Antwi Milton Boaheng, Jennings Ariann, Lefere Sander, Clarisse Dorien, Geerts Anja, Devisscher Lindsey, De Bosscher Karolien
Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium.
Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
NPJ Metab Health Dis. 2024 Jul 3;2(1):13. doi: 10.1038/s44324-024-00013-6.
Nuclear receptors (NRs) regulate cellular processes and serve as key targets in treating metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Their ability to interact and influence each other's signaling pathways introduces a complex yet underexplored dimension in the pharmacotherapy of MASLD and MASH. This review delineates the emerging NRs in this field-estrogen-related receptor alpha (ERRα), glucocorticoid receptor (GR), estrogen receptor alpha (ERα), liver receptor homolog-1 (LRH-1), and vitamin D receptor (VDR)-and their interplay with established NRs, including peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, PPARγ), farnesoid X receptor (FXR), liver X receptors (LXR), hepatocyte nuclear factor 4α (HNF4α), and thyroid hormone receptor beta (THRβ). We discuss their collective impact on hepatic lipid metabolism, inflammation, fibrosis, and glucose homeostasis. We explore recent findings on dual NR crosstalk, via direct and indirect mechanisms, and discuss the potential of targeting receptor pathways using selective agonists, inverse agonists, antagonists, or specific modulators to combat MASLD and MASH. Elucidating NR interactions opens up new avenues for targeted therapies, emphasizing the critical need for further research in the evolving field of hepatology.
核受体（NRs）调节细胞过程，是治疗代谢功能障碍相关脂肪性肝病（MASLD）和脂肪性肝炎（MASH）的关键靶点。它们相互作用并影响彼此信号通路的能力，为MASLD和MASH的药物治疗引入了一个复杂但尚未充分探索的维度。本综述阐述了该领域新出现的核受体——雌激素相关受体α（ERRα）、糖皮质激素受体（GR）、雌激素受体α（ERα）、肝脏受体同源物1（LRH-1）和维生素D受体（VDR）——以及它们与已确立的核受体之间的相互作用，这些已确立的核受体包括过氧化物酶体增殖物激活受体（PPARα、PPARβ/δ、PPARγ）、法尼酯X受体（FXR）、肝脏X受体（LXR）、肝细胞核因子4α（HNF4α）和甲状腺激素受体β（THRβ）。我们讨论了它们对肝脏脂质代谢、炎症、纤维化和葡萄糖稳态的综合影响。我们探讨了关于通过直接和间接机制进行双核受体相互作用的最新发现，并讨论了使用选择性激动剂、反向激动剂、拮抗剂或特异性调节剂靶向受体途径对抗MASLD和MASH的潜力。阐明核受体相互作用为靶向治疗开辟了新途径，强调了在不断发展的肝病学领域进行进一步研究的迫切需求。
