Effect of L-aminocarnitine, an inhibitor of mitochondrial fatty acid oxidation, on the exocrine pancreas and liver in fasted rats

Fasting induces pancreatic secretory lipase, possibly through an increased utilization of fatty acids and/or ketone bodies by the acinar cells. To tes t this hypothesis, the effects of L-aminocarnitine (ACA), an inhibitor of m itochondrial beta-oxidation and ketone body formation, on the pancreatic en zyme composition were studied in rats. The characteristics and reversibilit y of the hepatic steatosis produced by ACA in fasted animals were also inve stigated. In fasted rats, ACA decreased the plasma levels of beta-hydroxybu tyrate, glucose and insulin, but increased that of glucagon. Fasting for 3 days increased the pancreatic lipase content by 80%. Administration of ACA (3, 10 or 30 mg kg(-1) daily) for 3 days to fasted rats led to dose-related decreases in pancreatic lipase content, the fasting-induced increase was p revented even by the lowest dose. Nevertheless, ACA in the fasted rats like wise decreased the pancreatic contents of protein, amylase and trypsinogen to varying degrees, suggesting a general defect of protein synthesis. The 3 -day treatment with ACA during fasting led to dose-related, marked increase s in hepatic weight and triglyceride content. Light and electron microscopy revealed lipid vesicles of varying sizes in the hepatocytes; the fat depos ition was predominant in the periportal zones of the hepatic lobules. By me ans of electron microscopy, lipid vacuoles were observed in the centroacina r cells, but not in the acinar cells of the pancreas. In rats treated with 30 mg kg(-1) of ACA daily for 3 days while they were fasted, cessation of A CA treatment and refeeding with normal chow led to normalization of the pan creatic enzyme contents within 6 days, and gradual and complete disappearan ce of the hepatic steatosis within 24 days. Microscopy also demonstrated co mplete recovery in both the liver and the pancreas. The results indicate th at pancreatic secretory lipase induction during the adaptive phase of starv ation is dependent on an unhindered mitochondrial beta-oxidation of fatty a cids and ketogenesis. The dose-related degree of hepatic triglyceride accum ulation which can be produced readily by administration of ACA during short -term starvation in the rat may serve as a new, convenient experimental mod el for studies of fatty liver. (C) 2000 Academic Press.