Skip to main content

Advertisement

Log in

Effects and relationship of intermittent hypoxia on serum lipid levels, hepatic low-density lipoprotein receptor-related protein 1, and hypoxia-inducible factor 1α

  • Original Article
  • Published:
Sleep and Breathing Aims and scope Submit manuscript

Abstract

Objective

This study investigated the influence of intermittent hypoxia on serum lipid level, hepatic low-density lipoprotein receptor-related protein (LRP)1, and hepatic hypoxia-inducible factor (HIF)-1α and the underlying mechanisms of action.

Methods

Male Sprague Dawley rats were subjected to different levels of hypoxia. After 1–4 weeks hypoxemia, routine blood tests were performed and the levels of LRP1 and HIF-1α in liver were examined. Intermittent hypoxia (IH) was induced in HepG2 cells with or without HIF-1α inhibitor YC-1 pretreatment, and the levels of LRP1 and HIF-1α in cells were examined.

Results

IH caused elevated serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein in rats. IH caused elevated hepatic levels of LRP1 and HIF-1α. After pretreatment with YC-1, HIF-1α protein expression decreased but mRNA expression did not change in HepG2 cells.

Conclusions

IH caused dyslipidemia and elevated LRP1 and HIF-1α. Elevated LRP1 expression was caused by HIF-1α.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

LRP1:

Low-density lipoprotein receptor-related protein 1

HIF-1α:

Hypoxia- inducible factor 1α

IH:

Intermittent hypoxia

OSAS:

Obstructive sleep apnea syndrome

LDL:

Low-density lipoprotein

TG:

Total cholesterol

TC:

Triglyceride

VLDL:

Very low-density lipoprotein

References

  1. Wang Z, Si LY (2013) Hypoxia-inducible factor-1α and vascular endothelial growth factor in the cardioprotective effects of intermittent hypoxia in rats. Ups J Med Sci 118:65–74

    Article  PubMed  PubMed Central  Google Scholar 

  2. Zhou J, Liu Y (2013) Effects of genistein and estrogen on the genioglossus in rats exposed to chronic intermittent hypoxia may be HIF-1α dependent. Oral Dis 19:702–711

    Article  CAS  PubMed  Google Scholar 

  3. da Rosa DP, Forgiarini LF, Baronio D, Feijó CA, Martinez D, Marroni NP (2012) Simulating sleep apnea by exposure to intermittent hypoxia induces inflammation in the lung and liver. Mediators Inflamm 2012:879419

    PubMed  PubMed Central  Google Scholar 

  4. Börgel J, Sanner BM, Bittlinsky A, Keskin F, Bartels NK, Buechner N, Huesing A, Rump LC, Mügge A (2006) Obstructive sleep apnoea and its therapy influence high-density lipoprotein cholesterol serum levels. Eur Respir J 27:121–127

    Article  PubMed  Google Scholar 

  5. Kono M, Tatsumi K, Saibara T, Nakamura A, Tanabe N, Takiguchi Y, Kuriyama T (2007) Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome. Chest 131:1387–1392

    Article  CAS  PubMed  Google Scholar 

  6. Kowal RC, Herz J, Goldstein JL, Esser V, Brown MS (1989) Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci U S A 86:5810–5814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rohlmann A, Gotthardt M, Hammer RE, Herz J (1998) Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. J Clin Invest 101:689–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Botham KM, Wheeler-Jones CP (2007) Introduction to the biochemical society focused meeting on diet and cardiovascular health: chylomicron remnants and their emerging roles in vascular dysfunction in atherosclerosis. Biochem Soc Trans 35:437–439

    Article  CAS  PubMed  Google Scholar 

  9. Pieper-Fürst U, Lammert F (2013) Low-density lipoprotein receptors in liver: old acquaintances and a newcomer. Biochim Biophys Acta 1831:1191–1198

    Article  PubMed  Google Scholar 

  10. Shang J, Yang YY, Guo XL, Liu HG (2013) Ang II type 1 receptor expression in rat aorta exposed to chronic intermittent hypoxia: effects of p38MAPK and ERK1/2 signaling. Chin Med J (Engl) 126:3264–3269

    CAS  Google Scholar 

  11. Li RC, Haribabu B, Mathis SP, Kim J, Gozal D (2011) Leukotriene B4 receptor-1 mediates intermittent hypoxia-induced atherogenesis. Am J Respir Crit Care Med 184:124–131

    Article  PubMed  PubMed Central  Google Scholar 

  12. Llorente-Cortés V, Costales P, Bernués J, Camino-Lopez S, Badimon L (2006) Sterol regulatory element-binding protein-2 negatively regulates low density lipoprotein receptor-related protein transcription. J Mol Biol 359:950–960

    Article  PubMed  Google Scholar 

  13. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D’Agostino RB, Newman AB, Lebowitz MD, Pickering TG (2000) Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283:1829–1836

    Article  CAS  PubMed  Google Scholar 

  14. Peppard PE, Young T, Palta M, Skatrud J (2000) Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342:1378–1384

    Article  CAS  PubMed  Google Scholar 

  15. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, O’Connor GT, Boland LL, Schwartz JE, Samet JM (2001) Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 163:19–25

    Article  CAS  PubMed  Google Scholar 

  16. Mooe T, Franklin KA, Holmström K, Rabben T, Wiklund U (2001) Sleep-disordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med 164:1910–1913

    Article  CAS  PubMed  Google Scholar 

  17. Gami AS, Howard DE, Olson EJ, Somers VK (2005) Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 352:1206–1214

    Article  CAS  PubMed  Google Scholar 

  18. de Lucas-Ramos P, Izquierdo-Alonso JL, Rodriguez- Gonzalez Moro JM, Frances JF, Lozano PV, Bellón-Cano JM, CONSISTE study group (2012) Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case–control study (CONSISTE study). Int J Chron Obstruct Pulmon Dis 7:679–686

