Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta.
Lipoprotein lipase (LPL) is a key enzyme for lipoprotein metabolism and is responsible for hydrolysis of triglycerides in circulating lipoproteins, releasing free fatty acids to peripheral tissues. In liver, LPL is also believed to promote uptake of high density lipoprotein (HDL)-cholesterol and thereby facilitate reverse cholesterol transport. In this study we show that the Lpl gene is a direct target of the oxysterol liver X receptor, LXRalpha. Mice fed diets containing high cholesterol or an LXR-selective agonist exhibited a significant increase in LPL expression in the liver and macrophages, but not in other tissues (e.g. adipose and muscle). Studies in Lxr-deficient mice confirmed that this response was dependent more on the presence of LXRalpha than LXRbeta. Analysis of the Lpl gene revealed the presence of a functional DR4 LXR response element in the intronic region between exons 1 and 2. This response element directly binds rexinoid receptor (RXR)/LXR heterodimers and is sufficient for rexinoid- and LXR agonist-induced transcription of the Lpl gene. Together, these studies further distinguish the roles of LXRalpha and beta and support a growing body of evidence that LXRs function as key regulators of lipid metabolism and are anti-atherogenic.
Zhang
Y
Y
Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA.
Repa
J J
JJ
Gauthier
K
K
Mangelsdorf
D J
DJ
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D015152:Blotting, Northern; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004032:Diet; D004036:Diet, Atherogenic; D019281:Dimerization; D005091:Exons; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007438:Introns; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D002784:Cholesterol; D008071:Lipoprotein Lipase