Pawar Anjali, Botolin Daniela, Mangelsdorf David J, Jump Donald B
Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA.
J Biol Chem. 2003 Oct 17;278(42):40736-43. doi: 10.1074/jbc.M307973200. Epub 2003 Aug 13.
Liver X receptors (LXR) alpha and beta play an important role in regulating the expression of genes involved in hepatic bile and fatty acid synthesis, glucose metabolism, as well as sterol efflux. Studies with human embryonic kidney 293 cells indicate that unsaturated fatty acids interfere with oxysterols binding to LXR and antagonize oxysterol-induced LXRalpha activity. In this report, we evaluated the effects of unsaturated fatty acids on LXR-regulated hepatic gene expression. The LXR agonist, T1317, induced mRNAs encoding sterol regulatory element-binding protein 1c (SREBP-1c) and two SREBP-1c-regulated lipogenic genes, e.g. fatty-acid synthase and the S14 protein in primary hepatocytes. Treatment of hepatocytes with eicosapentaenoic acid (20:5n-3) suppressed these mRNAs in the absence and presence of T1317. The cis-regulatory elements targeted by T1317 were not required for fatty-acid suppression of FAS or S14 promoter activity. In contrast to SREBP-1-regulated lipogenic genes, 20:5n-3 had no effect on the T1317 induction of ABCG5 or ABCG8 in the rat hepatoma cell line, FTO-2B. These two genes require LXR but not SREBP-1c for their expression. Feeding rats a diet supplemented with fish oil suppressed hepatic SREBP-1c-regulated genes and induced PPARalpha-regulated genes but had no effect on the LXR-regulated transcripts, CYP7A1, ABCG5, or ABCG8. Transfection studies, using either full-length hLXRalpha or a chimera containing only the LXRalpha ligand binding domain, indicate that a wide array of unsaturated fatty acids had little effect on LXRalpha activity in primary hepatocytes or FTO-2B. These studies suggest that LXRalpha is not a target for unsaturated fatty acid regulation in primary rat hepatocytes or in liver. Thus, oxysterol/LXR-mediated regulation of transcripts involved in bile acid synthesis or sterol efflux appear insensitive to dietary unsaturated fatty acids. The unsaturated fatty acid suppression of SREBP-1 and its targeted lipogenic genes is independent of LXRalpha
肝脏X受体（LXR）α和β在调节参与肝脏胆汁和脂肪酸合成、葡萄糖代谢以及固醇流出的基因表达中发挥重要作用。对人胚肾293细胞的研究表明，不饱和脂肪酸会干扰氧化固醇与LXR的结合，并拮抗氧化固醇诱导的LXRα活性。在本报告中，我们评估了不饱和脂肪酸对LXR调节的肝脏基因表达的影响。LXR激动剂T1317可诱导原代肝细胞中编码固醇调节元件结合蛋白1c（SREBP-1c）的mRNA以及两个受SREBP-1c调节的脂肪生成基因的mRNA，例如脂肪酸合酶和S14蛋白。在存在和不存在T1317的情况下，用二十碳五烯酸（20:5n-3）处理肝细胞均会抑制这些mRNA。脂肪酸对FAS或S14启动子活性的抑制作用并不需要T1317靶向的顺式调节元件。与SREBP-1调节的脂肪生成基因不同，20:5n-3对大鼠肝癌细胞系FTO-2B中ABCG5或ABCG8的T1317诱导没有影响。这两个基因的表达需要LXR，但不需要SREBP-1c。给大鼠喂食补充鱼油的饮食会抑制肝脏中受SREBP-1c调节的基因，并诱导受PPARα调节的基因，但对受LXR调节的转录本CYP7A1、ABCG5或ABCG8没有影响。使用全长hLXRα或仅包含LXRα配体结合域的嵌合体进行的转染研究表明，多种不饱和脂肪酸对原代肝细胞或FTO-2B中的LXRα活性影响很小。这些研究表明，LXRα不是原代大鼠肝细胞或肝脏中不饱和脂肪酸调节的靶点。因此，氧化固醇/LXR介导的参与胆汁酸合成或固醇流出的转录本调节似乎对饮食中的不饱和脂肪酸不敏感。不饱和脂肪酸对SREBP-1及其靶向的脂肪生成基因的抑制作用独立于LXRα
