Retinoic acids and hepatic stellate cells in liver disease.
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.
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Young-Sun
YS
Lee
Won-Il
WI
Jeong
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism* / Q000627:therapeutic use; D014801:Vitamin A / Q000378:metabolism
D014801:Vitamin A; D014212:Tretinoin