Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator?activated receptor ?
Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator?activated receptor ?
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DOI：
10.1074/jbc.ra120.013700
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发表时间：
2020-07-17
影响因子：
4.8
通讯作者：
Hinds, Terry D., Jr.
中科院分区：
文献类型：
--
作者：
Gordon, Darren M.;Neifer, Kari L.;Hinds, Terry D., Jr.
激活储存脂肪的白色脂肪组织（WAT）中的脂质燃烧途径是改善代谢健康、减少肥胖、胰岛素抵抗和II型糖尿病的一种有前途的策略。由于未知的原因，胆红素水平与肥胖和糖尿病呈负相关。在这里，使用小鼠和一系列方法，包括MRI评估身体成分，生化分析测量胆红素和脂肪酸，基于mitotracker的线粒体分析，免疫荧光和高通量共调节分析，我们表明胆红素作为核受体转录因子过氧化物酶体增殖因子的分子开关。激活受体？(PPAR吗?)胆红素通过在WAT中招募和解离特异性共调节因子来发挥其作用，从而驱动PPAR？靶基因如解偶联蛋白1 （Ucp1）和肾上腺素受体？3 (Adrb3)。我们还发现胆红素是PPAR的选择性配体。不影响相关蛋白PPAR的活性？和PPAR ?。我们进一步发现，饮食诱导的肥胖小鼠伴有轻度高胆红素血症，WAT大小减少，线粒体数量增加，这与PPAR？绑定coregulators。我们得出结论，胆红素通过重塑PPAR来强烈影响机体体重。共同调节谱，重塑WAT以改善代谢功能，减少脂肪积累。
Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator?activated receptor ? (PPAR?). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPAR? target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor ? 3 (Adrb3). We also found that bilirubin is a selective ligand for PPAR? and does not affect the activities of the related proteins PPAR? and PPAR?. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPAR?-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPAR? coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.