HEPATOCYTE GROWTH-FACTOR STIMULATES SYNTHESIS OF LIPIDS AND SECRETIONOF LIPOPROTEINS IN RAT HEPATOCYTES

We have reported that infusion of recombinant human hepatocyte growth factor (rhHGF) stimulates liver regeneration after hepatectomy in cirr hotic rats and increases the level of serum lipids and secretion of ve ry-low density lipoprotein (VLDL), Studies were now performed to deter mine whether rhHGF directly influences lipid synthesis and its secreti on in cultured rat hepatocytes, Isolated cells were cultured in the pr esence or absence of rhHGF (20 ng/mL) for 2 days. During the first 12 hours, rhHGF transiently inhibited the release of lipids (triacylglyce rol, total cholesterol, and phospholipids), but stimulated their relea ses with maximal levels achieved at 36 hours. [H-3]-glycerol experimen t with the transcriptional and translational inhibitors revealed that rhHGF stimulated de novo synthesis of lipids by affecting activities o f lipid metabolic gene. [S-35]-Methionine experiment also revealed de novo synthesis of apolipoprotein B by rhHGF. Furthermore, lipid analys is of lipoprotein fractions in the conditioned medium showed that rhHG F enhanced levels of triacylglycerol, total cholesterol, and phospholi pids by 50% to 200% in both VLDL and low-density lipoproteins (LDL)/hi gh-density lipoprotein (HDL). Genistein, a tyrosine kinase inhibitor, blocked the secretion of VLDL, as well as synthesis of lipids and apol ipoprotein B stimulated by rhHGF. These results indicate that HGF like ly stimulates lipid biosynthesis and lipoprotein secretion in hepatocy tes through its tyrosine kinase-associated receptor, c-met, and accele rates the progress of cell maturation in liver regeneration.