Serum sdLDL-C and Cellular SREBP2-Dependent Cholesterol Levels; Is there a Challenge on Targeting PCSK9?

Open access


Background: Serum small dense LDL-cholesterol (sdLDL-C) value is suggested to be an important risk factor for atherosclerosis. Since sdLDL-C changes may be related to PCSK9 and SREBP-2 functions, the aim of this study was to investigate correlations between sdLDL-C, circulating PCSK9, SREBP-2 expression and some lipid parameters in serum and buffy coat fraction of healthy subjects.

Methods: One hundred and twenty-four subjects were randomly included in the study. The lipid profile was measured using routine laboratory methods. The serum sdLDL-C level was calculated by a heparin-related precipitation technique. The cellular LDL-C/protein and cholesterol/protein values were measured after lysing of cells with methanol/chloroform binary solvent. The circulating PCSK9 level was measured using ELISA technique. The SREBP-2 expression level was estimated using the RT-qPCR technique.

Results: Data showed significant correlations between LDL-C, TG and sdLDL-C levels (r=0.34, p=0.001; r=0.2, p=0.04). The circulating PCSK9 level was correlated to LDL-C (r=0.29, p=0.04), but not to sdLDL-C (r=−0.08, p=0.57). Also, cellular LDL-C value was not related to serum LDL-C level (r=−0.12, p=0.39). Furthermore, there was an inverse correlation between cellular LDL-C/protein value and estimated de novo cholesterol/protein value (r=−0.5, p=0.001). Similar results were observed for cellular LDL-C/protein value and SREBP-2 expression level (r=−0.52, p=0.004).

Conclusions: We concluded that the serum sdLDL-C value is not related to circulating PCSK9. Furthermore, SREBP-2 regulatory system was able to elevate the cellular cholesterol level after reducing LDL influx. We suggest to investigate the cellular sdLDL fate and lipid synthesis pathways in PCSK9-targeting studies.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Conti P Shaik-Dasthagirisaeb Y. Atherosclerosis: a chronic inflammatory disease mediated by mast cells. Cent Eur J Immunol 2015; 40(3): 380–6.

  • 2. Najafi M Roustazadeh A Alipoor B. Ox-LDL Particles: Modified Components Cellular Uptake Biological Roles and Clinical Assessments. Cardiovasc Hematol Disord Drug Targets 2011; 11(2): 119–28.

  • 3. Zhang PY Xu X Li XC. Cardiovascular diseases: oxidative damage and antioxidant protection. Eur Rev Med Pharmacol Sci 2014; 18(20): 3091–6.

  • 4. Hirayama S Miida T. Small dense LDL: An emerging risk factor for cardiovascular disease. Clin Chim Acta 2012; 414: 215–24.

  • 5. Shen H Xu L Lu J Hao T Ma C Yang H Lu Z Gu Y Zhu T Shen G. Correlation between small dense low-density lipoprotein cholesterol and carotid artery intima-media thickness in a healthy Chinese population. Lipids Health Dis 2015 Oct 29; 14: 137.

  • 6. Superko HR. Small dense low-density lipoprotein subclass pattern B: issues for the clinician. Curr Atheroscler Rep 1999; 1(1): 50–7.

  • 7. Giunzioni I Tavori H. New developments in atherosclerosis: clinical potential of PCSK9 inhibition. Vase Health Risk Manag 2015; 11: 493–501.

  • 8. Gu HM Zhang DW. Hypercholesterolemia low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9. Biomed Res 2015; 29(5): 356–61.

  • 9. Haskins JW Zhang S Means RE Kelleher JK Cline GW Canfrán-Duque A Suárez Y Stern DF. Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake. Sci Signal 2015; 8(401): ra111.

  • 10. Hirano T Ito Y Saegusa H Yoshino G. A novel and simple method for quantification of small dense LDL. J Lipid Res 2003; 44(11): 2193–201.

  • 11. Bligh EG Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959; 37(8): 911–7.

  • 12. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248–54.

  • 13. Roberts R. A genetic basis for coronary artery disease. Trends Cardiovasc Med 2015; 25(3): 171–8.

  • 14. Roth EM Bujas-Bobanovic M Louie MJ Cariou B. Patient and Physician Perspectives on Mode of Administration of the PCSK9 Monoclonal Antibody Alirocumab an Injectable Medication to Lower LDL-C Levels. Clin Ther 2015; 37(9): 1945–54.e6.

  • 15. Trifunović D Stanković S Marinković J Banović M Đukanović N Olga Vasović Bosiljka Vujisić-Tešić Milan Petrović Jelena Stepanović Đorđević-Dikić A Beleslin B Nedeljković I Tešić M Ostojić M. Oxidized low density lipoprotein and high sensitive c-reactive protein in non-diabetic pre-diabetic and diabetic patients in the acute phase of the first myocardial infarction treated by primary percutaneous coronary intervention. J Med Biochem 2015; 34: 160–9.

  • 16. Huang YC Chang PY Hwang JS Ning HC. Association of small dense low density lipoprotein cholesterol in type 2 diabetics with coronary artery disease. Biomed J 2014; 37(6): 375–9.

  • 17. Patel JV Caslake MJ Vyas A Cruickshank JK Prabhakaran D Bhatnagar D Reddy KS Lip GY Mackness MI Hughes EA Durrington PN. Triglycerides and small dense low density lipoprotein in the discrimination of coronary heart disease risk in South Asian populations. Atherosclerosis 2010; 209(2): 579–84.

  • 18. Rizzo M Berneis K. Low-density lipoprotein size and cardiovascular risk assessment. QJM 2006; 99(1): 1–14.

  • 19. Zimmerman MR. How Do PCSK9 Inhibitors Stack Up to Statins for Low-Density Lipoprotein Cholesterol Control? Am Health Drug Benefits 2015; 8(8): 436–42.

  • 20. Packard C Caslake M Shepherd J. The role of small dense low density lipoprotein (LDL): a new look. Int J Cardiol 2000; 74 Suppl 1: S17–22.

  • 21. Dong B Singh AB Fung C Kan K Liu J. CETP inhibitors down regulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2 dependent mechanism. Atherosclerosis 2014; 235(2): 449–62.

Journal information
Impact Factor

IMPACT FACTOR 2018: 2.000
5-year IMPACT FACTOR: 1.075

CiteScore 2018: 1.47

SCImago Journal Rank (SJR) 2018: 0.523
Source Normalized Impact per Paper (SNIP) 2018: 0.581

Cited By
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 244 159 6
PDF Downloads 113 80 8