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Molecular Endocrinology 14 (5): 741-752
Copyright © 2000 by The Endocrine Society

Cross-Talk between Fatty Acid and Cholesterol Metabolism Mediated by Liver X Receptor-{alpha}

Kari Anne Risan Tobin1, Hilde Hermansen Steineger1, Siegfried Alberti, Øystein Spydevold, Johan Auwerx, Jan-Åke Gustafsson and Hilde Irene Nebb

Institute for Nutrition Research (K.A.R.T., H.I.N.) Institute of Medical Biochemistry (K.A.R.T., H.H.S., O.S., H.I.N.) Institute of Basic Medical Sciences University of Oslo N-0316 Oslo, Norway
Center for Biotechnology (S.A., J.-A.G.) Department of Medical Nutrition Novum, S-141 86 Huddinge, Sweden
Institut de Genetique et Biologie Moleculaire et Cellulaire (J.A.) 67404 Illkirch, France

LXR{alpha} (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 LXR{alpha} 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 LXR{alpha} (up to 3.5- and 7-fold, respectively) but not LXRß (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 LXR{alpha} gene account for the major part of the induction of LXR{alpha} 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)LXR{alpha} gene, show a peroxisome proliferator-activated receptor-{alpha}-dependent increase in luciferase activity upon treatment with tetradecylthioacetic acid and the synthetic peroxisome proliferator-activated receptor-{alpha} activator, Wy 14.643, suggesting that the mLXR{alpha} 5'-flanking region contains the necessary sequence elements for fatty acid responsiveness. In addition, in vivo LXR{alpha} expression was induced by fatty acids, consistent with the in vitro cell culture data. These observations demonstrate that LXR{alpha} expression is controlled by fatty acid signaling pathways and suggest an important cross-talk between fatty acid and cholesterol regulation of lipid metabolism.




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