Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
FASEB J. 2022 Oct;36(10):e22529. doi: 10.1096/fj.202200522R.
Hepatic fibrosis occurs in response to prolonged tissue injury in the liver, which results in abnormal accumulation of extracellular matrix. Hepatic stellate cells (HSCs) have been suggested to play a major role in liver fibrosis. However, the molecular mechanisms remain incompletely understood. Sirtuin 6 (SIRT6), an NAD -dependent deacetylase, has been previously implicated in the regulation of the transforming growth factor β (TGFβ)-SMAD3 pathway that plays a significant role in liver fibrosis. In this work, we aimed to identify other important players during hepatic fibrogenesis, which are modulated by SIRT6. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ or WWTR1), key players in the Hippo pathway, have been implicated in the promotion of hepatic fibrosis. Our data show that HSC-specific Sirt6 knockout mice are more susceptible to high-fat-cholesterol-cholate diet-induced hepatic fibrosis than their wildtype counterparts. Our signaling analyses suggest that in addition to the TGFβ-SMAD3 pathway, YAP and TAZ are also highly activated in the SIRT6-deficient HSCs. As it is not clear how SIRT6 might regulate YAP and TAZ, we have decided to elucidate the mechanism underlying the regulation of YAP and TAZ by SIRT6 in HSCs. Overexpression or knockdown of SIRT6 corroborates the role of SIRT6 in the negative regulation of YAP and TAZ. Further biochemical analyses reveal that SIRT6 deacetylates YAP and TAZ and reprograms the composition of the TEA domain transcription factor complex to suppress their downstream target genes, particularly those involved in hepatic fibrosis. In conclusion, our data suggest that SIRT6 plays a critical role in the regulation of the Hippo pathway to protect against hepatic fibrosis.
肝纤维化是肝脏组织损伤持续存在的结果，导致细胞外基质异常积聚。肝星状细胞（HSCs）被认为在肝纤维化中起主要作用。然而，其分子机制尚不完全清楚。Sirtuin 6（SIRT6）是一种 NAD 依赖性去乙酰化酶，先前已被认为参与调节转化生长因子 β（TGFβ）-SMAD3 途径，该途径在肝纤维化中起着重要作用。在这项工作中，我们旨在确定其他在肝纤维化过程中起重要作用的因子，这些因子受 SIRT6 调节。Yes 相关蛋白（YAP）和转录共激活因子与 PDZ 结合基序（TAZ 或 WWTR1），Hippo 途径的关键因子，已被牵连到肝纤维化的促进中。我们的数据表明，HSC 特异性 Sirt6 敲除小鼠比其野生型对照更易受高脂肪胆固醇-胆酸盐饮食诱导的肝纤维化影响。我们的信号分析表明，除了 TGFβ-SMAD3 途径外，YAP 和 TAZ 在 SIRT6 缺陷的 HSCs 中也高度激活。由于尚不清楚 SIRT6 如何调节 YAP 和 TAZ，我们决定阐明 SIRT6 在 HSCs 中调节 YAP 和 TAZ 的机制。SIRT6 的过表达或敲低证实了 SIRT6 在负调控 YAP 和 TAZ 中的作用。进一步的生化分析表明，SIRT6 去乙酰化 YAP 和 TAZ，并重新编程 TEA 结构域转录因子复合物的组成，以抑制它们的下游靶基因，特别是那些与肝纤维化相关的基因。总之，我们的数据表明，SIRT6 在调节 Hippo 途径以防止肝纤维化中起关键作用。
