Hepatic metabolism of the genetically diabetic ( db/db) mice. II. Lipid metabolism

Abstract

Hepatic lipogenesis measured in vivo with 3H 2O was elevated 2- to 4-fold in diabetic ( db/db) mice aged 4–8 weeks. Lipogenesis in adipose tissue was 2-fold normal at 4 weeks, but declined to normal by 8 weeks. Hepatocytes from db/db mice also showed increased lipogenesis. Incorporation of 14C from labeled glucose, lactate, acetate and glycerol into total lipid and fatty acid, sterol and glycerol fractions was markedly elevated in hepatocytes from 5–6 week old db/db mice, but declined with age. Activities of hepatic malic enzyme, ATP citrate lyase, citrate synthase, acetyl-CoA carboxylase and pyruvate dehydrogenase were increased in db/db mice. Oxidation of [1- 14C]octanoate or [1- 14C]oleate to 14CO 2 was similar in hepatocytes from normal and db/db mice, but endogenous and fatty acidstimulated ketogenesis were markedly reduced. The incorporation of radioactivity] from 0.5 mM [1- 14C]oleate into glyceride and sterol fractions was increased 2- to 3-fold in hepatocytes from db/db mice. These data indicate that hepatic fatty acid synthesis and esterification are elevated in db/db mice as early as 4–5 weeks. It is suggested that these changes are due to hyperinsulinemia and contribute to the development of obesity in these animals.