Sirtuin 6 protects against hepatic fibrogenesis by suppressing the YAP and TAZ function.
Sirtuin 6 protects against hepatic fibrogenesis by suppressing the YAP and TAZ function.
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DOI：
10.1096/fj.202200522r
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发表时间：
2022-10
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肝纤维化的发生是由于肝脏长期的组织损伤，导致细胞外基质的异常积累。肝星状细胞（hepatic stellate cells，HSCs）在肝纤维化中起重要作用。然而，分子机制仍然不完全理解。Sirtuin 6（SIRT 6）是一种NAD+依赖性脱乙酰酶，以前曾参与调节转化生长因子β（TGFβ）-SMAD 3通路，该通路在肝纤维化中起重要作用。在这项工作中，我们的目的是确定肝纤维化过程中的其他重要参与者，这些参与者受到SIRT 6的调节。是相关蛋白（雅普）和具有PDZ结合基序的转录共激活因子（TAZ或WWTR 1）是Hippo通路中的关键参与者，与肝纤维化的促进有关。我们的数据表明，HSC特异性Sirt 6敲除小鼠比野生型小鼠更容易受到高脂肪胆固醇胆酸盐饮食诱导的肝纤维化。我们的信号分析表明，除了TGFβ-SMAD 3通路外，雅普和TAZ在SIRT 6缺陷型HSC中也高度活化。由于尚不清楚SIRT 6如何调节雅普和TAZ，我们决定阐明HSC中SIRT 6调节雅普和TAZ的潜在机制。SIRT 6的过表达或敲低证实了SIRT 6在雅普和TAZ的负调控中的作用。进一步的生物化学分析显示，SIRT 6使雅普和TAZ脱乙酰化，并重新编程TEA结构域转录因子复合物的组成，以抑制其下游靶基因，特别是参与肝纤维化的那些基因。总之，我们的数据表明SIRT 6在调节Hippo通路以防止肝纤维化中起着关键作用。
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.