Hepatic steatosis during convalescence from influenza B infection in ferrets with postprandial hyperinsulinemia.
The possibility that postprandial hyperinsulinemia could play a role in the development of hepatic lipid disturbances during convalescence from influenza B infection was explored in the ferret as a possible model of the steatosis of Reye's syndrome. Postprandial hyperinsulinemia was produced by feeding young ferrets glucose/water and a regular diet (glucose-treated group), as reflected by the mean serum insulin levels attained, which were 57 and 135 microU/ml during control and postinfluenza periods, respectively. By comparison, ferrets fed water and a regular diet (untreated group) had mean insulin levels of 19 and 22 microU/ml, while postprandial glucose levels were comparable in the two groups of animals for each period. In contrast to untreated animals, grossly visible fatty livers were found in glucose-treated ferrets during convalescence. The total lipid content of these livers had doubled compared with preinfection samples and compared with livers of untreated ferrets. By electron microscopy hepatic mitochondria showed striking changes with diminution of matrix density and reduction in cristae surface area only in convalescent samples from glucose-treated animals. Serum free fatty acid (FFA) levels were considerably higher in the glucose-treated animals during fasting before influenza and also after feeding during convalescence. Serum triglyceride (TG) levels were also high during convalescence in the glucose-treated group. Adipose tissue lipoprotein lipase activities were similar between groups, but hormone-sensitive lipase activity was twelvefold higher in glucose-treated ferrets before and after influenza B. These findings indicate that for a given stimulus, glucose-treated ferrets would mobilize more FFA than untreated ferrets. The total capacity for beta-oxidation of FA by the mitochondrial pathway was identical in all groups of animals. Total carnitine palmitoyl transferase (CPT) activity was the same in both control groups, but was significantly diminished in glucose-treated animals during convalescence. As CPT regulates the entry of FA into the mitochondrial matrix, its reduction in response to higher insulin concentrations would limit the oxidation of FA and stimulate TG accumulation. Therefore, the accumulation of lipid in the liver in this model is regarded to have been caused by the simultaneous occurrence of increased lipolysis and increased hepatic TG synthesis owing, in part, to diversion of activated FA by CPT, which is reduced in activity due to the regulatory action of insulin. These findings may have pathophysiologic relevance for the lipid changes that occur in Reye's syndrome and to fatty liver formation in hyperinsulinemic states.