Alteration of alanine-327 in LXRα to LXRβ-type histidine deteriorates its subtype-selective activation by riccardin C

IF 5.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Norimasa Tamehiro , Yukari Shigemoto-Mogami , Hongyan Cui , Yoshinori Asakawa , Norihito Shibata , Tomoko Nishimaki-Mogami
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Abstract

Liver X receptors (LXRα and LXRβ) are nuclear receptors critical for lipid homeostasis and inflammation regulation, making them potential therapeutic targets for atherosclerosis and inflammatory diseases. While LXR agonists hold promise, their use is limited by adverse effects on hepatic lipogenesis. Riccardin C (RC) has shown promise as an LXRα partial agonist/ LXRβ antagonist with cell-type-selective properties. This study investigates the molecular mechanisms behind RC-induced LXRα activation. A series of LXRα/β chimera and point-mutated receptors was generated to identify the domains and residues required for RC-induced transactivation. Functional analysis revealed that mutating alanine-327 of LXRα to LXRβ-type histidine in helix 6 impaired RC-induced association with coactivator peptides, reducing transactivation. Conversely, mutating histidine-341 of LXRβ or the inactive chimera to the LXRα-type alanine partially restored the response to RC, highlighting the significance of the A327H mutation in selective LXRα activation by RC. Furthermore, in vivo experiments revealed that when administered orally to mice, RC selectively induced hepatic and intestinal Abca1 expression without stimulating hepatic lipogenic gene expression, thereby elevating HDL levels without increasing plasma and hepatic triglycerides. These findings offer valuable insights for the development of novel therapeutic agents.

Abstract Image

LXRα中alanine-327对lxr β型组氨酸的改变使其在riccardin C作用下的亚型选择性活化恶化。
肝脏 X 受体(LXRα和LXRβ)是脂质稳态和炎症调节的关键核受体,使其成为动脉粥样硬化和炎症性疾病的潜在治疗靶点。虽然LXR激动剂有希望,但它们的使用受到对肝脏脂肪生成的不利影响的限制。Riccardin C (RC)是一种具有细胞类型选择性的LXRα部分激动剂/ LXRβ拮抗剂。本研究探讨了rc诱导LXRα活化的分子机制。生成了一系列LXRα/β嵌合体和点突变受体,以鉴定rc诱导转激活所需的结构域和残基。功能分析显示,将LXRα的丙氨酸-327突变为螺旋6中的lxr β型组氨酸,会破坏rc诱导的与辅激活因子肽的关联,降低转激活。相反,将LXRβ或失活嵌合体的组氨酸-341突变为LXRα型丙氨酸,可以部分恢复对RC的应答,这突出了A327H突变在RC选择性激活LXRα中的意义。此外,体内实验显示,口服给药小鼠,RC选择性地诱导肝脏和肠道Abca1表达,而不刺激肝脏脂质基因表达,从而提高HDL水平,而不增加血浆和肝脏甘油三酯。这些发现为开发新的治疗药物提供了有价值的见解。
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来源期刊
Biochemical pharmacology
Biochemical pharmacology 医学-药学
CiteScore
10.30
自引率
1.70%
发文量
420
审稿时长
17 days
期刊介绍: Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.
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