Oral Supplementation of Phosphatidylcholine Attenuates the Onset of a Diet-Induced Metabolic Dysfunction–Associated Steatohepatitis in Female C57BL/6J Mice

Article

作者: Baumann, Anja ; Bergheim, Ina ; Staltner, Raphaela ; Brandt, Annette ; Sánchez, Victor ; Wodak, Maximilian F

BACKGROUND & AIMSChanges in phosphatidylcholine levels in the liver have been associated with the development of metabolic dysfunction-associated steatotic liver disease. Here, the effects of supplementing phosphatidylcholine on the development of early signs of metabolic dysfunction-associated steatohepatitis were assessed.METHODSMale and female C57BL/6J mice were fed a liquid control or a fructose-, fat-, and/or cholesterol-rich diet for 7 or 8 weeks. The diets of female mice were fortified ± phosphatidylcholine (12.5 mg/g diet). In liver tissue and portal blood, indices of liver damage, inflammation, and bacterial endotoxemia were measured. J774A.1 cells and human monocytes preincubated with phosphatidylcholine (0.38 mmol/L) were challenged with lipopolysaccharide (50-100 ng/mL) ± the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (10 μmol/L) or ± a liver receptor homolog 1 (LRH-1) antagonist 1-(3'-[1-(2-[4-morpholinyl]ethyl)-1H-pyrazol-3-yl]-3-biphenylyl)ethanon (1-10 μmol/L).RESULTSIn fructose-, fat-, and/or cholesterol-rich diet-fed mice the development of fatty liver and the beginning of inflammation were associated with significantly lower hepatic phosphatidylcholine levels when compared with controls. Supplementing phosphatidylcholine significantly attenuated the development of fatty liver and inflammation, being associated with protection against the induction of PPARγ2, and activation of nuclear factor of κ light polypeptide gene enhancer in B-cell inhibitor α whereas Lrh1 expression was unchanged. The protective effects of phosphatidylcholine on the lipopolysaccharide-induced activation of J774A.1 cells and human monocytes were attenuated significantly by the PPARγ activator pioglitazone and the LRH-1 antagonist.CONCLUSIONSOur data suggest that phosphatidylcholine levels in the liver are lower in early metabolic dysfunction-associated steatohepatitis in mice and that supplementation of phosphatidylcholine can diminish the development of metabolic dysfunction-associated steatotic liver disease through mechanisms involving LRH-1/PPARγ2/ nuclear factor κ-light-chain enhancer of activated B-cell signaling.

2020-08-01·Bioorganic & Medicinal Chemistry Letters4区 · 医学

Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition

4区 · 医学

Article

作者: Cato, Michael L ; Ortlund, Eric A ; D'Agostino, Emma H ; Melchers, Diana ; Patel, Anamika B ; Jui, Nathan T ; Cornelison, Jeffery L ; Houtman, René ; Johnson, Alyssa M ; Mays, Suzanne G

LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand binding pocket to alter LRH-1 target gene expression.

2019-12-26·Journal of Medicinal Chemistry1区 · 医学

Discovery of the First Low Nanomolar Liver Receptor Homolog-1 (LRH-1) Agonist

1区 · 医学

Article

作者: Zhang, Yan ; Xu, Yong ; Wu, Xishan

The liver receptor homolog-1 (LRH-1, NR5A2), a member of the nuclear receptor superfamily, has emerged as a promising drug target for the treatment of diabetes, nonalcoholic fatty liver disease, inflammatory bowel disease, and cancers. However, the discovery of LRH-1 modulators remains a challenge since the large and hydrophobic ligand binding pocket of LRH-1 has been difficult to target. This Viewpoint discusses the recent discovery, published in this journal, that the first low nanomolar LRH-1 agonist was identified through structure-guided design. The agonist binds deep inside the LRH-1 ligand binding pocket by a novel mechanism of action.

100 项与 LRH-1 Inverse agonists (TES Pharma) 相关的药物交易

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