Recent epidemiological studies have shown that almost a quarter of adults in the United States have metabolic syndrome or syndrome X and prevalence of this syndrome is increasing world-wide owing to lifestyle changes leading to obesity [1–3]. A cluster of abnormalities define metabolic syndrome including insulin resistance, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, obesity and hypertension [4–6]; individuals with syndrome have an increased risk of developing cardiovascular disease [5, 6]. Insulin resistance is now considered a central factor among these various abnormalities associated with the metabolic syndrome. With this in mind, much effort is being invested in improving the insulin resistance through lifestyle modification (e.g., weight reduction, dietary interventions, and increased physical activity) and development of new therapeutic agents that sensitize insulin action, ameliorate hypertriglyceridemia, raise HDL levels and improve hypertension [2, 7–12].
In an animal model, high fructose fed (HFF) diets induce metabolic dysfunction typically resulting in a rapid elevation of serum triglycerides with a corresponding increase in blood pressure within two weeks of diet intitiation. Animals maintained on this diet for longer periods of time develop elevated free fatty acids and hyperinsulinemia at the expense of glycemic control. If HFF animals are subjected to an exercise regimen, the diet-induced effects can be ameliorated . Thus this animal model exhibits an early stage of the Metabolic Syndrome in which a combination of physical inactivity and diet results in cardiovascular disease and metabolic complications.
High fructose corn sweeteners began widespread use in the food industry in 1967. Since that time the amount of fructose consumption has steadily risen and now accounts for about 9% of daily caloric intake in the United States. Unlike glucose, which is widely utilized by tissues throughout the body, fructose is primarily metabolized in the liver [14, 15]. Recent epidemiological data suggests that high fructose corn sweeteners may be contributing to the overall epidemic of obesity and metabolic disease in the US .
We initiated studies to test the effects of lipoxygenase/cyclooxygenase inhibitors on the metabolic and hepatic status of HFF rats. We examined two structurally different LOX/COX inhibitors because NDGA, which has previously demonstrated effects in this model , also exhibits numerous other biological effects. In an initial report we showed that high levels of dietary fructose induced the JNK/AP-1 stress response pathway. This observation was confirmed by Wei and Pagliassotti, who correlated fructose-induced JNK activity with hepatic insulin resistance . In our first report, we focused on the correlation between normalization of the stress response pathway and reduction of serum triglycerides. In this report, we expanded these studies to examine diet-induced effects on hepatic peroxisome proliferators-activated receptor α (PPARα) activity and the relationship between LOX/COX inhibitor treatment and of PPARα expression.
PPARα (NR1C1) is a ligand (lipid)-activated transcription factor that belongs to the superfamily of nuclear receptor [19–22]. In addition to PPARα, the NR1C subset of receptors includes two closely related members, PPARβ (or δ, NR1C2) and PPARγ (NR1C3). PPARα is highly expressed in the liver, cardiac muscle, intestine and renal cortex tissues [19, 23], serves an essential function in the regulation of lipid metabolism and controls the expression of a number of genes involved in mitochondrial and peroxisomal β-oxidation [19–22]. It increases gene transcription by binding as a heterodimer with retinoid X receptor (RXR) to PPAR response elements (PPRE) on the promoter regions of the target gene . Activators of PPARα, such as fibrates, lower circulating levels of lipid and are commonly used to treat hypertriglyceridemia [21, 22, 24]. More recent studies have shown an inverse relationship between PPAR activity and abnormalities in fatty acid metabolism leading to the development of insulin resistance and alterations in glucose metabolism [25–27]. In addition, animal studies suggest that that the activation of PPARα improved the insulin resistance that was triggered by the excessive production and accumulation of lipids [28–32].
Our studies indicate hypertriglyceridemia induced by fructose feeding greatly reduces the hepatic expression of both PPARα protein and mRNA levels. We further demonstrate that diet-induced suppression of hepaic PPARα is reversed upon treatment with lipoxygenase/cyclooxygenase inhibitory compounds. Our findings also suggest that these compounds to some extent also up-regulated the mRNA levels of ubiquitous PPARβ/δ. From these studies, we conclude that anti-inflammatory agents have the potential to prevent or treat multiple aspects of the metabolic syndrome.