Discontinuous Total Parenteral Nutrition Prevents Postischemic Mitochondrial Dysfunction in Rat Liver

Abstract

Although discontinuous total parenteral nutrition (d-TPNAlthough total parenteral nutrition (TPN) is a lifesaving therapy for those who are unable to be nourished enterally, its associated hepatic complications of steatosis, cholestasis, and hepatic failure restrict its application. 1 In neonates and infants undergoing the TPN treatment, cholestasis is a major complication that can occur progressively, often resulting in death from chronic hepatic failure. 2 Although multiple factors including calorie excess, 3 essential fatty acid deficiency, 4 amino acid imbalance, 5 loss of enteric stimulation, 6 and bacterial translocation 7,8 might contribute to TPN-associated hepatobiliary dysfunction, its etiology and mechanisms have not fully been investigated experimentally.Continuous infusion of a high-calorie solution is thought to contribute to TPN-induced steatosis by enhancing de novo liver fatty acid synthesis and by suppressing fatty acid oxidation as a result of high plasma insulin. 9 Discontinuous TPN (d-TPN) has been therefore devised to mimic the physiological circadian pattern of feeding in an attempt to lower the high levels of insulin. This strategy has thus been applied clinically to prevent the liver from incurring steatosis. 10,11 Little information is available, however, to explain the mechanism whereby d-TPN attenuates postoperative liver injury, although possible effects on hepatic mitochondrial function have been postulated. 12 Katayama et al. 12 reported that continuous TPN (c-TPN) resulted in decreased hepatic energy charge and rates of oxidative phosphorylation in the hepatic mitochondria of immature rats, and speculated that this deterioration in mitochondrial function may contribute to hepatic dysfunction in infants. Because cholestasis, a major hepatic complication of TPN in infants, is closely associated with adenosine triphosphate breakdown in hepatocytes, 13 it is not unreasonable to examine whether TPN may alter the susceptibility of mitochondrial function in the liver, particularly following surgical intervention. This study was thus designed to compare the changes in hepatic mitochondrial membrane potential (⌬⌿) and biliary function during c-TPN and d-TPN. MATERIALS AND METHODSAnimal Pretreatment With TPN. Protocols for the present study were approved by the guidelines of Animal Care Facility in Keio University School of Medicine. Male Wistar rats weighing 200 to 250 g were randomized into four groups: 1) a group treated with an ordinary chow diet followed by overnight fasting; 2) a c-TPN group; 3) a d-TPN group in which the livers were excised in a fed state (fed d-TPN); and 4) a d-TPN group in which the livers were excised in a fasted state (fasted d-TPN). Compositions of the chow diet were as follows: fibers, 3.5%; fats, 4.8%; proteins, 27.1%; soluble nonAbbreviations: d-TPN, discontinuous total parenteral nutrition; c-TPN, continuous total parenteral nutrition; LDH, lactate dehydrogenase; Rh123, rhodamine 123; ⌬⌿, membrane potential; PI, propidium iodide; FITC-BSA, fluorescein isothi...

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