Liver Pathobiology Laboratory, Cannon Research Center, Carolinas Medical Center, Charlotte, NC.
Hepatology. 2014 Jun;59(6):2383-96. doi: 10.1002/hep.27049. Epub 2014 Apr 29.
Hepatic stellate cell (HSC) transdifferentiation from a quiescent, adipocyte-like cell to a highly secretory and contractile myofibroblast-like phenotype contributes to negative pathological consequences, including fibrosis/cirrhosis with portal hypertension (PH). Antiadipogenic mechanisms have been shown to underlie activation of HSCs. We examined the role of heme-sensing nuclear receptor Rev-erbα, a transcriptional repressor involved in metabolic and circadian regulation known to promote adipogenesis in preadipocytes, in HSC transdifferentiation. We discovered that Rev-erbα protein was up-regulated in activated HSCs and injured livers; however, transcriptional repressor activity was not affected by fibrogenic treatments. Surprisingly, increased protein expression was accompanied with increased cytoplasmic accumulation of Rev-erbα, which demonstrated distributions similar to myosin, the major cellular motor protein. Cells overexpressing a cytoplasm-localized Rev-erbα exhibited enhanced contractility. Ectopically expressed Rev-erbα responded to both adipogenic ligand and fibrogenic transforming growth factor beta treatment. Rev-erb ligand SR6452 down-regulated cytoplasmic expression of Rev-erbα, decreased expression of fibrogenic markers and the activated phenotype in HSCs, and ameliorated fibrosis and PH in rodent models.
Up-regulation of Rev-erbα is an intrinsic fibrogenic response characterized by cytoplasmic accumulation of the protein in activated HSCs. Cytoplasmic expression of Rev-erbα promotes a contractile phenotype. Rev-erbα acts as a bifunctional regulator promoting either anti- or profibrogenic response, depending on milieu. Rev-erb ligand SR6452 functions by a previously undescribed mechanism, targeting both nuclear activity and cytoplasmic expression of Rev-erbα. Our studies identify Rev-erbα as a novel regulator of HSC transdifferentiation and offers exciting new insights on the therapeutic potential of Rev-erb ligands.
从静止的、脂肪细胞样细胞向高度分泌和收缩的肌成纤维细胞样表型的肝星状细胞（HSC）转分化导致了负面的病理后果，包括纤维化/肝硬化伴门静脉高压（PH）。抗脂肪生成机制被证明是 HSC 激活的基础。我们研究了血红素感应核受体 Rev-erbα在 HSC 转分化中的作用，Rev-erbα是一种参与代谢和昼夜节律调节的转录抑制剂，已知其在脂肪前体细胞中促进脂肪生成。我们发现 Rev-erbα蛋白在激活的 HSC 和受损的肝脏中上调；然而，纤维生成治疗并不影响转录抑制剂的活性。令人惊讶的是，蛋白质表达的增加伴随着 Rev-erbα的细胞质积累增加，其分布类似于肌球蛋白，这是主要的细胞运动蛋白。过表达细胞质定位的 Rev-erbα的细胞表现出增强的收缩性。异位表达的 Rev-erbα对脂肪生成配体和纤维生成转化生长因子β治疗有反应。Rev-erb 配体 SR6452 下调 Rev-erbα的细胞质表达，降低 HSC 中纤维生成标志物和激活表型的表达，并改善啮齿动物模型中的纤维化和 PH。
Rev-erbα的上调是一种内在的纤维生成反应，其特征是在激活的 HSC 中蛋白质的细胞质积累。Rev-erbα的细胞质表达促进收缩表型。Rev-erbα作为一种双功能调节剂，根据环境，既可以促进抗纤维化反应，也可以促进纤维化反应。Rev-erb 配体 SR6452 通过以前未描述的机制起作用，靶向 Rev-erbα的核活性和细胞质表达。我们的研究确定 Rev-erbα是 HSC 转分化的新调节剂，并为 Rev-erb 配体的治疗潜力提供了令人兴奋的新见解。
