Preventing type 2 diabetes and cardiovascular disease in metabolic syndrome: the role of PPARalpha.

The clustering of cardiovascular risk factors associated with the metabolic syndrome and type 2 diabetes suggests central mechanisms may exist that account for the presence of these abnormalities. Likewise, this clustering also suggests that key therapeutic targets may exist that could allow improvements in many of these parameters. Extensive data implicate peroxisome proliferator-activated receptor-alpha (PPARalpha) as an important transcriptional regulator of lipid metabolism, energy balance and inflammation. PPARalpha is also an established drug target. Experimental data show that activation of PPARalpha by agonists such as fenofibrate improves dyslipidaemia, increases cholesterol efflux and limits inflammation. All of these effects would also be predicted to decrease atherosclerotic risk. Evidence from surrogate markers in humans is also supportive of the concept that PPARalpha may act as a central target capable of influencing a variety of different pathways involved in lipid metabolism. Thus, fenofibrate offers the potential for inducing a co-ordinated PPARalpha response that may improve dyslipidaemia, repress inflammation and limit atherosclerosis in patients with the metabolic syndrome or type 2 diabetes.