Tumor necrosis factor alpha (TNFα) and its soluble receptor p75 (sTNF-R p75) in familial combined hyperlipidemia (FCHL)

Background and aim: Familial combined hyperlipidemia (FCHL) is a genetic disorder of lipid metabolism associated with insulin resistance and abnormalities in fatty acid metabolism whose underlying mechanisms are largely unknown. Perturbations in the TNF alpha/TNF-R pathway may play a rote in these abnormalities. Methods and results: We determined plasma levels of TNF alpha and sTNF-R p75 in 85 FCHL patients (TC 245 +/- 45 mg/dl; TG 260 +/- 148 mg/dl; apoB 148 +/- 37 mg/dl) and in 29 age- and sex-matched normolipemic relatives (NL) (TC 187 +/- 22.8 mg/dl; TG 115 +/- 37 mg/dl; apoB 106 16 mg/dl). Thirty-four normolipemic subjects (TC 180 +/- 34 mg/dl.; TG 107 +/- 42 mg/dl; apoB 95 +/- 22 mg/dl) were also included as unrelated controls (NC). Plasma free fatty acids (NEFA) were also measured and insulin sensitivity was evaluated by HOMA. Levels of sTNF-R p75 were significantly reduced in FCHL compared to NL (2.30 +/- 0.55 ng/ml vs. 2.64 +/- 0.88 ng/ml, p < 0.05) but not compared to NC (2.35 +/- 0.68 ng/ml). HOMA values were comparable in all groups and did not show any relation with plasma levels of sTNF-R p75. Logistic analysis demonstrated that a tow concentration of sTNF-R p75 was an independent predictor of the affected status within FCHL families, but this rote was no longer evident when FCHL patients were compared to NC. In FCHL, age (p < 0.001) was positively, and TG (p = 0.029) and HDL-C (p = 0.025) were negatively correlated with plasma concentrations of sTNF-R p75. In the other groups, age (in NL) and non-HDL-C (in NC) were significantly correlated with sTNF-R p75. Conclusions: Although our data do not support a causative rote of TNF alpha/TNF-R alterations in FCHL, they confirm that variation in TNF-R shedding may influence lipid phenotypic expression in FCHL families. (C) 2005 Elsevier B.V. All rights reserved.