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Long‐term Adaptations in Hepatic Substrate Utilization in 1 Year Old Rat Model of Bronchopulmonary Dysplasia
Author(s) -
Levin Taylor S.,
Tetri Laura,
Haraldsdottir Kristin,
Pegelow David F.,
Braun Rudolf K.,
Gross Kara N.,
Eldridge Marlowe W.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1025.3
Subject(s) - glycolysis , medicine , endocrinology , oxidative phosphorylation , pyruvate dehydrogenase complex , carbohydrate metabolism , bronchopulmonary dysplasia , lactate dehydrogenase , metabolism , andrology , biology , biochemistry , gestational age , pregnancy , enzyme , genetics
Background Approximately 12% of births in the United States are preterm, and this number is rising globally. Preterm birth is associated with increased long‐term risk for insulin resistance, metabolic syndrome, and cardiovascular disease. Infants born preterm often receive oxygen therapy, which, while life saving, can cause many changes in metabolism at the cellular level, especially in the liver. Hyperoxic exposure can inhibit processes such as glucose‐induced insulin secretion, which is linked to the inhibition of oxidative phosphorylation. We hypothesized that a two‐week postnatal hyperoxic exposure would result in a shift in metabolism from oxidative phosphorylation to a glycolytic pathway in the liver that persists into adulthood. Methods Harlan Sprague‐Dawley (SD) rat pups were exposed to either 21% oxygen (NORM, n=8; 3 males) or 85% oxygen (HYP, n=13; 6 males) for 14 days beginning within 12 hours of birth. After this 14‐day period, they were placed in room air and aged out to 1 year in standard normoxic conditions, at which point their livers were harvested and flash frozen in liquid nitrogen. Alterations in the expression of key metabolic regulators were analyzed by Western blotting. Key metabolic regulators include phosphofructokinase 1 (PFK‐1), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH), and phosphorylated PDH (pPDH). The effects of sex and oxygen levels were compared using two‐way ANOVA with Tukey's for multiple comparisons. Results Expression of LDHA was increased in male HYP rats as compared to the male NORM group (P=0.02; increase of 36.9%). PDH was downregulated in the male HYP rats as compared to the male NORM rats (P<0.001; decrease of 34.8%). Finally, PFK‐1 is downregulated in the HYP females as compared to NORM females (P=0.001; decrease of 49.9%). There was no significant change in the pPDH/PDH ratio in either sex. Conclusions PDH converts pyruvate to acetyl‐CoA at the end of glycolysis. Acetyl‐CoA is then used in the TCA cycle to carry out respiration and energy formation. The downregulation of PDH seen in the HYP male group suggests that there is less cellular respiration as a result of postnatal HYP exposure. Together, the upregulation of LDHA and downregulation of PDH suggest that pyruvate is shunted away from the TCA cycle to form lactate. Alternatively, this could represent a downregulation of the TCA cycle and an increased utilization of lactate for gluconeogenesis. Overall, these findings suggest an increase in anaerobic metabolism and a decrease in aerobic metabolism within the liver following postnatal HYP exposure. Support or Funding Information Funding source: NHLBI, R01 HL115061‐03, Suppl (Eldridge) & NHLBI, R01 HL115061 (Eldridge)