Abstract
Critical roles for liver sinusoidal endothelial cells (LSECs) in liver fibrosis have been demonstrated, while little is known regarding the underlying molecular mechanisms of drugs delivered to the LSECs. Our previous study revealed that plumbagin plays an antifibrotic role in liver fibrosis. In this study, we investigated whether plumbagin alleviates capillarization of hepatic sinusoids by downregulating endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), laminin (LN), and type IV collagen on leptin-stimulated LSECs. We found that normal LSECs had mostly open fenestrae and no organized basement membrane. Leptin-stimulated LSECs showed the formation of a continuous basement membrane with few open fenestrae, which were the features of capillarization. Expression of ET-1, VEGF, LN, and type IV collagen was enhanced in leptin-stimulated LSECs. Plumbagin was used to treat leptin-stimulated LSECs. The sizes and numbers of open fenestrae were markedly decreased, and no basement membrane production was found after plumbagin administration. Plumbagin decreased the levels of ET-1, VEGF, LN, and type IV collagen in leptin-stimulated LSECs. Plumbagin promoted downregulation of ET-1, VEGF, LN, and type IV collagen mRNA. Altogether, our data reveal that plumbagin reverses capillarization of hepatic sinusoids by downregulation of ET-1, VEGF, LN, and type IV collagen.
Highlights
Inflammation, chronic viral hepatitis, and liver injury are considered to be canonical causes of hepatic fibrogenesis
Our purpose was to illustrate that the effects of plumbagin on alleviating phenotype changes and dysfunction in the leptin-stimulated liver sinusoidal endothelial cells (LSECs) were achieved via the decreased expression of ET-1, vascular endothelial growth factor (VEGF), LN, and type IV collagen, effectively alleviating the mechanism causative of hepatic fibrosis
Defenestration of LSECs and Formation of Basement Membrane Are Induced by Leptin
Summary
Inflammation, chronic viral hepatitis, and liver injury are considered to be canonical causes of hepatic fibrogenesis. The loss of fenestrae accompanied by a decrease in the diameter of the fenestrae is termed defenestration and results in the formation of a continuous basement membrane [9, 10] This process is termed the “capillarization” of the hepatic sinusoid [11] and is often seen in LSECs. The sinusoidal capillarization of the LSEC phenotype precedes obvious inflammation in the early stages and promotes liver fibrosis progression [12]. We hypothesized that plumbagin would reverse liver fibrosis in another way, through its accumulation in LSEC and subsequent amelioration of phenotype changes and dysfunction via decreasing profibrogenic factors, including ET-1 and VEGF, as well as reducing components of basement membrane LN and type IV collagen. Our purpose was to illustrate that the effects of plumbagin on alleviating phenotype changes and dysfunction in the leptin-stimulated LSEC were achieved via the decreased expression of ET-1, VEGF, LN, and type IV collagen, effectively alleviating the mechanism causative of hepatic fibrosis
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