Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Clinical Studies and Practice

Circulating sCD36 levels in patients with non-alcoholic fatty liver disease and controls

International Journal of Obesity volume 41, pages 262–267 (2017)Cite this article

Subjects

Abstract

Background and objective:

CD36 is implicated in fatty-acid uptake in multiple tissues, including hepatocytes and adipocytes. Circulating CD36 (sCD36) is increased in non-alcoholic fatty liver disease (NAFLD). We explored this association further by investigating correlations between sCD36 levels, intrahepatic lipid content and markers of obesity in NAFLD patients and controls.

Methods:

In total, 111 NAFLD patients and 33 normal/overweight controls were included. Intrahepatic lipid content was measured by magnetic resonance spectroscopy; and subgroups of participants had a dual-energy X-ray absorptiometry (n=99), magnetic resonance imaging (n=94, subcutaneous and visceral adipose tissue) and liver biopsy (n=28 NAFLD patients) performed. Plasma sCD36 was assessed by enzyme-linked immunosorbent assay.

Results:

NAFLD patients had elevated sCD36 levels compared with controls (0.68 (0.12–2.27) versus 0.43 (0.10–1.18), P<0.01). sCD36 correlated with intrahepatic lipid (rs=0.30), alanine transaminase (ALT) (r=0.31), homeostasis model assessment index-insulin resistance (r=0.24), high-density lipoprotein (r=−0.32) and triglyceride (r=0.44, all P<0.01). Intrahepatic lipid and plasma triglyceride were independent predictors of sCD36 levels in a multiple regression analysis. Further, sCD36 and body mass index were weakly correlated (r=0.17, P=0.04); yet, we found no correlations between sCD36 and other measures of fat distribution except an inverse relation to visceral adipose tissue (rs=−0.21, P<0.05). We observed a trend for correlation between sCD36 and hepatic CD36 mRNA expression (r=0.37, P=0.07).

Conclusions:

sCD36 levels increased with the level of intrahepatic lipid, insulin resistance and dyslipidemia. The weak association with markers of obesity and the association with hepatic CD36 mRNA expression suggest that excess sCD36 in NAFLD patients is derived from the hepatocytes, which may support that CD36 is involved in NAFLD development. An unhealthy and unbalanced CD36 expression in adipose and hepatic tissue may shift the fatty-acid load to the liver.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766–781.

    Article  Google Scholar 

  2. Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg 2004; 14: 635–637.

    Article  Google Scholar 

  3. Welsh JA, Karpen S, Vos MB . Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr 2013; 162: 496–500 e1.

    Article  Google Scholar 

  4. Vernon G, Baranova A, Younossi ZM . Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011; 34: 274–285.

    Article  CAS  Google Scholar 

  5. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ . Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115: 134351.

    Article  Google Scholar 

  6. Koonen DP, Jensen MK, Handberg A . Soluble CD36- a marker of the (pathophysiological) role of CD36 in the metabolic syndrome? Arch Physiol Biochem 2011; 117: 57–63.

    Article  CAS  Google Scholar 

  7. Miquilena-Colina ME, Lima-Cabello E, Sanchez-Campos S, Garcia-Mediavilla MV, Fernandez-Bermejo M, Lozano-Rodriguez T et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 2011; 60: 1394–1402.

    Article  CAS  Google Scholar 

  8. Garcia-Monzon C, Lo Iacono O, Crespo J, Romero-Gomez M, Garcia-Samaniego J, Fernandez-Bermejo M et al. Increased soluble CD36 is linked to advanced steatosis in nonalcoholic fatty liver disease. Eur J Clin Invest 2014; 44: 65–73.

    Article  CAS  Google Scholar 

  9. Handberg A, Højlund K, Gastaldelli A, Flyvbjerg A, Dekker JM, Petrie J et al. Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population. J Intern Med 2012; 271: 294–304.

    Article  CAS  Google Scholar 

  10. Heebøll S, Kreuzfeldt M, Hamilton-Dutoit S, Kjær Poulsen M, Stødkilde-Jørgensen H, Møller HJ et al. Placebo-controlled, randomised clinical trial: high-dose resveratrol treatment for non-alcoholic fatty liver disease. Scand J Gastroenterol 2016; 51: 456–464.

    Article  Google Scholar 

  11. Ornstrup MJ, Harsløf T, Kjær TN, Langdahl BL, Pedersen SB . Resveratrol increases bone mineral density and bone alkaline phosphatase in obese men: a randomized placebo-controlled trial. J Clin Endocrinol Metab 2014; 99: 4720–4729.

