Reversal of high dietary fructose-induced PPARalpha suppression by oral administration of lipoxygenase/cyclooxygenase inhibitors

Abstract

High fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity, hallmark of which is a rapid and profound hypertriglyceridemia. One of the mechanisms that contribute to serum hypertriglyceridemia in this model is suppression of hepatic PPARalpha. HMG-CoA inhibitors, which reduce serum triglycerides in these animals, also elevate/restore hepatic PPARalpha. Previously we demonstrated that two known lipoxygenase/cyclooxygenase inhibitors reversed diet-induced hypertriglyceridemia in this model and that reversal of certain inflammatory markers in the liver correlated with the metabolic benefit. In this paper we extended these studies by examining the impact of these compounds on expression of PPARalpha, both at the level of transcription and expression. Our data show that diet-induced suppression of hepaic PPARalpha is reversed upon treatment with lipoxygenase/cyclooxygenase compounds. We then tested one of these compounds, BW-755c, over a range of doses from 10 mg/kg to 100 mg/kg to establish a dose-response relationship with the reduction of serum hypertriglyceridemia in this model. These experiments support the concept of using anti-inflammatory medications as one method to correct metabolic dysfunction.

Figure 1

Dose-responsive reduction of serum triglycerides upon treatment with BW-755c (mean +/- SD). The statistical significance of each of the dose groups is shown in Table 2.

Figure 2

Representative Western blots for PPARα expression in hepatic tissue from chow-fed (control) rats and high fructose-fed rats that were subsequently treated with vehicle alone, NDGA or BW755c. Each lane represents hepatic tissue from each of four different animals in each group.