Detailed studies of hepatic metabolism of lipemic BHE and nonlipemic Wistar rats were conducted. Hepatic lipogenic capacity was varied through the use of starvation or meal feeding. Livers were clamped in precooled copper plates and used for the assay of glycolytic, gluconeogenic, and lipogenic metabolites. Redox and phosphorylation states were calculated. Mitochondrial metabolism was evaluated through studies of the oxygen consumption of isolated mitochondria and through the study of the activities of the alpha-glycerophosphate and malate aspartate shuttles and ATPase. BHE rats have higher phosphorylation states, higher redox ratios, and lower shuttle activities and oxygen consumption by isolated mitochondria than their Wistar cohorts. The differences in oxidative phosphorylation, redox and phosphorylation states, and in the various shuttle activities suggest that BHE liver cells are geared towards lipogenesis at the expense of oxidative phosphorylation. It appears that the activity of the shuttles is controlled in part by phosphorylation state which in turn appears to affect respiration. We theorize from these data that genetically determined differences in the structure and function of the mitochondrial membrane (and perhaps the cell membrane as well) may affect the communication (via metabolites and adenine nucleotides) between the cytosol and mitochondria. Subtle differences in the exchange of metabolites and/or adenine nucleotides across the mitochondrial membrane could thus explain the lipogenic tendency of the liver of the BHE rat and the subsequent development of maturity onset hyperlipemia and hyperglycemia in this strain of rat.

The effects of age and the duration of feeding either a 65% sucrose or a 65% starch diet to normolipemic Wistar and potentially hyperlipemic-hyperglycemic BHE male rats on hepatic metabolite levels, calculated redox and phosphorylation states were studied. Consistent with previous reports, the feeding of sucrose to BHE rats hastened the appearance of hyperlipemia while having little effect in Wistar rats. The changes in hepatic metabolites were consistent with an increased hepatic lipogenesis in BHE rats. The results suggest that the effects of feeding sucrose to BHE rats potentiate the genetically increased hepatic lipogenesis in these rats.

Supported by the BLY Memorial Research Fund and the Veterans Administration Hospital. Present address: Department of Foods and Nutrition, University of Georgia, Athens, Georgia 30602 (Dawson Hall). Wistar rats were purchased from Charles River Breeding Laboratories, Wilmington, Massachusetts. The original BHE animals were purchased from Flow Laboratories, Dublin, Virginia. The BHE colony has been moved from this facility to the NIH Animal Resource Center.5 0037-9727/78/1571-0005$01 .OO/O Copyright 0 1978 by t h e S o c i e t y f o r E x p e r i m e n t a l B i o l o g y and M e d i c i n e All rights r e s e r v e d .

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Studies of the metabolic responses of rats to 0.2% dietary theophylline were conducted. Young male rats were fed theophylline-containing diets or control diets for 8 wk and killed after 22 hr without food. Levels of serum lipids, glucose, and ketones were determined as were hepatic glycogen, lipid, calcium, magnesium, and zinc levels. Epididymal fat pad lipid content, as well as kidney cation levels and hepatic mitochondrial respiration, was also determined. Chronic theophylline feeding lowered blood glucose levels, serum triglyceride levels, hepatic lipid and calcium levels, and the state III respiration with succinate as the substrate. Kidney calcium and magnesium levels were elevated in theophylline-fed rats as were the serum cholesterol levels. The relationship of these metabolic responses to theophylline feeding is discussed as a function of the theophylline effect on tissue cation levels.