Dipartimento di Medicina, Università degli Studi di Perugia, Nuova Facoltà di Medicina e Chirurgia, Sant'Andrea delle Fratte, Perugia, Italy.
Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia Nuova Facoltà di Medicina e Chirurgia, Sant' Andrea delle Fratte, Perugia, Italy.
Sci Rep. 2017 Jan 24;7:41055. doi: 10.1038/srep41055.
The small heterodimer partner (SHP) is an orphan nuclear receptor that lacks the DNA binding domain while conserves a putative ligand-binding site, thought that endogenous ligands for this receptor are unknown. Previous studies have determined that SHP activation protects against development of liver fibrosis a process driven by trans-differentiation and activation of hepatic stellate cells (HSCs), a miofibroblast like cell type, involved in extracellular matrix (ECM) deposition. To dissect signals involved in this activity we generated SHP-overexpressing human and rat HSCs. Forced expression of SHP in HSC-T6 altered the expression of 574 genes. By pathway and functional enrichment analyses we detected a cluster of 46 differentially expressed genes involved in HSCs trans-differentiation. Using a isoxazole scaffold we designed and synthesized a series of SHP agonists. The most potent member of this group, ISO-COOH (EC: 9 μM), attenuated HSCs trans-differentiation and ECM deposition in vitro, while in mice rendered cirrhotic by carbon tetrachloride (CCl) or α-naphthyl-isothiocyanate (ANIT), protected against development of liver fibrosis as measured by morphometric analysis and expression of α-SMA and α1-collagen mRNAs. In aggregate, present results identify SHP as a counter-regulatory signal for HSCs transactivation and describe a novel class of SHP agonists endowed with anti-fibrotic activity.
小异二聚体伴侣（SHP）是一种孤儿核受体，缺乏 DNA 结合域，但保留了一个假定的配体结合位点，据认为该受体的内源性配体尚不清楚。先前的研究已经确定，SHP 的激活可防止肝纤维化的发展——这是一个由肝星状细胞（HSCs）的转分化和激活驱动的过程，HSCs 是一种类似于肌成纤维细胞的细胞类型，参与细胞外基质（ECM）的沉积。为了剖析涉及这种活性的信号，我们生成了 SHP 过表达的人源和大鼠 HSCs。在 HSC-T6 中强制表达 SHP 改变了 574 个基因的表达。通过途径和功能富集分析，我们检测到一组 46 个差异表达基因，涉及 HSCs 的转分化。我们使用异恶唑支架设计并合成了一系列 SHP 激动剂。该组中最有效的成员 ISO-COOH（EC：9 μM），可在体外减弱 HSCs 的转分化和 ECM 沉积，而在四氯化碳（CCl）或α-萘基异硫氰酸酯（ANIT）诱导的肝硬化小鼠中，可防止肝纤维化的发展，这可通过形态计量分析和α-SMA 和α1-胶原 mRNAs 的表达来衡量。总的来说，目前的结果表明 SHP 是 HSCs 转激活的反向调节信号，并描述了一类具有抗纤维化活性的新型 SHP 激动剂。
