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A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

机译：具有抗糖尿病作用的依赖核受体的磷脂酰胆碱途径

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摘要

过多的肝脏脂肪或脂肪变性是与肥胖相关的糖 尿病的一个重要风险因子。一种天然产物，即 “二月桂酰基卵磷脂”(DLPC)，现已被发现 是一种可能的抗脂肪变性药物，对糖尿病前期 患者有治疗潜力。DLPC激发“孤儿核受体” LRH-1，它的缺失降低胆汁酸的水平。胆汁酸 水平的升高已知降低脂肪变性。%Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis~(1,2). Structural studies have identified phospholipids as potential LRH-1 ligands~(3-5), but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.
机译：过多的肝脏脂肪或脂肪变性是与肥胖相关的糖 尿病的一个重要风险因子。一种天然产物，即 “二月桂酰基卵磷脂”(DLPC)，现已被发现 是一种可能的抗脂肪变性药物，对糖尿病前期 患者有治疗潜力。DLPC激发“孤儿核受体” LRH-1，它的缺失降低胆汁酸的水平。胆汁酸 水平的升高已知降低脂肪变性。%Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis~(1,2). Structural studies have identified phospholipids as potential LRH-1 ligands~(3-5), but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.

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  • 来源
    《Nature》 |2011年第7352期|p.506-510407409|共7页
  • 作者

    Jae Man Lee; Yoon Kwang Lee; Jennifer L. Mamrosh; Scott A. Busby; Patrick R. Griffin; Manish C. Pathak; Eric A. Ortlund; David D. Moore;

  • 作者单位

    Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA;

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio 44272, USA;

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;

    The Scripps Research Molecular Screening Center, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA;

    The Scripps Research Molecular Screening Center, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA;

    Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA;

    Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA;

    Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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