    Article  CAS  Google Scholar 

  12. Poulsen MK, Nellemann B, Stødkilde-Jørgensen H, Pedersen SB, Grønbæk H, Nielsen S . Impaired insulin suppression of VLDL-triglyceride kinetics in non-alcoholic fatty liver disease. J Clin Endocrinol Metab 2016; 101: 1637–1646.

    Article  Google Scholar 

  13. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462–E468.

    Article  CAS  Google Scholar 

  14. Ornstrup MJ, Kjær TN, Harsløf T, Stødkilde-Jørgensen H, Hougaard DM, Cohen A et al. Adipose tissue, estradiol levels, and bone health in obese men with metabolic syndrome. Eur J Endocrinol 2015; 172: 205–216.

    Article  Google Scholar 

  15. Wallace TM, Levy JC, Matthews DR . Use and abuse of HOMA modeling. Diabetes Care 2004; 27: 1487–1495.

    Article  Google Scholar 

  16. Handberg A, Levin K, Hojlund K, Beck-Nielsen H . Identification of the oxidized low-density lipoprotein scavenger receptor CD36 in plasma: a novel marker of insulin resistance. Circulation 2006; 114: 1169–1176.

    Article  CAS  Google Scholar 

  17. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313–1321.

    Article  Google Scholar 

  18. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012; 56: 1751–1759.

    Article  Google Scholar 

  19. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA 2009; 106: 15430–15435.

    Article  CAS  Google Scholar 

  20. Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P, Kiviluoto T et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 2008; 294: G1281–G1287.

    Article  CAS  Google Scholar 

  21. Bechmann LP, Gieseler RK, Sowa JP, Kahraman A, Erhard J, Wedemeyer I et al. Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis. Liver Int 2010; 30: 850–859.

    Article  CAS  Google Scholar 

  22. Sheedfar F, Sung MM, Aparicio-Vergara M, Kloosterhuis NJ, Miquilena-Colina ME, Vargas-Castrillon J et al. Increased hepatic CD36 expression with age is associated with enhanced susceptibility to nonalcoholic fatty liver disease. Aging 2014; 6: 281–295.

    Article  CAS  Google Scholar 

  23. Krssak M, Hofer H, Wrba F, Meyerspeer M, Brehm A, Lohninger A et al. Non-invasive assessment of hepatic fat accumulation in chronic hepatitis C by 1H magnetic resonance spectroscopy. Eur J Radiol 2010; 74: e60–e66.

    Article  Google Scholar 

  24. Knøsgaard L, Thomsen SB, Stockel M, Vestergaard H, Handberg A . Circulating sCD36 is associated with unhealthy fat distribution and elevated circulating triglycerides in morbidly obese individuals. Nutr Diabetes 2014; 4: e114.

    Article  Google Scholar 

  25. Liani R, Halvorsen B, Sestili S, Handberg A, Santilli F, Vazzana N et al. Plasma levels of soluble CD36, platelet activation, inflammation, and oxidative stress are increased in type 2 diabetic patients. Free Radic Biol Med 2012; 52: 1318–1324.

    Article  CAS  Google Scholar 

  26. Lykkeboe S, Larsen AL, Handberg A . Lack of consistency between two commercial ELISAs and against an in-house ELISA for the detection of CD36 in human plasma. Clin Chem Lab Med 2012; 50: 1071–1074.

    Article  CAS  Google Scholar 

  27. Bieghs V, Verheyen F, van Gorp PJ, Hendrikx T, Wouters K, Lutjohann D et al. Internalization of modified lipids by CD36 and SR-A leads to hepatic inflammation and lysosomal cholesterol storage in Kupffer cells. PloS One 2012; 7: e34378.

    Article  CAS  Google Scholar 

  28. Bieghs V, Wouters K, van Gorp PJ, Gijbels MJ, de Winther MP, Binder CJ et al. Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice. Gastroenterology 2010; 138: 2477–2486 e1−3.

    Article  CAS  Google Scholar 

  29. Glatz JF, Luiken JJ, Bonen A . Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev 2010; 90: 367–417.

    Article  CAS  Google Scholar 

  30. Liang CP, Han S, Okamoto H, Carnemolla R, Tabas I, Accili D et al. Increased CD36 protein as a response to defective insulin signaling in macrophages. J Clin Invest 2004; 113: 764–773.

