PPARG的一种交替翻译异构体表明AF-1结构域抑制作为胰岛素增敏靶点。
An Alternatively Translated Isoform of PPARG Suggests AF-1 Domain Inhibition as an Insulin Sensitization Target.
作者信息
Du Xiaomi, Mendez-Lara Karen, Hu Siqi, Diao Rachel, Bhavimani Guru, Hernandez Ruben, Glass Kimberly, De Arruda Saldanha Camila, Flannick Jason, Heinz Sven, Majithia Amit R
机构信息
Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA.
Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA.
出版信息
Diabetes. 2025 Apr 1;74(4):651-663. doi: 10.2337/db24-0497.
Genetic screens were performed across PPARG to study how disruptive mutations across the full coding sequence affect function. An alternative translational start site in PPARG generates a truncated isoform, peroxisome proliferator-activated receptor γ (PPARγ) M135, which lacks the N-terminal activation function 1 (AF-1) domain and shows increased agonist-induced transactivation of target genes. In human carriers of rare PPARG variants, AF-1 domain-disrupting genetic variants increase agonist-induced PPARγ activity and decrease metabolic syndrome severity. Targeting the AF-1 domain is a potential therapeutic strategy for insulin sensitization.
对过氧化物酶体增殖物激活受体γ（PPARG）进行了全基因筛选，以研究整个编码序列中的破坏性突变如何影响其功能。PPARG中的一个替代翻译起始位点产生了一种截短的异构体，即过氧化物酶体增殖物激活受体γ（PPARγ）M135，它缺乏N端激活功能1（AF-1）结构域，并显示出激动剂诱导的靶基因反式激活增加。在罕见PPARG变体的人类携带者中，破坏AF-1结构域的基因变体增加了激动剂诱导的PPARγ活性，并降低了代谢综合征的严重程度。靶向AF-1结构域是一种潜在的胰岛素增敏治疗策略。
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