Maternal perinatal calorie restriction temporally regulates the hepatic autophagy and redox status in male rat

• Published in: Free radical biology & medicine Vol. 130; pp. 592 - 600
• Main Authors: Devarajan, Asokan, Rajasekaran, Namakkal S., Valburg, Claire, Ganapathy, Ekambaram, Bindra, Snehal, Freije, William A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2019
• Subjects: AMP activated protein kinase; AMP-Activated Protein Kinases - genetics; Animals; Animals, Newborn; Autophagy; Autophagy - genetics; Caloric Restriction; Energy Intake - genetics; Female; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; Fetal Growth Retardation - pathology; Glucose-6-phosphate dehydrogenase; Glutathione; Intrauterine and postnatal calorie restriction; Intrauterine growth restriction; Lipid Metabolism - genetics; Liver - metabolism; Liver - pathology; Male; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Oxidation-Reduction - drug effects; Oxidative stress; Oxidative Stress - genetics; Perinatal calorie restriction; Pregnancy; Prenatal Exposure Delayed Effects - metabolism; Prenatal Exposure Delayed Effects - pathology; Rats; Signal Transduction; Oxidative stress; G6PD; AMP activated protein kinase; Autophagy; Intrauterine growth restriction; IPCR; 4-HNE; IUGR; Intrauterine and postnatal calorie restriction; AMPK; Glucose-6-phosphate dehydrogenase; Perinatal calorie restriction; Glutathione
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.09.029

Intrauterine growth restriction (IUGR) leads to adult obesity, cardiovascular disease, and non-alcoholic fatty liver disease/steatohepatitis. Animal models have shown that combined intrauterine and early postnatal calorie restriction (IPCR) ameliorates these sequelae in adult life. The mechanism by which IPCR protects against adult onset disease is not understood. Autophagy, a lysosomal degradative process, recycles cellular constituents and eliminates damaged organelles, proteins, and oxidants. In this study, we hypothesized that IPCR could regulate autophagy in the liver of male rat offspring. At birth (d1) of male IUGR rat offspring and on day 21 (p21) of life, IPCR male rat offspring had a profound decrease in hepatic autophagy in all three stages of development: initiation, elongation, and maturation. However, upon receiving a normal diet ad-lib throughout adulthood, aged IPCR rats (day 450 of life (p450)), had increased hepatic autophagy, in direct contrast to what was seen in early life. The decreased autophagy at d21 led to the accumulation of ubiquitinated proteins and lipid oxidative products, whereas the increased autophagy in late life had the opposite effect. Oxidized lipids were unchanged at d1 by IUGR treatment indicating that decreased autophagy precedes oxidative stress in early life. When cellular signaling pathways regulating autophagy were examined, the 5′ adenosine monophosphate-activated protein kinase pathway (AMPK), and not endoplasmic stress pathways, was found to be altered, suggesting that autophagy is regulated through AMPK signaling pathway in IPCR rats. Taken together, this study reveals that the perinatal nutritional status establishes a nutritionally sensitive memory that enhances hepatic autophagy in late life, a process that perhaps acts as a protective mechanism to limited nutrition.
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•IPCR male rat offspring had a profound decrease in hepatic autophagy on postnatal day 21 (p21) of life.•Aged IPCR rat, which received a normal diet ad-lib throughout adulthood, had increased hepatic autophagy at day 450.•The reduction in autophagy at p21 led to the accumulation of poly-ubiquitinated proteins and lipid oxidative products.•Increased autophagy in late life was associated with decreased poly-ubiquitinated proteins and oxidized lipids.