We have reported that infusion of recombinant human hepatocyte growth factor (rhHGF) stimulates liver regeneration after hepatectomy in cirrhotic rats and increases the level of serum lipids and secretion of very-low density lipoprotein (VLDL). Studies were now performed to determine whether rhHGF directly influences lipid synthesis and its secretion in cultured rat hepatocytes. Isolated cells were cultured in the presence or absence of rhHGF (20 ng/mL) for 2 days. During the first 12 hours, rhHGF transiently inhibited the release of lipids (triacylglycerol, total cholesterol, and phospholipids), but stimulated their releases with maximal levels achieved at 36 hours. [ 3 H]-glycerol experiment with the transcriptional and translational inhibitors revealed that rhHGF stimulated de novo synthesis of lipids by affecting activities of lipid metabolic gene. [ 35 S]-Methionine experiment also revealed de novo synthesis of apolipoprotein B by rhHGF. Furthermore, lipid analysis of lipoprotein fractions in the conditioned medium showed that rhHGF enhanced levels of triacylglycerol, total cholesterol, and phospholipids by 50% to 200% in both VLDL and low-density lipoproteins (LDL)/high-density lipoprotein (HDL). Genistein, a tyrosine kinase inhibitor, blocked the secretion of VLDL, as well as synthesis of lipids and apolipoprotein B stimulated by rhHGF. These results indicate that HGF likely stimulates lipid biosynthesis and lipoprotein secretion in hepatocytes through its tyrosine kinase-associated receptor, c-met, and accelerates the progress of cell maturation in liver regeneration. (HEPATOL-OGY 1998;27:1354-1361.)
Hepatocyte growth factor (HGF), also known as a scatter factor, was isolated and purified from the plasma of patients Abbreviations: rhHGF, recombinant human hepatocyte growth factor; VLDL, very-lowdensity lipoprotein; LDL/HDL, low-density and high-density lipoproteins; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl coenzyme A reductase; PBS, phosphate-buffered saline.