Nutr Metab Cardiovasc Dis. 2014 Jun;24(6):594-9.

HDL lipid composition is profoundly altered in patients with type 2 diabetes and atherosclerotic vascular disease.

Cecilia Morgantinia,b, David Meriwether b, Simona Baldia, Silvia Pinnolaa, Elena Venturia, Alan M. Fogelmanb, Ele Ferranninia, Andrea Natalia , Srinivasa T. Reddy c,d

aDepartment of Internal Medicine, University of Pisa, Italy

b Scuola Superiore Sant’Anna c Department of Medicine and dDepartment of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles


To whom correspondence should be addressed:

Srinivasa T. Reddy, Ph.D
Department of Medicine/Cardiology,
Department of Molecular and Medical Pharmacology,
University of California Los Angeles,
650 Charles E. Young Drive South, MRL 3736,
Los Angeles, CA 90095
Phone: 310-206-3915. Fax: 310-206-3605



We have previously shown that in type 2 diabetes (T2D) patients the anti-inflammatory and anti-oxidant functions of HDL are impaired. Recent studies suggest that HDL dysfunction correlates with the lipoprotein content of oxidized fatty acids derived from arachidonic (HETEs) and linoleic acid (HODEs). In this study, we examined whether HDL from T2D patients contain elevated levels of oxidized fatty acids and correlate with cardiovascular diseases (CVD).

HDL contents of HETEs and HODEs were determined by LC-MS/MS in 40 non diabetic controls (ND), 40 T2D without MVC (D-CVD) and 38 T2D with known history of CVD (D+CVD). HDL oxidant index was evaluated by a cell-free assay using dichlorofluorescein. Twenty-six randomly selected subjects from the three groups underwent coronary calcium score evaluation (CAC).

D+CVD patients showed significantly lower total cholesterol, LDL-C and HDL-C, and significantly higher levels of plasma triglycerides. Other major cardiovascular risk factors were similar among the groups. HETEs and HODEs contents, expressed as ng per mg of HDL-C, were significantly increased in D+CVD as compared to D-CVD and ND  patients (p<0.01): 5-HETE 68.4±75.3 vs. 42.2±34.8 and 26.1±16.5; 12-HETE 18.5±20.3 vs. 11.2±7.6 and  10.6±14.7; 15-HETE 9.4±1.2 vs. 5.2±4.7 and 2.7±1.6; 9-HODE 11.2±12.9 vs 7.1±6.1 and 4.5±2.3; 13-HODE 14.2±13.4 vs. 9.0±6.3 and 5.1±3.1. HDL oxidant index was not different among the three groups; however, it was significantly higher in patients with CAC score >100 than in patients with CAC score <100 (1.7±0.4 vs. 1.2±0.4; p<0.008).

In conclusion, patients with diabetes and diabetes+CVD are characterized by a severe, graded enrichment of oxidized fatty acids on HDL. A loss of HDL function (as estimated by the HDL oxidant index) is observed only in patients with more advanced atherosclerosis.



The main result of this study is the significant progressive enrichment of oxidized phospholipids on HDL isolated from patients a) without type 2 diabetes, b) with diabetes but without CVD [D-CVD] and c) diabetes with CVD [D+CVD]. These findings confirm previous preliminary observations suggesting that HDL composition can be profoundly altered in patients with high cardiovascular risk, and for the first time, show that the change in lipid composition is more profound in patients with diabetes and clinical evidence of CVD. It is worth noting that despite the better cardiovascular risk profile, probably related to the expected more intensive pharmacologic and lifestyle intervention, D+CVD showed double the levels of ox-lipids on their HDL compared to D-CVD.

Lipid composition plays an important role in maintaining normal HDL metabolism as well as function. HDL is an assembly of neutral lipid core and an outer shell consisting of polar lipids and proteins that confer distinct chemical and physical properties including density flotation, protein composition, molecular size, and electrophoretic migration. The high heterogeneity in their structure is largely responsible for the differences in metabolism and biological functions. The presence of products of the arachidonic and linoleic acid metabolism (namely, HETEs and HODEs), which are enzymatically and non-enzymatically generated, indicates that lipid peroxidation (accumulation) most likely occurred on these HDLs in response to both inflammation and enhanced oxidative stress from other pathways (e.g. glucose).

The antioxidant properties of HDL studied with the DCF assay showed an increased (pro-oxidative) HDL index in all study groups.  However the differences in HDL index did not reach significance among groups probably because, in the present study, the control population (without diabetes) was selected to have similar risk factors to the diabetic one (i.e. age, high blood pressure, smoke habits, lipid profile, overweight). Furthermore, the DCF assay might be particularly sensitive to the presence of CVD risk factors and a larger sample size may be needed to detect small differences. However, when the study patients were grouped according to a more sensitive measurement of atherosclerosis (i.e. Cardiac Scan), the HDL anti-oxidant properties and HDL composition were altered in patients with abnormal CAC score.

In conclusion the data from this study suggest a direct relationship between CVD severity and HDL composition beyond HDL-cholesterol concentration and anti-oxidant function. Therefore qualitative, in addition to quantitative, differences in these lipoproteins might be, at least in part, responsible for the “unexplained” residual risk of diabetic patients. Pharmacological normalization of HDL metabolism concomitantly with correction of circulating levels, composition and biological activities of HDL particles, with enrichment in apoA-I and reduction in HDL ox-lipids, may constitute an efficacious therapeutic approach to attenuate atherosclerosis progression in type 2 diabetic patients.



Fig.1 Schematic representation of HDL composition changes’ in absence of diabetes, in the presence of diabetes and in the presence of diabetes and cardiovascular diseases. (CVD; cardiovascular diseases; CE: cholesterol, TG: triglycerides, Apo A-I: apolipoprotein A-I; PON1: paroxonase-1; SAA: serum amyloid A; ox-lipids: oxidized lipids)



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