Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of fenofibrate on plasma cholesteryl ester transfer protein (CETP) activity in relation to the quantitative and qualitative features of apoB- and apoA-I-containing lipoprotein subspecies was investigated in nine patients presenting with combined hyperlipidemia. Fenofibrate (200 mg/d for 8 weeks) induced significant reductions in plasma cholesterol (-16%; P < .01), triglyceride (-44%; P < .007), VLDL cholesterol (-52%; P = .01), LDL cholesterol (-14%; P < .001), and apoB (-15%; P < .009) levels and increased HDL cholesterol (19%; P = .0001) and apoA-I (12%; P = .003) levels. An exogenous cholesteryl ester transfer (CET) assay revealed a marked decrease (-26%; P < .002) in total plasma CETP-dependent CET activity after fenofibrate treatment. Concomitant with the pronounced reduction in VLDL levels (37%; P < .005), the rate of CET from HDL to VLDL was significantly reduced by 38% (P = .0001), whereas no modification in the rate of cholesteryl ester exchange between HDL and LDL occurred after fenofibrate therapy. Combined hyperlipidemia is characterized by an asymmetrical LDL profile in which small, dense LDL subspecies (LDL-4 and LDL-5, d = 1.039 to 1.063 g/mL) predominate. Fenofibrate quantitatively normalized the atherogenic LDL profile by reducing levels of dense LDL subspecies (-21%) and by inducing an elevation (26%; P < .05) in LDL subspecies of intermediate density (LDL-3, d = 1.029 to 1.039 g/mL), which possess optimal binding affinity for the cellular LDL receptor. However, no marked qualitative modifications in the chemical composition or size of LDL particles were observed after drug treatment. Interestingly, the HDL cholesterol concentration was increased by fenofibrate therapy, whereas no significant change was detected in total plasma HDL mass. In contrast, the HDL subspecies pattern was modified as the result of an increase in the total mass (11.7%) of HDL2a, HDL3a, and HDL3b (d = 1.091 to 1.156 g/mL) at the expense of reductions in the total mass (-23%) of HDL2b (d = 1.063 to 1.091 g/mL) and HDL3c (d = 1.156 to 1.179 g/mL). Such changes are consistent with a drug-induced reduction in CETP activity. In conclusion, the overall mechanism involved in the fenofibrate-induced modulation of the atherogenic dense LDL profile in combined hyperlipidemia primarily involves reduction in CET from HDL to VLDL together with normalization of the intravascular transformation of VLDL precursors to receptor-active LDLs of intermediate density.
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PMID:Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia. 864 Apr 4

Endpoint studies have been performed with fibrates in coronary heart disease since 1971. The results have been confusing - starting with initial benefits in small studies, but contradicted by either minimal benefits in the Coronary Drug Project or adverse noncardiovascular (non-CV) effects in the World Health Organization Clofibrate Study. Fibrates returned for patients with low HDL-C and low LDL-C after a 25% event reduction were seen in the Veterans Affairs HDL Intervention Trial. The greater prominence ascribed to the lipid triad of the metabolic syndrome and the increasing prevalence of diabetes increased the topicality of fibrates given their main action of converting small dense to light buoyant LDL. The Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) Study has carried on the tradition. Fenofibrate therapy in 9795 patients comprising a mixed low-risk primary and a medium-risk secondary prevention cohort resulted in an 11% reduction in coronary events (p = 0.16), a similar but significant reduction in CV events (p = 0.04; number needed to treat = 70). The benefits were concentrated in primary prevention and on nonfatal myocardial events, but the study was confounded by asymmetrical statin drop-in due to the LDL-C-lowering effect of fenofibrate. Safety was generally good, including in combination with statins, but old concerns about sudden death, pancreatitis and venous thrombosis returned. Unexpected benefits were seen with fenofibrate on microvascular endpoints including microalbuminuria and retinopathy. Fenofibrate is a reasonable second-line therapy for dyslipidaemia in diabetes and safe in combination therapy. Its benefits on microvascular disease and in combination therapy require further confirmation.
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PMID:FIELDS of dreams, fields of tears: a perspective on the fibrate trials. 1662 Mar 58