Chapter 21 - Retinoids in Liver Fibrosis: Induction of Proteolytic Activation of Transforming Growth Factor-β by Retinoic Acid and Its Therapeutic Control by Protease Inhibitors

Abstract

Retinoic acid (RA), an active metabolite of vitamin A, has antiinflammatory and scar formation effects in the process of wound healing. These multifunctional actions of RA may be linked to the controversy over its effects on liver fibrosis, depending on the models examined. RA exacerbates liver fibrosis induced by porcine serum that is not accompanied by hepatic necroinflammation. Hepatic stellate cells (HSCs) play central roles in the storage of retinoids in the quiescent phase as well as in fibrogenesis of the liver in the activated phase. During the progression of liver fibrosis, HSCs lose retinoid-containing lipid droplets from the cytoplasm, transform into myofibroblast-like cells, and start to produce a significant amount of extracellular matrices (ECMs). Thus, it is of great interest to understand the relationship between the loss of retinoids and the production of ECM in HSCs. This chapter discusses the ECM-producing effect of RA in HSCs. Generation of a certain isomer of RA may provoke HSC activation in culture and during liver fibrosis in vivo. This RA enhances proteolytic activation of transforming growth factor (TGF)-β, a strong fibrogenic cytokine, by upregulating the plasminogen activator (PA)/plasmin system. Active transforming growth factor (TGF)-β autostimulates its own synthesis by HSCs and enhances ECM production. This sequence of mechanisms of RA may suggest a clue to use protease inhibitors to sever an autoinduction of TGF-β. This chapter presents a study in which a drug that suppresses proteolytic activation of TGF-β and thereby inhibits hepatic fibrosis in rats is investigated.