Campisano Sabrina Edith, Echarte Stella Maris, Podaza Enrique, Chisari Andrea Nancy
Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Dean Funes 3350, B7602AYL, Buenos Aires, Argentina.
Instituto de Investigaciones Biológicas, CONICET-Universidad Nacional de Mar del Plata, 4th level Dean Funes 3250, B7602AYL, Buenos Aires, Argentina.
J Physiol Biochem. 2017 May;73(2):275-285. doi: 10.1007/s13105-017-0549-1. Epub 2017 Feb 3.
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.
我们评估了蛋白质营养不良对采用不同营养不良方案的大鼠肝脏形态和生理的影响。给怀孕大鼠喂食对照饮食或低蛋白饮食（LPD）。雄性后代大鼠在妊娠、哺乳期间以及直到60日龄都接受LPD（MM组），断奶后开始的晚期LPD（CM组），或仅在妊娠 - 哺乳期给予LPD，随后给予对照饮食（MC组）。在第60天，采集血液并解剖肝脏。我们发现MM组大鼠的总体重（p < 0.001）和肝脏重量（p < 0.05）下降。这些大鼠以及CM组大鼠表现出明显的肝功能障碍，表现为血清谷丙转氨酶（SGOT）（MM组p < 0.001）和血清谷草转氨酶（SGPT）（MM组和CM组p < 0.001）酶增加，以及肝脏胆固醇含量（MM组和CM组p < 0.001）和甘油三酯含量（MM组p < 0.01；CM组p < 0.001）增加，此外组织学检查也有发现。γ-谷氨酰转移酶（GGT）（MM组、MC组和CM组p < 0.001）和谷胱甘肽S-转移酶pi1（GST-pi1）（MM组和CM组p < 0.001，MC组p < 0.05）表达水平增加也表明存在肝功能障碍。MC组大鼠GST-pi1表达的增加幅度最低（MC组与MM组比较；p < 0.001，MC组与CM组比较；p < 0.01）。所有营养不良动物组的肝脏中活性氧（ROS）产生（MM组、CM组和MC组：p < 0.001）、脂质过氧化（MM组、CM组和MC组p < 0.001）、肝脏蛋白质羰基含量（MM组和CM组p < 0.001，MC组p < 0.01）和总抗氧化能力（MM组、CM组和MC组p < 0.001）均增加。然而，MM组大鼠的增加幅度最高。我们发现MM组和CM组血清肿瘤坏死因子-α（TNF-α）（MM组和CM组p < 0.001）和白细胞介素-6（IL-6）（MM组和CM组p < 0.001）水平以及肝脏转化生长因子-β（TGF-β）含量（MM组p < 0.01；CM组p < 0.05）较高，而MC组大鼠的值恢复到正常水平。由酪氨酸或丝氨酸/苏氨酸激酶（pAKT）（MM组和CM组p < 0.001；MC组p < 0.01）和细胞外信号调节激酶（pERKs）（MM组p < 0.01；CM组p < 0.05）介导的促生存信号通路似乎在所有营养不良大鼠组的肝脏中被激活，这表明存在对凋亡有抗性的细胞，这些细胞可能会癌变。总之，低蛋白饮食会导致肝脏损伤，其程度与营养不良发生的发育阶段及其持续时间有关。
