Acute inhibition of glucose-6-phosphate translocator activity leads to increased de novo lipogenesis and development of hepatic steatosis without affecting VLDL production in rats

Glucose-6-phosphatase (G6Pase) is a key enzyme in hepatic glucose metabolis m. Altered G6Pase activity in glycogen storage disease and diabetic states is associated with disturbances in lipid metabolism. We studied the effects of acute inhibition of G6Pase activity on hepatic lipid metabolism in nona nesthetized rats. Rats were infused with an inhibitor of the glucose-6-phos phate (G6P) translocator (S4048, 30 mg . kg(-1) . h(-1)) for 8 h. Simultane ously, [1-C-13]acetate was administered for determination of de novo lipoge nesis and fractional cholesterol synthesis rates by mass isotopomer distrib ution analysis. In a separate group of rats, Triton WR 1339 was injected fo r determination of hepatic VLDL-triglyceride production. S4048 infusion sig nificantly decreased plasma glucose (-11%) and insulin (-48%) levels and in creased hepatic G6P (201%) and glycogen (182%) contents. Hepatic triglyceri de contents increased from 5.8 +/- 1.4 mu mol/g liver in controls to 20.6 /- 5.5 mu mol/g liver in S4048-treated animals. De novo lipogenesis was inc reased > 10-fold in S4048-treated rats, without changes in cholesterol synt hesis rates. Hepatic mRNA levels of acetyl-CoA carboxylase and fatty acid s ynthase were markedly induced. Plasma triglyceride levels increased fourfol d, but no differences in plasma cholesterol levels were seen. Surprisingly, hepatic VLDL-triglyceride secretion was not increased in S4048-treated rat s. These studies demonstrate that inhibition of the G6Pase system leads to acute stimulation of fat synthesis and development of hepatic steatosis, wi thout affecting hepatic cholesterol synthesis and VLDL secretion. The resul ts emphasize the strong interactions that exist between hepatic carbohydrat e and fat metabolism.