Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids

Abstract

Activation of hepatic stellate cells (HSC) is a central event in the pathogenesis of liver fibrosis during chronic liver injury. We examined the expression of retinoic acid (RAR) and retinoid X receptors (RXR) during HSC activation and evaluated the influence of natural and synthetic retinoic acids (RA) on the phenotype of culture-activated HSC. The expression of the major RAR/RXR subtypes and isoforms was analyzed by Northern hybridization. Presence of functional receptor proteins was established by gel shift analysis. Retinoic acids, RAR, and RXR selective agonists and an RAR antagonist were used to evaluate the effects of retinoid signalling on matrix synthesis by Northern blotting and immunoprecipitation, and on cell proliferation by BrdU incorporation. The 9-cisRA and synthetic RXR agonists reduced HSC proliferation and synthesis of collagen I and fibronectin. All-trans RA and RAR agonists both reduced the synthesis of collagen I, collagen III, and fibronectin, but showed a different effect on cell proliferation. Synthetic RAR agonists did not affect HSC proliferation, indicating that ATRA inhibits cell growth independent of its interaction with RARs. In contrast, RAR specific antagonists enhance HSC proliferation and demonstrate that RARs control proliferation in a negative way. In conclusion, natural RAs and synthetic RAR or RXR specific ligands exert differential effects on activated HSC. Our observations may explain prior divergent results obtained following retinoid administration to cultured stellate cells or to animals subjected to fibrogenic stimuli. (HEPATOLOGY 2004;39:97-108.)

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

“…Although loss of retinoid is a prominent feature accompanying stellate cell activation both in vivo (421) and in culture (175), it is unknown whether this process is a prerequisite for activation to occur. The reports about effects of retinoids on stellate cells and fibrogenesis are contradictory (115,116,199,236,423,460,461,563,582,583,588). In culture, both retinol and retinoic acid suppress stellate cell proliferation, and retinoic acid (RA) is 1,000 times more potent than retinol (116).…”

“…More recently, divergent effects of all-trans-RA and 9-cis-RA on stellate cells have been observed (234). There are also different effects between natural and synthetic retinoids (236).…”

Transdifferentiation of vocal-fold stellate cells and all-trans retinol-induced deactivation

“…Activated HSCs respond to exogenous retinoids in culture (Hellemans et al 2004;Martucci et al 2004;Vogel et al 2000). Studies have shown that supplementation of cultured HSCs with ATROH prevents the activation of HSCs, inhibits transdifferentiation, and promotes the lipofibroblastic vitamin-A-storing phenotype (Vogel et al 2000;Fortuna et al 2003;Hellemans et al 2004).…”

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

“…In liver, it attenuated ischemia/reperfusion liver injury, suppressing the inflammatory signals via increased IκBα and repressed NF-κB p65 expression [152] . In addition, the activation of RXR and RAR in hepatic stellate cells may attenuate their activation and proliferation [153] , subsequently ameliorating carbon tetrachloride-induced liver fibrosis in vivo [154][155][156][157] . Furthermore, ATRA treatment repressed CYP7A1 promotor activity [158] .…”