Hepatic stellate cells (HSCs), the principal producers of extracellular matrix proteins, play a major role in the development of liver fibrosis which is accompanied with elevated sinusoidal pressure and portal hypertension. We have isolated primary rat HSCs and investigated the effect of mechanical pressure and tensile strain on retinol metabolism in the cells. Mechanical force and tensile strain significantly increased the expression of alpha-smooth muscle actin (alpha-SMA) and collagen I, and notably inhibited the expression of cellular retinol-binding protein I (CRBP-I), lecithin-retinol acyltransferase (LRAT), retinyl ester hydrolase (REH), retinoic acid receptor-beta (RAR-beta) and retinoid X receptor-alpha (RXR-alpha). Such effects were partially reversed by the retinoid X receptor antagonist, HX531, and the retinoic acid receptor antagonist, LE135. Mechanical force and tensile strain significantly activate HSCs by regulating the retinoid metabolic pathway. Activation of HSCs can therefore be manipulated through mechanical force and tensile strain in vitro.