A high-fat diet has previously been shown to be a key factor for induction of alcoholic liver fibrosis in a rat model of intragastric ethanol infusion. To explore a possible mechanism by which the high-fat diet facilitated such an effect, the present study examined how the high-fat diet with or without ethanol affected proliferation and collagen formation of hepatic lipocytes, perisinusoidal cells that have been suggested to be involved in liver fibrogenesis. We also evaluated effects of the high-fat diet on the sensitivity of lipocytes to stimulatory effects of Kupffer cell-derived factors. Intragastric infusion of ethanol and the high-fat diet for 9 to 10 wk resulted in induction of a varying degree of perivenular fibrosis in 75% of animals. Lipocytes isolated from these animals (A) had significantly higher basal rates of proliferation (three to four times) and collagen formation (1.5 times) than those isolated from control animals, which were isocalorically infused with the high-fat diet (H) or the low-fat diet (L), or those that were fed chow ad libitum (C). Lipocytes from the H group exhibited significantly higher relative production of collagen than those from the L group, but their net collagen production was not enhanced. The dialyzed Kupffer cell-conditioned medium from the A group markedly stimulated proliferation and collagen formation of lipocytes from the groups given the high-fat diet (A and H) but had minimal effects on those from the L and C groups, establishing the order of decreasing lipocyte sensitivity from the A, H, L to C group. Similarly, lipocytes from the H and A groups exhibited a more profound responsiveness to the stimulatory effect of transforming growth factor β 1 on collagen formation. These results demonstrate (a) that lipocytes isolated from the rats given the high-fat diet and ethanol are markedly proliferative and produce more collagen; and (b) that the Kupffer cells derived from these animals release factors that stimulate proliferation and collagen formation of lipocytes and (c) that the high-fat diet sensitizes lipocytes for stimulatory effects of the Kupffer cell-derived factors and transforming growth factor β1.