Retinoic acid modulates rat Ito cell proliferation, collagen, and transforming growth factor beta production.

Abstract

Recent studies suggest that vitamin A plays an inhibitory role with respect to "activation" of the hepatic Ito cell, a likely effector of hepatic fibrogenesis. Ito cell "activation" during fibrogenesis is characterized by a decrease in intracellular vitamin A and an increase in cellular proliferation and collagen production. To explore the hypothesis that retinoids have the capacity to diminish Ito cell activation, cultured Ito cells were exposed to retinoic acid and its effects assessed on three key features: cell proliferation, collagen protein production and mRNA abundance, and transforming growth factor j9 protein production. Retinoic acid was 100-1,OOOX more potent than retinol with respect to inhibition of Ito cell proliferation. Interstitial collagen and transforming growth factor f production were also reduced by 10-6 M retinoic acid. The relative abundance of type I collagen mRNA however, was not significantly altered. By contrast, retinoic acid administration to rats caused a marked reduction in the abundance of type I collagen mRNA in both total hepatic and purified Ito cell RNA. The relative abundance of rat hepatic fibronectin or apolipoprotein E mRNA was not significantly altered. These studies demonstrate that retinoic acid can differentially modulate several key features of hepatic fibrogenesis in vitro and in vivo. (J. Clin.

Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-? in liver stellate cells

“…44 Several previous A hepatotoxicity. 40 The suppression of stromelysin and colla-studies have shown that both RA and retinol may reduce genase gene promoters by RA 41,42 may partly account for this SC proliferation both in basal conditions, [45][46][47] and following fibrosis-enhancing effect. Previously, we have observed that stimulation with growth factors involved in liver inflammanthe acyclic retinoid used in the current study reduces the tion.…”

Hepatic Stellate Cells: Unique Characteristics in Cell Biology and Phenotype

“…Retinoic acid signaling is greatly suppressed in HSCs during experimental cholestatic liver fibrosis and correlated with a decrease in the mRNA levels for RXR and retinoic acid receptors (Ohta et al, 1997). Furthermore, retinoic acids have been reported to prevent phenotypic change and proliferation in activated HSCs (Davis et al, 1988;Davis et al, 1990;Pinzani et al, 1992). Although intracellular lipid droplets containing vitamin A disappear by HSC activation, whether or not retinoid loss is directly related to HSC activation is still unclear.…”

The plasminogen-activating system in hepatic stellate cells

“…Activation of HSC is associated with release and metab-produce components of the plasminogen-activating system, olism of endogenous retinyl palmitate to free retinoids includ-suggesting that these cells not only produce MMPs but may ing recently identified retroretinoids, which may be also regulate the activities of those members of the MMP important autrocrine modulators of HSC function. 13,35 The family that require activation by plasmin, e.g., interstitial effect of retinoic acid on uPA and PAI-1 production was as-collagenase and stromelysin. The detection of mRNA for uPA sessed in 14-day cultured HSCs, at which time they are and PAI-1, and the demonstration by zymography of uPA largely depleted of their endogenous retinoids.…”