The Liver X Receptors (LXRs) alpha and beta and the Peroxisome Proliferator-Activated Receptor alpha (PPARalpha) are transcription factors that belong to class II nuclear receptors. They drive the expression of genes involved in hepatic lipid homeostasis and therefore are important targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). LXRs and PPARalpha are regulated by endogenous ligands, oxysterols and fatty acid derived molecules, respectively. In the liver, pharmacological activation of LXRs leads to the over-expression of genes involved in de novo lipogenesis, while PPARalpha is critical for fatty acid catabolism in nutrient deprivation. Even if these two nuclear receptors seemed to play opposite parts, recent studies have highlighted that PPARalpha also influence the expression of genes involved in fatty acids synthesis. In this study, we used pharmacological approaches and genetically engineered mice to investigate the cross-talk between LXRs and PPARalpha in the regulation of genes responsible for lipogenesis. We first investigated the effect of T0901317 and fenofibrate, two synthetic agonists of LXRs and PPARalpha, respectively. As expected, T0901317 and fenofibrate induce expression of genes involved LXR-dependent and PPARalpha-dependent lipogenic responses. Considering such overlapping effect, we then tested whether LXR agonist may influence PPARalpha driven response and vice versa. We show that the lack of PPARalpha does not influence the effects of T0901317 on lipogenic genes expression. However, PPARalpha deficiency prevents the up-regulation of genes involved in omega-hydroxylation that are induced by the LXR agonist. In addition, over-expression of lipogenic genes in response to fenofibrate is decreased in LXR knockout mice as well as the expression of PPARalpha target genes involved in fatty acid oxidation. Altogether, our work provides in vivo evidence for a central interconnection between nuclear receptors that drive hepatic lipid metabolism in response to oxysterol and fatty acids.