Regulation of differentiated phenotype of rat hepatic lipocytes by retinoids in primary culture.

Activation of hepatic lipocytes to myofibroblastlike cells observed in cell culture and during liver fibrogenesis is characterized by an increase in collagen formation and cell proliferation. These changes appear to be associated with the loss of intracellular retinoid in lipocytes, the principal storage site for vitamin A in the body. To evaluate whether retinoids have the capability to suppress lipocyte activation, we exposed cultured lipocytes in both native and myofibroblastlike states to retinoids and determined their effects on collagen production, intracellular retinoid level, and cell proliferation. Retinol (1 microM) and retinoic acid (1 microM) supplementation of primary rat lipocyte cultures inhibited the spontaneous increase in collagen synthesis associated with lipocyte activation; lower concentrations of retinol (10 or 100 nM) were also effective. Simultaneously, retinol addition prevented a precipitous decline in intracellular retinoid content in the absence of added retinoid. These retinoid effects were reversed by a change to unsupplemented control medium. When cells in the myofibroblastlike state were exposed to retinol (> or = 1 microM), a significant increase in intracellular retinoid levels and reduction in collagen synthesis occurred. Lipocytes in both native and myofibroblastlike states secreted four to five times higher amounts of type I collagen than type III collagen, but retinol and retinoic acid particularly inhibited production of type I collagen. Cell proliferation measured by [3H]thymidine incorporation was also inhibited by retinol. These results demonstrate that extracellular retinoids suppress lipocyte-activated collagen synthesis and cell proliferation and support the interpretation that retinoids themselves are regulatory factors in maintenance of the lipocyte in its native, differentiated state.