Abstract
In the present study, the effect of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on long-chain fatty acid oxidation by hepatocytes isolated from suckled neonatal pig liver (a low ketogenic and lipogenic tissue) was tested. Incubation of hepatocytes with AICAR (0.5 mM) in the presence of 1 mM of carnitine and 10 mM of glucose for 1 hour at 37°C had no significant effect on total [1-14C]-palmitate (0.5 mM) oxidation (14CO2 and 14C-Acid soluble products (ASP)). Consistent with the fatty acid oxidation, carnitine palmitoyltransferase I activity and inhibition of its activity by malonyl-CoA (10 μM) assayed in cell homogenate also remained constant. However, addition of AICAR to the hepatocytes decreased 14CO2 production by 18% compared to control (p < 0.06). The reduction of labeled carboxylic carbon accumulated in CO2 caused a significant difference in distribution of oxidative products between 14CO2 and 14C-ASP (p < 0.03) compared with the control. It was also noticed that acetyl-CoA carboxylase (ACC) was increased by AICAR (p < 0.03), indicating that ACC might drive acetyl-CoA toward fatty acid synthesis pathway and induce an increase in distribution of fatty acid carbon to 14C-ASP. Addition of insulin to hepatocyte incubations with AICAR did not change the oxidative product distribution between CO2 and ASP, but further promoted ACC activity. The increased ACC activity was 70% higher than in the control group when citrate was absent in the reaction medium and was 30% higher when citrate was present in the medium. Our results suggest that AICAR may affect the distribution of metabolic products from fatty acid oxidation by changing ACC activity in hepatocyte isolated from suckled neonatal piglets; however, the basis for the increase in ACC activity elicited by AICAR is not apparent.
Highlights
The carnitine palmitoyltransferase (CPT) enzyme system is among the most important sites of regulation of hepatic long-chain fatty acid oxidation
Fatty-acid-oxidation: Accumulation of 14C in CO2 was decreased by addition of aminoimidazole-4-carboxamide ribonucleoside (AICAR) to hepatocytes isolated from suckled neonatal pigs. 14CO2 production in cells incubated with AICAR or AICAR plus insulin was 18% lower than the control
In this study the concentration of AICAR adapted from rodent species was sufficient to change malonyl-CoA concentrations in rat or mice, but there was no effect on the total [1-14C] palmitic acid oxidation in hepatocytes isolated from suckled neonatal piglets
Summary
The carnitine palmitoyltransferase (CPT) enzyme system is among the most important sites of regulation of hepatic long-chain fatty acid oxidation. The rate of long-chain fatty acid oxidation in liver mitochondria isolated from 24 h-old fasted pigs showed only a mild increase over newborns which was 70% lower than that observed in fasted adult rats. CPT I activity in pig liver mitochondria doubled between birth and 24 hour of age, and liver malonyl-CoA levels were very low due to a low hepatic lipogenesis in neonatal piglets. Duée et al [1] reported that CPT I in neonatal pig liver was 50 times more sensitive than that from fasted adult rats. Studies from our laboratory [2,3,4] showed that the rate of long-chain fatty acid oxidation in hepatocytes, liver homogenates and mitochondria from neonatal piglets could be altered by
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