino R, Durazzo M , et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology 2005; 42 (5) 1175-1183
• 101 Musso G, Gambino R, Cassader M. Non-alcoholic fatty liver disease from pathogenesis to management: an update. Obes Rev 2010; 11 (6) 430-445
• 102 Xu H, Barnes GT, Yang Q , et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112 (12) 1821-1830
• 103 Makkonen J, Westerbacka J, Kolak M , et al. Increased expression of the macrophage markers and of 11beta-HSD-1 in subcutaneous adipose tissue, but not in cultured monocyte-derived macrophages, is associated with liver fat in human obesity. Int J Obes (Lond) 2007; 31 (10) 1617-1625
• 104 Pasarica M, Sereda OR, Redman LM , et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 2009; 58 (3) 718-725
• 105 Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 2007; 455 (3) 479-492
• 106 Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007; 293 (4) E1118-E1128
• 107 Yin J, Gao Z, He Q, Zhou D, Guo Z, Ye J. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab 2009; 296 (2) E333-E342
• 108 Nakagawa Y, Kishida K, Kihara S, Yoshida R, Funahashi T, Shimomura I. Nocturnal falls of adiponectin levels in sleep apnea with abdominal obesity and impact of hypoxia-induced dysregulated adiponectin production in obese murine mesenteric adipose tissue. J Atheroscler Thromb 2011; 18 (3) 240-247
• 109 Nakagawa Y, Kishida K, Kihara S , et al. Nocturnal reduction in circulating adiponectin concentrations related to hypoxic stress in severe obstructive sleep apnea-hypopnea syndrome. Am J Physiol Endocrinol Metab 2008; 294 (4) E778-E784
• 110 Tanné F, Gagnadoux F, Chazouillères O , et al. Chronic liver injury during obstructive sleep apnea. Hepatology 2005; 41 (6) 1290-1296
• 111 Singh H, Pollock R, Uhanova J, Kryger M, Hawkins K, Minuk GY. Symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liver disease. Dig Dis Sci 2005; 50 (12) 2338-2343
• 112 Tatsumi K, Saibara T. Effects of obstructive sleep apnea syndrome on hepatic steatosis and nonalcoholic steatohepatitis. Hepatol Res 2005; 33 (2) 100-104
• 113 Kallwitz ER, Herdegen J, Madura J, Jakate S, Cotler SJ. Liver enzymes and histology in obese patients with obstructive sleep apnea. J Clin Gastroenterol 2007; 41 (10) 918-921
• 114 Jouët P, Sabaté JM, Maillard D , et al. Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study. Obes Surg 2007; 17 (4) 478-485
• 115 Mishra P, Nugent C, Afendy A , et al. Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis. Liver Int 2008; 28 (8) 1080-1086
• 116 Campos GM, Bambha K, Vittinghoff E , et al. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology 2008; 47 (6) 1916-1923
• 117 Norman D, Bardwell WA, Arosemena F , et al. Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea. Sleep 2008; 31 (1) 121-126
• 118 Polotsky VY, Patil SP, Savransky V , et al. Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity. Am J Respir Crit Care Med 2009; 179 (3) 228-234
• 119 Daltro C, Cotrim HP, Alves E , et al. Nonalcoholic fatty liver disease associated with obstructive sleep apnea: just a coincidence?. Obes Surg 2010; 20 (11) 1536-1543
• 120 Turkay C, Ozol D, Kasapoglu B , et al. Influence of obstructive sleep apnea on fatty liver disease: role of chronic intermittent hypoxia. Respir Care 2012; 57 (2) 244-249
• 121 Aron-Wisnewsky J, Minville C, Tordjman J , et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol 2012; 56 (1) 225-233
• 122 Chin K, Nakamura T, Takahashi K , et al. Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients. Am J Med 2003; 114 (5) 370-376
• 123 Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D. Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea. Chest 2008; 133 (1) 92-99
• 124 Shpirer I, Copel L, Broide E, Elizur A. Continuous positive airway pressure improves sleep apnea associated fatty liver. Lung 2010; 188 (4) 301-307
• 125 Kohler M, Pepperell JC, Davies RJ, Stradling JR. Continuous positive airway pressure and liver enzymes in obstructive sleep apnoea: data from a randomized controlled trial. Respiration 2009; 78 (2) 141-146
• 126 Savransky V, Nanayakkara A, Vivero A , et al. Chronic intermittent hypoxia predisposes to liver injury. Hepatology 2007; 45 (4) 1007-1013
• 127 Li J, Grigoryev DN, Ye SQ , et al. Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J Appl Physiol 2005; 99 (5) 1643-1648
• 128 Savransky V, Bevans S, Nanayakkara A , et al. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol 2007; 293 (4) G871-G877
• 129 Drager LF, Li J, Reinke C, Bevans-Fonti S, Jun JC, Polotsky VY. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring) 2011; 19 (11) 2167-2174
• 130 Feng SZ, Tian JL, Zhang Q , et al. An experimental research on chronic intermittent hypoxia leading to liver injury. Sleep Breath 2011; 15 (3) 493-502
• 131 Musso G, Gambino R, Cassader M. Need for a three-focused approach to nonalcoholic fatty liver disease. Hepatology 2011; 53 (5) 1773 , author reply 1774
• 132 Harsch IA, Schahin SP, Brückner K , et al. The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes. Respiration 2004; 71 (3) 252-259
• 133 Coughlin SR, Mawdsley L, Mugarza JA, Wilding JP, Calverley PM. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 2007; 29 (4) 720-727
• 134 Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005; 9 (3) 211-224