Retinoic acids and hepatic stellate cells in liver disease
Retinoic acids and hepatic stellate cells in liver disease
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DOI：
10.1111/j.1440-1746.2011.07007.x
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发表时间：
2012-03-01
影响因子：
4.1
通讯作者：
Jeong, Won-Il
中科院分区：
文献类型：
--
作者：
Lee, Young-Sun;Jeong, Won-Il
健康肝脏中静止的肝星状细胞（HSC）储存80%的总肝脏视黄醇，并根据细胞外视黄醇状态释放它们。然而，肝损伤激活的HSC失去其视黄醇并产生大量的细胞外基质，随后导致肝纤维化。新出现的证据表明，视黄醇及其代谢产物，如视黄酸（RA）有助于肝再生，纤维化和肿瘤。然而，目前尚不清楚为什么HSC失去视黄醇，哪些酶参与HSC的视黄醇代谢以及肝损伤时HSC上的视黄醇代谢物的功能。最近，我们的小组和合作者已经证明，在激活过程中，HSC不仅失去视黄醇，而且还通过醇脱氢酶和视黄醇脱氢酶将其代谢为RA。作为转录因子，代谢的RA诱导HSC中的视黄酸早期诱导因子-1和细胞因子信号抑制因子-1，在HSC与自然杀伤细胞的相互作用中发挥重要作用。此外，从HSC释放的RA可以诱导酒精性肝脂肪变性中的肝大麻素受体1表达或调节肝脏炎症后的免疫反应。本文综述了内源性代谢RA对造血干细胞本身和其他肝细胞（包括肝细胞和免疫细胞）的作用。此外，外源性视黄醇和RA治疗对HSC和肝脏疾病的影响进行了讨论。
Quiescent hepatic stellate cells (HSCs) in healthy liver store 80% of total liver retinols and release them depending on the extracellular retinol status. However, HSCs activated by liver injury lose their retinols and produce a considerable amount of extracellular matrix, subsequently leading to liver fibrosis. Emerging evidence suggests that retinols and their metabolites such as retinoic acids (RAs) contribute to liver regeneration, fibrosis and tumor. However, it is not clear yet why HSCs lose retinol, which enzymes are involved in the retinol metabolism of HSCs and what function of retinol metabolites on HSCs upon liver injury. Recently, our group and collaborators have demonstrated that during activation, HSCs not only lose retinols but also metabolize them into RAs by alcohol dehydrogenases and retinaldehyde dehydrogenases. As transcriptional factors, metabolized RAs induce retinoic acid early inducible-1 and suppressor of cytokine signaling 1 in HSCs, which plays an important role in the interaction between HSCs and natural killer cells. In addition, RAs released from HSCs may induce hepatic cannabinoid receptor 1 expression in alcoholic liver steatosis or regulate immune responses upon liver inflammation. The present review summarizes the role of endogenous metabolized RAs on HSCs themselves and on other liver cells including hepatocytes and immune cells. Moreover, the effects of exogenous retinol and RA treatments on HSCs and liver disease are discussed.