Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-α

LXRα (liver X receptor, also called RLD-1) is a nuclear receptor, highly expressed in tissues that play a role in lipid homeostasis. In this report we show that fatty acids are positive regulators of LXRα gene expression and we investigate the molecular mechanisms underlying this regulation. In cultured rat hepatoma and primary hepatocyte cells, fatty acids and the sulfur-substituted fatty acid analog, tetradecylthioacetic acid, robustly induce LXRα (up to 3.5- and 7-fold, respectively) but not LXRβ (also called OR-1) mRNA steady state levels, with unsaturated fatty acids being more effective than saturated fatty acids. RNA stability and nuclear run-on studies demonstrate that changes in the transcription rate of the LXRα gene account for the major part of the induction of LXRα mRNA levels. A similar induction of protein level was also seen after treatment of primary hepatocytes with the same fatty acids. Consistent with such a transcriptional effect, transient transfection studies with a luciferase reporter gene, driven by 1.5 kb of the 5′-flanking region of the mouse (m)LXRα gene, show a peroxisome proliferator-activated receptor-α-dependent increase in luciferase activity upon treatment with tetradecylthioacetic acid and the synthetic peroxisome proliferator-activated receptor-α activator, Wy 14.643, suggesting that the mLXRα 5′-flanking region contains the necessary sequence elements for fatty acid responsiveness. In addition, in vivo LXRα expression was induced by fatty acids, consistent with the in vitro cell culture data. These observations demonstrate that LXRα expression is controlled by fatty acid signaling pathways and suggest an important cross-talk between fatty acid and cholesterol regulation of lipid metabolism.