Free fatty acid metabolism during fenofibrate treatment of the metabolic syndrome.

Abstract

Our objective was to determine whether fenofibrate modifies the metabolism of nonesterified (free) fatty acids as a component of its triglyceride-lowering action in male patients with the metabolic syndrome. In a placebo-controlled trial lasting 16 weeks, patients were randomly assigned to fenofibrate (200 mg/d) or placebo for 8 weeks. They were then crossed over to placebo or treatment with fenofibrate for another 8 weeks. Thirteen adult men had clinical characteristics of the metabolic syndrome that included atherogenic dyslipidemia, hypertension, elevated fasting glucose levels, or central obesity or a combination of these. They had measurements of plasma lipid and lipoprotein levels, postheparin lipase activities, and fasting concentrations and turnover rates of nonesterified fatty acids, as well as oral glucose tolerance testing with insulin and nonesterified fatty acid measurements. Levels of apolipoprotein C-II, C-III, and B were also measured, along with levels of low-density lipoprotein cholesterol in lipoprotein species. Fenofibrate therapy did not change plasma concentrations and turnover rates of nonesterified fatty acids. For fasting nonesterified fatty acids, the values (mean +/- SD) for placebo versus fenofibrate were 446 +/- 31 micromol/L versus 493 +/- 71 micromol/L, respectively (not significant); nonesterified fatty acid turnover rates were 336 +/- 36 micromol/min versus 334 +/- 42 micromol/min for placebo versus fenofibrate, respectively. Moreover, no changes were noted in fasting or postprandial levels of plasma glucose and insulin. Despite this lack of change, fenofibrate therapy reduced the plasma levels of triglyceride by 30% (305 +/- 143 mg/dL versus 206 +/- 90 mg/dL for placebo versus fenofibrate, respectively; P <.045), with a similar reduction in cholesterol levels of triglyceride-rich lipoproteins. Large low-density lipoprotein species were increased and small low-density lipoprotein species were decreased by fenofibrate therapy. Levels of apolipoprotein C-III were reduced significantly (P <.03), as were ratios of postheparin hepatic lipase to lipoprotein lipase (P <.05). Fenofibrate therapy markedly reduced plasma triglyceride levels. However, it did not lower concentrations or turnover rates of nonesterified fatty acids, nor did it change glucose or insulin responses to an oral glucose challenge. These findings indicate that fenofibrate modifies fatty acid metabolism either in the liver or in triglyceride-rich lipoproteins but not in adipose tissue. Multiple mechanisms are likely involved as a consequence of the action of fenofibrate to activate peroxisomal-proliferator-activated receptor alpha.