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 inc rease in collagen formation and cell proliferation. These changes appe ar to be associated with the loss of intracellular retinoid in lipocyt es, 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 st ates to retinoids and determined their effects on collagen production, intracellular retinoid level, and cell proliferation. Retinol (1 mu M ) and retinoic acid (1 mu M) supplementation of primary rat lipocyte c ultures inhibited the spontaneous increase in collagen synthesis assoc iated with lipocyte activation; lower concentrations of retinol (10 or 100 nM) were also effective. Simultaneously, retinol addition prevent ed a precipitous decline in intracellular retinoid content in the abse nce of added retinoid. These retinoid effects were reversed by a chang e to unsupplemented control medium. When cells in the myofibroblastlik e state were exposed to retinol (greater than or equal to 1 mu M), a s ignificant increase in intracellular retinoid levels and reduction in collagen synthesis occurred. Lipocytes in both native and myofibroblas tlike states secreted four to five times higher amounts of type I coll agen than type III collagen, but retinol and retinoic acid particularl y inhibited production of type I collagen. Cell proliferation measured by [H-3]thymidine incorporation was also inhibited by retinol. These results demonstrate that extracellular retinoids suppress lipocyte-act ivated collagen synthesis and cell proliferation and support the inter pretation that retinoids themselves are regulatory factors in maintena nce of the lipocyte in its native, differentiated state. (C) 1995 Acad emic Press, Inc.