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

Abstract

Fasting induces pancreatic secretory lipase, possibly through an increased utilization of fatty acids and/or ketone bodies by the acinar cells. To test this hypothesis, the effects of L-aminocarnitine (ACA), an inhibitor of mitochondrial beta-oxidation and ketone body formation, on the pancreatic enzyme composition were studied in rats. The characteristics and reversibility of the hepatic steatosis produced by ACA in fasted animals were also investigated. In fasted rats, ACA decreased the plasma levels of beta-hydroxybutyrate, 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 prevented even by the lowest dose. Nevertheless, ACA in the fasted rats likewise 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 increases in hepatic weight and triglyceride content. Light and electron microscopy revealed lipid vesicles of varying sizes in the hepatocytes; the fat deposition was predominant in the periportal zones of the hepatic lobules. By means of electron microscopy, lipid vacuoles were observed in the centroacinar 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 ACA treatment and refeeding with normal chow led to normalization of the pancreatic enzyme contents within 6 days, and gradual and complete disappearance of the hepatic steatosis within 24 days. Microscopy also demonstrated complete recovery in both the liver and the pancreas. The results indicate that pancreatic secretory lipase induction during the adaptive phase of starvation is dependent on an unhindered mitochondrial beta-oxidation of fatty acids and ketogenesis. The dose-related degree of hepatic triglyceride accumulation which can be produced readily by administration of ACA during short-term starvation in the rat may serve as a new, convenient experimental model for studies of fatty liver.