The regulation of the leptin receptor in the liver: A role for PPAR-alpha?

Abstract

Introduction: A recent study, investigating hepatic gene expression in the hyperlipidemic APOE2 knock in (APOE2ki) mouse model, revealed an up-regulation of leptin receptor upon high-fat diet enriched with fenofibrate, an agonist of peroxisome proliferator activated-receptor α (PPARα). It was shown that the synthethic hypolipidemic drug fenofibrate induced a marked decrease in cholesterol and triglyceride levels of these mice. These observations indicate that the nuclear receptor PPARα is possibly involved in the regulation of the expression of the leptin receptor in the liver. Accordingly, our hypothesis is that the combination of high-fat diet with fenofibrate leads to an increased expression of the leptin receptor in the liver, possibly mediated via PPARα. Materials and methods: To determine whether hepatic leptin receptor up-regulation is dependent on PPARα, gene expression was assessed in both APOE2ki mice and mice with a liver-specific deletion of PPARα, that were fed a high-fat diet with or without co-administration of fenofibrate. Subsequently, liver slices were cultured with fenofibrate to asses whether regulation of the leptin receptor is the result of a cellular or a systemic effect. To investigate whether the increased mRNA production of leptin receptor in the liver is coupled to an increase in protein levels, immunostaining of hepatic leptin receptor was performed. The expression of leptin receptor was also validated in other tissues. Results: In response to the combination of high-fat diet with fenofibrate, APOE2ki mice show an up-regulation of the leptin receptor in the liver. PPARα knock out mice, did not reveal an increased expression of the leptin receptor upon fenofibratetreatment. Incubation of liver slices with fenofibrate was not very successful, as the RNA concentration in the slices rapidly diminished. Furthermore, immostaining of liver slides resulted in a brown smear, therefore it was not possible to detect the leptin receptor on protein level. Adipose tissue also revealed expression of the leptin receptor. Conclusions: These results are in line with the previous study and indicate the importance of PPARα for the regulation of the leptin receptor in the liver. How these two factors are coupled to each other, and what the exact role of fenofibrate is in this whole process, still remains to be elucidated.