Fasting-induced oxidative stress in very long chain acyl-CoA dehydrogenase-deficient mice.
Hepatopathy and hepatomegaly as consequences of prolonged fasting or illnesses are typical clinical features of very long chain acyl-CoA dehydrogenase (VLCACD) deficiency, the most common long-chain fatty acid β-oxidation defect. Supplementation with medium-chain triglycerides (MCTs) is an important treatment measure in these defects, in order to supply sufficient energy. Little is known about the pathogenetic mechanisms leading to hepatopathy. Here, we investigated the effects of prolonged fasting and an MCT diet on liver function. Wild-type (WT) and VLCAD knockout mice were fed with either a regular long-chain triglyceride diet or an MCT diet for 5 weeks. In both groups, we determined liver and blood lipid contents under nonfasting conditions and after 24 h of fasting. Expression of genes regulating peroxisomal and microsomal oxidation pathways was analyzed by RT-PCR. In addition, glutathione peroxidase and catalase activities, as well as thiobarbituric acid reactive substances, were examined. In VLCAD knockout mice fed with a long-chain triglyceride diet, fasting is associated with excessive accumulation of liver lipids, resulting in hepatopathy and strong upregulation of peroxisomal and microsomal oxidation pathways as well as antioxidant enzyme activities and thiobarbituric acid reactive substances. These effects were even evident in nonfasted mice fed with an MCT diet, and were particularly pronounced in fasted mice fed with an MCT diet. This study strongly suggests that liver damage in fatty acid oxidation defects is attributable to oxidative stress and generation of reactive oxygen species as a result of significant fat accumulation. An MCT diet does not prevent hepatic damage during catabolism and metabolic derangement.
Tucci
Sara
S
Department of General Pediatrics, University Children's Hospital, Duesseldorf, Germany. sara.tucci@uni-duesseldorf.de
Primassin
Sonja
S
Spiekerkoetter
Ute
U
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D002374:Catalase / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D005215:Fasting / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014280:Triglycerides / Q000737:chemistry / Q000378:metabolism
D004041:Dietary Fats; D005227:Fatty Acids; D017392:Thiobarbituric Acid Reactive Substances; D014280:Triglycerides; D002374:Catalase; D005979:Glutathione Peroxidase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D005978:Glutathione