Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets.
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.
Wang
Hui
H
Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX, USA.
Khaoustov
Vladimir I
VI
Krishnan
Buvaneswari
B
Cai
Wei
W
Stoll
Barbara
B
Burrin
Douglas G
DG
Yoffe
Boris
B
D000255:Adenosine Triphosphate / Q000032:analysis; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000032:analysis; D003600:Cytosol / Q000737:chemistry; D053938:DNA Fragmentation; D004721:Endoplasmic Reticulum / Q000502:physiology; D004750:Enteral Nutrition; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D022781:Hepatocytes / Q000737:chemistry / Q000648:ultrastructure; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry; D018384:Oxidative Stress; D010289:Parenteral Nutrition, Total / Q000009:adverse effects*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013552:Swine; D025801:Ubiquitin / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis; D019014:fas Receptor / Q000502:physiology
D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D025801:Ubiquitin; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020169:Caspases; D001663:Bilirubin