    Article  PubMed  PubMed Central  Google Scholar 

  19. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP (2004) Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 25:735–741

    Article  PubMed  Google Scholar 

  20. Roche F, Sforza E, Pichot V, Maudoux D, Garcin A, Celle S, Picard-Kossovsky M, Gaspoz JM, Barthélémy JC, PROOF Study Group (2009) Obstructive sleep apnoea/hypopnea influences high-density lipoprotein cholesterol in the elderly. Sleep Med 10:882–886

    Article  PubMed  Google Scholar 

  21. Li J, Thorne LN, Punjabi NM, Sun CK, Schwartz AR, Smith PL, Marino RL, Rodriguez A, Hubbard WC, O’Donnell CP, Polotsky VY (2005) Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res 97:698–706

    Article  CAS  PubMed  Google Scholar 

  22. Perry JC, D’Almeida V, Souza FG, Schoorlemmer GH, Colombari E, Tufik S (2007) Consequences of subchronic and chronic exposure to intermittent hypoxia and sleep deprivation on cardiovascular risk factors in rats. Respir Physiol Neurobiol 156:250–258

    Article  PubMed  Google Scholar 

  23. Li J, Savransky V, Nanayakkara A, Smith PL, O’Donnell CP, Polotsky VY (2007) Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol 102:557–563

    Article  CAS  PubMed  Google Scholar 

  24. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M (1996) Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271:518–520

    Article  CAS  PubMed  Google Scholar 

  25. Barceló A, Miralles C, Barbé F, Vila M, Pons S, Agustí AG (2000) Abnormal lipid peroxidation in patients with sleep apnoea. Eur Respir J 16:644–647

    Article  PubMed  Google Scholar 

  26. Tan KC, Chow WS, Lam JC, Lam B, Wong WK, Tam S, Ip MS (2006) HDL dysfunction in obstructive sleep apnea. Atherosclerosis 184:377–382

    Article  CAS  PubMed  Google Scholar 

  27. Rydberg EK, Krettek A, Ullström C, Ekström K, Svensson PA, Carlsson LM, Jönsson-Rylander AC, Hansson GI, McPheat W, Wiklund O, Ohlsson BG, Hultén LM (2004) Hypoxia increases LDL oxidation and expression of 15- lipoxygenase-2 in human macrophages. Arterioscler Thromb Vasc Biol 24:2040–2045

    Article  CAS  PubMed  Google Scholar 

  28. Savransky V, Nanayakkara A, Li J, Bevans S, Smith PL, Rodriguez A, Polotsky VY (2007) Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 175:1290–1297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yuan G, Nanduri J, Bhasker CR, Semenza GL, Prabhakar NR (2005) Ca2+/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J Biol Chem 280:4321–4328

    Article  CAS  PubMed  Google Scholar 

  30. Li J, Bosch-Marce M, Nanayakkara A, Savransky V, Fried SK, Semenza GL, Polotsky VY (2006) Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1. Physiol Genomics 25:450–457

    Article  CAS  PubMed  Google Scholar 

  31. Choy PC, Siow YL, Mymin D, O K (2004) Lipids and atherosclerosis. Biochem Cell Biol 82:212–224

  32. Kanekiyo T, Bu G (2014) The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease. Front Aging Neurosci 6:93

    Article  PubMed  PubMed Central  Google Scholar 

  33. Herz J, Strickland DK (2014) LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 108:779–784

    Article  Google Scholar 

  34. Tamaki C, Ohtsuki S, Iwatsubo T, Hashimoto T, Yamada K, Yabuki C, Terasaki T (2006) Major involvement of low-density lipoprotein receptor-related protein 1 in the clearance of plasma free amyloid b-peptide by the liver. Pharm Res 23:1407–1416

    Article  CAS  PubMed  Google Scholar 

  35. Castellano J, Aledo R, Sendra J, Costales P, Juan-Babot O, Badimon L, Llorente-Cortés V (2011) Hypoxia stimulates low-density lipoprotein receptor-related protein-1 expression through hypoxia-inducible factor-1α in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31:1411–1420

    Article  CAS  PubMed  Google Scholar 

  36. Moon JH, Kang SB, Park JS, Lee BW, Kang ES, Ahn CW, Lee HC, Cha BS (2011) Up-regulation of hepatic low-density lipoprotein receptor-related protein 1: a possible novel mechanism of antiatherogenic activity of hydroxymethylglutaryl-coenzyme A reductase inhibitor Atorvastatin and hepatic LRP1 expression. Metabolism 60:930–940

    Article  CAS  PubMed  Google Scholar 

  37. Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM (1994) YC-1, a novel activator of platelet guanylate cyclase. Blood 84:4226–4233

    CAS  PubMed  Google Scholar 

  38. Chun YS, Yeo EJ, Choi E, Teng CM, Bae JM, Kim MS, Park JW (2001) Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochem Pharmacol 61:947–954

    Article  CAS  PubMed  Google Scholar 

  39. Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW (2003) YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 95:516–525

    Article  CAS  PubMed  Google Scholar 

  40. Rankin EB, Rha J, Selak MA, Unger TL, Keith B, Liu Q, Haase VH (2009) Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Mol Cell Biol 29:4527–4538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Conflicts of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xue-wei Feng.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, P., Wu, J., Zhao, L. et al. Effects and relationship of intermittent hypoxia on serum lipid levels, hepatic low-density lipoprotein receptor-related protein 1, and hypoxia-inducible factor 1α. Sleep Breath 20, 167–173 (2016). https://doi.org/10.1007/s11325-015-1200-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11325-015-1200-4

Keywords

Navigation