    Article  CAS  Google Scholar 

  31. Steneberg P, Sykaras AG, Backlund F, Straseviciene J, Soderstrom I, Edlund H . Hyperinsulinemia enhances hepatic expression of the fatty acid transporter Cd36 and provokes hepatosteatosis and hepatic insulin resistance. J Biol Chem 2015; 290: 19034–19043.

    Article  CAS  Google Scholar 

  32. Buque X, Cano A, Miquilena-Colina ME, Garcia-Monzon C, Ochoa B, Aspichueta P . High insulin levels are required for FAT/CD36 plasma membrane translocation and enhanced fatty acid uptake in obese Zucker rat hepatocytes. Am J Physiol Endocrinol Metab 2012; 303: E504–E514.

    Article  CAS  Google Scholar 

  33. Nicholson AC . Expression of CD36 in macrophages and atherosclerosis: the role of lipid regulation of PPARgamma signaling. Trends Cardiovasc Med 2004; 14: 8–12.

    Article  CAS  Google Scholar 

  34. Glintborg D, Højlund K, Andersen M, Henriksen JE, Beck-Nielsen H, Handberg A . Soluble CD36 and risk markers of insulin resistance and atherosclerosis are elevated in polycystic ovary syndrome and significantly reduced during pioglitazone treatment. Diabetes Care 2008; 31: 328–334.

    Article  CAS  Google Scholar 

  35. Handberg A, Norberg M, Stenlund H, Hallmans G, Attermann J, Eriksson JW . Soluble CD36 (sCD36) clusters with markers of insulin resistance, and high sCD36 is associated with increased type 2 diabetes risk. J Clin Endocrinol Metab 2010; 95: 1939–1946.

    Article  CAS  Google Scholar 

  36. Alkhatatbeh MJ, Mhaidat NM, Enjeti AK, Lincz LF, Thorne RF . The putative diabetic plasma marker, soluble CD36, is non-cleaved, non-soluble and entirely associated with microparticles. J Thromb Haemost 2011; 9: 844–851.

    Article  CAS  Google Scholar 

  37. Gustafson CM, Shepherd AJ, Miller VM, Jayachandran M . Age- and sex-specific differences in blood-borne microvesicles from apparently healthy humans. Biol Sex Differ 2015; 6: 10.

    Article  Google Scholar 

  38. Alkhatatbeh MJ, Enjeti AK, Acharya S, Thorne RF, Lincz LF . The origin of circulating CD36 in type 2 diabetes. Nutr Diabetes 2013; 3: e59.

    Article  CAS  Google Scholar 

  39. Zhou D, Samovski D, Okunade AL, Stahl PD, Abumrad NA, Su X . CD36 level and trafficking are determinants of lipolysis in adipocytes. FASEB J 2012; 26: 4733–4742.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are thankful for the skilled technical assistance provided by Lone Larsen, Aarhus University Hospital, Denmark. The study was supported by the NOVO Nordisk Foundation, Aarhus University, the Danish Council for Independent Research, Medical Sciences (11-107912); 'Savværksejer Jeppe Juhl og hustru Ovita Juhls mindelegat'. The study is part of the research program LIRMOI Research Center (www.LIRMOI.com), which is supported by the Danish Council for Strategic Research (0-093499).

Author contributions

Declaration of contribution: SH, HG and AH conceived the study. SH collected and researched data and wrote the manuscript. MKP, MO and TNK collected the data and reviewed/edited the manuscript. SN, SBP and HG assisted in study design, data interpretation and reviewed/edited the manuscript. AH assisted in collecting and researching data and writing the manuscript. AH and HG shares last co-author ship.

Author information

Author notes

  1. H Grønbæk and A Handberg: These authors contributed equally to the work as shared last co-authors.

Authors and Affiliations

  1. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark,

    S Heebøll, M K Poulsen, M J Ornstrup, T N Kjær, S B Pedersen & S Nielsen

  2. Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    H Grønbæk

  3. Department of Clinical Biochemistry, and Department of Clinical Medicine, Aalborg University Hospital, Faculty of Health, Aalborg University, Aalborg, Denmark

    A Handberg

Authors
  1. S Heebøll
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M K Poulsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M J Ornstrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T N Kjær
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S B Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Grønbæk
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Handberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Heebøll.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heebøll, S., Poulsen, M., Ornstrup, M. et al. Circulating sCD36 levels in patients with non-alcoholic fatty liver disease and controls. Int J Obes 41, 262–267 (2017). https://doi.org/10.1038/ijo.2016.223

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2016.223

This article is cited by

Search

Advanced search

Quick links