Protein malnutrition during fetal programming induces fatty liver in adult male offspring rats.
We evaluated the effects of protein malnutrition on liver morphology and physiology in rats subjected to different malnutrition schemes. Pregnant rats were fed with a control diet or a low protein diet (LPD). Male offspring rats received a LPD during gestation, lactation, and until they were 60 days old (MM group), a late LPD that began after weaning (CM), or a LPD administrated only during the gestation-lactation period followed by a control diet (MC). On day 60, blood was collected and the liver was dissected out. We found a decrease in MM rats' total body (p < 0.001) and liver (p < 0.05) weight. These and CM rats showed obvious liver dysfunction reflected by the increase in serum glutamic pyruvic transaminase (SGOT) (MM p < 0.001) and serum glutamic pyruvic transaminase (SGPT) (MM and CM p < 0.001) enzymes, and liver content of cholesterol (MM and CM p < 0.001) and triglycerides (MM p < 0.01; CM p < 0.001), in addition to what we saw by histology. Liver dysfunction was also shown by the increase in gamma glutamyl transferase (GGT) (MM, MC, and CM p < 0.001) and GST-pi1 (MM and CM p < 0.001, MC p < 0.05) expression levels. MC rats showed the lowest increment in GST-pi1 expression (MC vs. MM; p < 0.001, MC vs. CM; p < 0.01). ROS production (MM, CM, and MC: p < 0.001), lipid peroxidation (MM, CM, and MC p < 0.001), content of carbonyl groups in liver proteins (MM and CM p < 0.001, MC p < 0.01), and total antioxidant capacity (MM, CM, and MC p < 0.001) were increased in the liver of all groups of malnourished animals. However, MM rats showed the highest increment. We found higher TNF-α (MM and CM p < 0.001), and IL-6 (MM and CM p < 0.001) serum levels and TGF-β liver content (MM p < 0.01; CM p < 0.05), in MM and CM groups, while MC rats reverted the values to normal levels. Pro-survival signaling pathways mediated by tyrosine or serine/threonine kinases (pAKT) (MM and CM p < 0.001; MC p < 0.01) and extrasellular signal-regulated kinase (pERKs) (MM p < 0.01; CM p < 0.05) appeared to be activated in the liver of all groups of malnourished rats, suggesting the presence of cells resistant to apoptosis which would become cancerous. In conclusion, a LPD induced liver damage whose magnitude was related to the developmental stage at which malnutrition occurs and to its length.
Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Dean Funes 3350, B7602AYL, Buenos Aires, Argentina.
Sabrina Edith
SE
Campisano
Instituto de Investigaciones Biológicas, CONICET-Universidad Nacional de Mar del Plata, 4th level Dean Funes 3250, B7602AYL, Buenos Aires, Argentina.
Stella Maris
SM
Echarte
Instituto de Investigaciones Biológicas, CONICET-Universidad Nacional de Mar del Plata, 4th level Dean Funes 3250, B7602AYL, Buenos Aires, Argentina.
Enrique
E
Podaza
Instituto de Investigaciones Biológicas, CONICET-Universidad Nacional de Mar del Plata, 4th level Dean Funes 3250, B7602AYL, Buenos Aires, Argentina. achisari@mdp.edu.ar.
Andrea Nancy
AN
Chisari
D000818:Animals; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D005260:Female; D047109:Fetal Development; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000209:etiology; D007774:Lactation; D015227:Lipid Peroxidation; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D018384:Oxidative Stress; D011247:Pregnancy; D050050:Protein Carbonylation; D011897:Random Allocation; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D015430:Weight Gain
D015415:Biomarkers; D016207:Cytokines; D017382:Reactive Oxygen Species
Fetal programming; Liver damage; Low protein diet; Metabolic syndrome; Non-alcoholic fatty liver; Wistar rats