Liver Sinusoidal Endothelial Cells at the Crossroad of Iron Overload and Liver Fibrosis

Significance:Liver fibrosis results from different etiologies and represents one of the most serious health issues worldwide. Fibrosis is the outcome of chronic insults on the liver and is associated with several factors, including abnormal iron metabolism. Recent Advances:Multiple mechanisms underlying the profibrogenic role of iron have been proposed. The pivotal role of liver sinusoidal endothelial cells (LSECs) in iron-level regulation, as well as their morphological and molecular dedifferentiation occurring in liver fibrosis, has encouraged research on LSECs as prime regulators of very early fibrotic events. Importantly, normal differentiated LSECs may act as gatekeepers of fibrogenesis by maintaining the quiescence of hepatic stellate cells, while LSECs capillarization precedes the onset of liver fibrosis. Critical Issues:In the present review, the morphological and molecular alterations occurring in LSECs after liver injury are addressed in an attempt to highlight how vascular dysfunction promotes fibrogenesis. In particular, we discuss in depth how a vicious loop can be established in which iron dysregulation and LSEC dedifferentiation synergize to exacerbate and promote the progression of liver fibrosis. Future Directions:LSECs, due to their pivotal role in early liver fibrosis and iron homeostasis, show great promises as a therapeutic target. In particular, new strategies can be devised for restoring LSECs differentiation and thus their role as regulators of iron homeostasis, hence preventing the progression of liver fibrosis or, even better, promoting its regression.