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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #206936
Title: Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets

Author
item WANG, H - BAYLOR COLLEGE MED
item KHAOUSTOV, V - BAYLOR COLLEGE MED
item KRISHNAN, B - BAYLOR COLLEGE MED
item CAI, W - BAYLOR COLLEGE MED
item STOLL, B - BAYLOR COLLEGE MED
item Burrin, Douglas - Doug
item YOFFE, B - BAYLOR COLLEGE MED

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/1/2006
Publication Date: 10/1/2006
Citation: Wang, H., Khaoustov, V.I., Krishnan, B., Cai, W., Stoll, B., Burrin, D.G., Yoffe, B. 2006. Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets. Journal of Nutrition. 136:2547-2552.

Interpretive Summary: Many infants born prematurely are not able to ingest food by mouth and often must be fed intravenously, by injecting nutrition directly into the bloodstream; this procedure is called total parenteral nutrition. One of the problems with TPN is that it leads to liver disease, and this is believed to be caused by increased production of fat in the liver. To test this question, we studied neonatal piglets fed by TPN for one week and examined whether this caused fatty liver and how this affects the cells within the liver. Our results showed that after only one week of TPN, increased fat deposits occurred in the liver when compared to piglets fed formula orally. In TPN fed piglets, we also found that the liver cells were dying at a greater rate by a process known as apoptosis. The results also demonstrated the upregulation of some of the key signals inside the cell that trigger the cell death process, such as caspase enzymes. The results suggest that TPN altered liver cell metabolism causing increased oxidative stress within the cell, which may be an early trigger of eventual cell death and liver dysfunction. The results highlight some key metabolic targets that could be altered nutritionally to prevent the development of fatty liver and disease in infants fed by TPN.

Technical Abstract: 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.