Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets

J Nutr. 2006 Oct;136(10):2547-52. doi: 10.1093/jn/136.10.2547.


Total parenteral nutrition (TPN) induces a high rate of liver disease in infants, yet the pathogenesis remains elusive. We used neonatal piglets as an animal model to assess early events leading to TPN-mediated liver injury. Newborn piglets (n = 7) were nourished for 7 d on TPN or enteral nutrition (EN) and the liver tissue and isolated hepatocytes were subjected to morphologic and molecular analysis. Histological analysis revealed prominent steatosis (grade > 2) in 6 of 7 TPN pigs, whereas minimal steatosis (grade < or = 1) was observed in only 2 EN pigs. Abundant cytosolic cytochrome C and DNA fragmentation were observed in hepatocytes from TPN compared with EN piglets. Markers of mitochondrial and Fas-mediated apoptosis were altered in TPN liver tissue, as indicated by a lower ATP concentration (P < 0.05), accumulation of ubiquitin, 9.9-fold activation of caspase-3 activity (P < 0.01), and increased cleavage of poly-(ADP-ribose) polymerase, caspase-8, -9, and -7 when compared with EN livers. Bcl-2 and proliferating cell nuclear antigen expression was downregulated, whereas Fas and Bax were upregulated in TPN livers. However, levels of caspase-12 and Bip/GRP78, both markers of endoplasmic reticulum-mediated apoptosis, did not differ between the groups. Short-term TPN induces steatosis and oxidative stress, which results in apoptosis mediated by the mitochondrial and Fas pathways. Thus, TPN-induced steatosis in newborn piglets may serve as a novel animal model to assess the pathogenesis of fatty liver and apoptosis-mediated liver injury in infants.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / analysis
  • Alanine Transaminase / blood
  • Animals
  • Animals, Newborn*
  • Apoptosis* / physiology
  • Aspartate Aminotransferases / blood
  • Bilirubin / blood
  • Caspases / metabolism
  • Cytochromes c / analysis
  • Cytosol / chemistry
  • DNA Fragmentation
  • Endoplasmic Reticulum / physiology
  • Enteral Nutrition
  • Fatty Liver / etiology*
  • Fatty Liver / pathology
  • Hepatocytes / chemistry
  • Hepatocytes / ultrastructure
  • Immunohistochemistry
  • Liver / chemistry
  • Oxidative Stress
  • Parenteral Nutrition, Total / adverse effects*
  • Proliferating Cell Nuclear Antigen / analysis
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Swine
  • Ubiquitin / analysis
  • bcl-2-Associated X Protein / analysis
  • fas Receptor / physiology


  • Proliferating Cell Nuclear Antigen
  • Proto-Oncogene Proteins c-bcl-2
  • Ubiquitin
  • bcl-2-Associated X Protein
  • fas Receptor
  • Adenosine Triphosphate
  • Cytochromes c
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Caspases
  • Bilirubin