Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Sep 13;15(1):132.
doi: 10.1186/s12933-016-0450-1.

Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients

Dong Zhao  1 , Long-Yan Yang  1 , Xu-Hong Wang  1 , Sha-Sha Yuan  1 , Cai-Guo Yu  1 , Zong-Wei Wang  1 , Jia-Nan Lang  1 , Ying-Mei Feng  2   3
Affiliations

Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients

Dong Zhao et al. Cardiovasc Diabetol. .

Abstract

Background: Angiopoietin-like protein 3 (ANGPTL3) is a major lipoprotein regulator and shows positive correlation with high-density lipoprotein-cholesterol (HDL-c) in population studies and ANGPTL3 mutated subjects. However, no study has looked its correlation with HDL components nor with HDL function in patients with type 2 diabetes mellitus (T2DM).

Methods: We studied 298 non-diabetic subjects and 300 T2DM patients who were randomly recruited in the tertiary referral centre. Plasma levels of ANGPTL3 were quantified by ELISA. Plasma samples were fractionated to obtain HDLs. HDL components including apolipoprotein A-I (apoA-I), triglyceride, serum amyloid A (SAA), phospholipid and Sphingosine-1-phosphate were measured. HDLs were isolated from female controls and T2DM patients by ultracentrifugation to assess cholesterol efflux against HDLs. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, body mass index and lipid lowering drugs were performed in male or female non-diabetic participants or diabetic patients, respectively.

Results: We demonstrated that plasma level of ANGPTL3 was lower in female T2DM patients than female controls although no difference of ANGPTL3 levels was detected between male controls and T2DM patients. After adjusting for confounding factors, one SD increase of ANGPTL3 (164.6 ng/ml) associated with increase of 2.57 mg/dL cholesterol and 1.14 μg/mL apoA-I but decrease of 47.07 μg/L of SAA in HDL particles of non-diabetic females (p < 0.05 for cholesterol and SAA; p < 0.0001 for apoA-I). By contrast, 1-SD increase of ANGPTL3 (159.9 ng/ml) associated with increase of 1.69 mg/dl cholesterol and 1.25 μg/mL apoA-I but decrease of 11.70 μg/L of SAA in HDL particles of female diabetic patients (p < 0.05 for cholesterol; p < 0.0001 for apoA-I; p = 0.676 for SAA). Moreover, one SD increase of ANGPTL3 associated with increase of 2.11 % cholesterol efflux against HDLs in non-diabetic females (p = 0.071) but decrease of 1.46 % in female T2DM patients (p = 0.13) after adjusting for confounding factors.

Conclusions: ANGPTL3 is specifically correlated with HDL-c, apoA-I, SAA and HDL function in female non-diabetic participants. The decrease of ANGPTL3 level in female T2DM patients might contribute to its weak association to HDL components and function. ANGPTL3 could be considered as a novel therapeutic target for HDL metabolism for treating diabetes.

