Maternal diet amplifies the hepatic aging trajectory of Cidea in male mice and leads to the development of fatty liver.
The importance of the early environment on long-term heath and life span is well documented. However, the molecular mechanisms mediating these effects remain poorly understood. Male offspring from a maternal protein restriction model, in which animals are exposed to a low-protein diet while in utero and then are cross-fostered to normally fed dams, demonstrate low birth weight, catch-up growth, and reduced life span (recuperated offspring). In the current study, we used microarray analysis to identify hepatic genes that changed with age. Cell death-inducing DNA fragmentation factor, α subunit-like effector A (Cidea), a transcriptional coactivator that has been implicated in lipid accumulation demonstrated one of the largest age-associated increases in expression (200-fold, P<0.001). This increase was exaggerated ∼3-fold in recuperated offspring. These demonstrated increased hepatic lipid accumulation, higher levels of transcription factors important in lipid regulation, and greater oxidative stress. In vitro analysis revealed that Cidea expression was regulated by oxidative stress and DNA methylation. These findings suggest that maternal diet modulates the age-associated changes in Cidea expression through several mechanisms. This expression affects hepatic lipid metabolism in these animals and thus provides a mechanism by which maternal diet can contribute to the metabolic health and ultimately the life span of the offspring.
1University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK. sb716@cam.ac.uk.
Sarah K
SK
Carr
Jian-Hua
JH
Chen
Wendy N
WN
Cooper
Miguel
M
Constância
Giles S H
GS
Yeo
Susan E
SE
Ozanne
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001835:Body Weight; D016922:Cellular Senescence; D053938:DNA Fragmentation; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D004272:DNA, Mitochondrial / Q000378:metabolism; D018753:Diet, Protein-Restricted; D044127:Epigenesis, Genetic; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D018384:Oxidative Stress; D014157:Transcription Factors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C112510:Cidea protein, mouse; D017931:DNA Primers; D004272:DNA, Mitochondrial; D008055:Lipids; D014157:Transcription Factors
catch-up growth; developmental programming; epigenetic; lipid accumulation; maternal low protein