Triglyceride-Rich HDL₃ from Patients with Familial Hypercholesterolemia Are Less Able to Inhibit Cytokine Release or to Promote Cholesterol Efflux
2006
Ottestad, Inger O. | Halvorsen, Bente | Balstad, Trude R. | Otterdal, Kari | Borge, Grethe I. | Brosstad, Frank | Myhre, Anne M. | Ose, Leiv | Nenseter, Marit S. | Holven, Kirsten B.
Familial hypercholesterolemia (FH) is associated with heterogeneity of the onset and severity of coronary heart disease (CHD). In this study, we investigated different low-grade proinflammatory markers and the atheroprotective function of the HDL₃ subfraction in FH-patients (n = 13) with identical LDL-receptor mutations and in age- and sex-matched healthy controls (n = 11). Compared with healthy controls, FH-patients had greater gene expressions of the proatherogenic mediators TNF-[alpha] and IL-8 in circulating peripheral blood mononuclear cells. In addition, they had a higher serum concentration of intercellular adhesion molecule-1 (ICAM-1) and a lower net antioxidant capacity. FH-derived HDL₃ with a high level of triglycerides had a reduced capacity to inhibit the release of IL-8 from TNF-[alpha]-stimulated human umbilical vein endothelial cells (HUVEC) [1.864 mg/L (1.461-2.208 mg/L) vs. 1.466 mg/L (1.225-1.643 mg/L); P < 0.05; median (range)], and a reduced capacity to promote cholesterol efflux from lipid-loaded macrophages [12% (12-14%) vs. 15% (14-18%); P < 0.05; median (range)] compared with HDL₃ with a lower triglyceride content. Notably, the degree of inhibition of IL-8 release from HUVEC by HDL₃ was correlated with the ability of HDL₃ to promote cholesterol efflux (r = -0.80, P = 0.03). In conclusion, compared with healthy controls, FH-patients are characterized by higher levels of low-grade proinflammatory markers, and FH-derived HDL₃ with high triglyceride content may be more proatherogenic. These triglyceride rich-HDL₃ might be partly responsible for the phenotypic variation among FH-patients with identical LDL-receptor mutations.
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