Keywords: Angiopoietin-like protein; Apolipoproteins; Cholesterol efflux; Diabetes; High-density lipoproteins; Serum amyloid A.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Plasma levels of ANGPTL3 and its association with total cholesterol, LDL-c or HDL-c in non-diabetic subjects and T2DM patients. a Quantification of plasma level of ANGPTL3 in non-diabetic subjects and T2DM patients. Univariate analysis showed the correlation between ANGPTL3 and total cholesterol (b), LDL-c (c) and HDL-c (d) in non-diabetic controls (n = 299). In parallel, the correlation between ANGPTL3 and total cholesterol (e), LDL-c (f) and HDL-c (g) in T2DM patients (n = 300). The parallel lines defined the 90 % prediction band
Fig. 2
Fig. 2
Univariate association between plasma level of Angptl3 and HDL-c, apoA-I or serum amyloid A in non-diabetic females (a–c) and diabetic females (d–f). The parallel lines defined the 90 % prediction band. Significance: §p < 0.0001; ǂp < 0.001; łp < 0.01; * p < 0.05
Fig. 3
Fig. 3
Association between ANGPTL3 levels and HDL function in non-diabetic and T2DM female subjects. HDL was isolated from plasma of non-diabetic or T2DM female subjects. RAW264.7 macrophages were loaded with fluorescent labeled cholesterol for 16 h and then exposed to 100 μg/ml HDLs for 4 h. Fluorescence intensity in the supernatant and cells were determined to calculate the percentage of cholesterol efflux towards HDLs. The correlation between ANGPTL3 levels and the percentage of cholesterol efflux in female non-diabetic participants (n = 42) or T2DM patients (n = 45) is shown in a and b, respectively. The parallel lines defined the 90 % prediction band
Fig. 4
Fig. 4
Plasma level of ANGPTL3 in relationship to HDL components and function in non-diabetic female subjects and female T2DM patients. Regression was performed between standardized ANGPTL3 and cholesterol (a), apoA-I (b), Serum Amyloid A (c) and the percentage of cholesterol efflux (d) in HDLs in non-diabetic female subjects and female T2DM patients. Estimates express as change in unit with 1-SD increase of ANGPTL3 in non-diabetic subjects and T2DM patients, respectively. §p < 0.0001; ǂp < 0.001; łp < 0.01; * p < 0.05
Fig. 5
Fig. 5
The effect of insulin on ANGPTL3 level in diabetic subjects. Unadjusted correlation analysis between plasma insulin level and ANGPTL3 level in non-diabetic participants (a) and diabetic patients (b). The parallel lines defined the 90 % prediction band. C57BL/6 and db/db mice were received peritoneal injection of 10 % glucose at 10 μl/g of body weight. Blood glucose was determined (c). d Representative western blot of pAkt and Akt in normal hepatocytes stimulated with 100 nM insulin ex vivo. (E) Western blot showing the expression of pAkt and Akt in diabetic hepatocytes stimulated with 100 nM insulin in the presence or absence of 1 μM pAkt inhibitor. f Hepatocytes were isolated from diabetic db/db mice and stimulated with 100 nM insulin in the presence or absence of pAkt inhibitor VIII. Representative western blot of pAkt and totak Akt in diabetic hepatocytes ex vivo. f ANGPTL3 and GAPDH expression in HepG2 cells by western blot and quantification of ANGPTL3 expression when adjusted by GAPDH expression. g Hepatocytes isolated from db/db mice were treated with 100 nM insulin in the presence or absence of Akt inhibitor VIII. Representative western blot of ANGPTL3 and GAPDH. ANGPTL3 expression was quantified by adjusting with GAPDH expression. Db/db mice were injected with insulin 2 U/kg. Plasma insulin (h) and ANGPTL3 was quantified (i). §p < 0.0001; ǂp < 0.001; łp < 0.01
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Saleheen D, Scott R, Javad S, Zhao W, Rodrigues A, Picataggi A, Lukmanova D, Mucksavage ML, Luben R, Billheimer J, et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. The Lancet Diabetes & Endocrinology. 2015;3(7):507–513. doi: 10.1016/S2213-8587(15)00126-6. - DOI - PMC - PubMed
    1. Kratzer A, Giral H, Landmesser U. High-density lipoproteins as modulators of endothelial cell functions: alterations in patients with coronary artery disease. Cardiovasc Res. 2014;103(3):350–361. doi: 10.1093/cvr/cvu139. - DOI - PubMed
    1. Tong X, Peng H, Liu D, Ji L, Niu C, Ren J, Pan B, Hu J, Zheng L, Huang Y. High-density lipoprotein of patients with type 2 diabetes mellitus upregulates cyclooxgenase-2 expression and prostacyclin I-2 release in endothelial cells: relationship with HDL-associated sphingosine-1-phosphate. Cardiovascular Diabetology. 2013;12:27. doi: 10.1186/1475-2840-12-27. - DOI - PMC - PubMed
    1. Tabet F, Vickers KC, Cuesta Torres LF, Wiese CB, Shoucri BM, Lambert G, Catherinet C, Prado-Lourenco L, Levin MG, Thacker S, et al. HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells. Nature Communications. 2014;5:3292. doi: 10.1038/ncomms4292. - DOI - PMC - PubMed
    1. Patel S, Drew BG, Nakhla S, Duffy SJ, Murphy AJ, Barter PJ, Rye KA, Chin-Dusting J, Hoang A, Sviridov D, et al. Reconstituted high-density lipoprotein increases plasma high-density lipoprotein anti-inflammatory properties and cholesterol efflux capacity in patients with type 2 diabetes. J Am Coll Cardiol. 2009;53(11):962–971. doi: 10.1016/j.jacc.2008.12.008. - DOI - PubMed

Publication types

MeSH terms