Hepatocyte growth factor, a potent hepatocyte mitogen in vitro, appears to trigger hepatocyte regeneration after partial hepatectomy and after acute liver cell netcrosis. Transforming growth factor-a and transforming growth factor+, may also be involved in the control of liver regeneration. In this study we assessed possible roles of hepatocyte growth factor, transforming growth factor-a and transforming growth facto-, on liver cell proliferation in uim, using a made1 of choline deficiency that is associated with liver cell necrosis and a model of a hypolipidemic agent (4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-@-hyhxyethyl) acetamide) without liver necrosis. Male F344 rats were fed a choline-deficient diet or 0.16% 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-phydmxyethyl) acetamide diet for 6 and 4 wk, respectively. Rats were killed periodically, and the expression of hepatocyte growth factor messenger RNA in the liver, lung and kidney was determined by Northern-blot analysis. The levels of transforming growth factor-a and transforming growth factor-& messenger RNAs in the liver were also determined. Feeding a choline-deficient diet for 1 to 6 wk led to gradual increases in the levels of hepatocyte growth factor, transforming growth factor-a and transforming growth factor+, messenger RNAs in the liver. Feeding a 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio CN-B-hydmxyethyl) acetamide diet for 3 days and 2 wk induced marked enhancement of liver cell proliferation as judged by hepatocyte S-bromo-2-deoxyuridine incorporation. In contrast to the choline-deficient diet-induced liver cell proliferation, 4chloro-6-(2,3 sylidino)-2-pyrimidinylthio (N-@hydroxyethyl) acetamide-induced liver cell proliferation was aesociated with decreased levels of hepatocyte growth factor and transforming growth factor+, messenger RNAs. Feeding of a cholinedeficient diet or 4-chloro-6-(2,3 xylidino)-2-pyrimi-