Stress-Induced Premature Senescence Related to Oxidative Stress in the Developmental Programming of Nonalcoholic Fatty Liver Disease in a Rat Model of Intrauterine Growth Restriction
Basile Keshavjee,
Valentine Lambelet,
Hanna Coppola,
David Viertl,
John O. Prior,
Laurent Kappeler,
Jean-Baptiste Armengaud,
Jean-Pierre Chouraqui,
Hassib Chehade,
Paul-Emmanuel Vanderriele,
Manon Allouche,
Anne Balsiger,
Alexandre Sarre,
Anne-Christine Peyter,
Umberto Simeoni,
Catherine Yzydorczyk
Affiliations
Basile Keshavjee
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Valentine Lambelet
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Hanna Coppola
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
David Viertl
Department of Nuclear Medicine and Molecular Imaging, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
John O. Prior
Department of Nuclear Medicine and Molecular Imaging, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Laurent Kappeler
INSERM, Centre de Recherche St Antoine, CRSA, Sorbonne Université, 75000 Paris, France
Jean-Baptiste Armengaud
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Jean-Pierre Chouraqui
Department of Woman-Mother-Child, Pediatric Nutrition and Gastroenterology Unit, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Hassib Chehade
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Paul-Emmanuel Vanderriele
Department of Biomedical Sciences, University of Lausanne, National Center of Competence in Research Kidney, 1011 Lausanne, Switzerland
Manon Allouche
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Anne Balsiger
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Alexandre Sarre
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Anne-Christine Peyter
Department Woman-Mother-Child, Neonatal Research Laboratory, Clinic of Neonatology, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Umberto Simeoni
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Catherine Yzydorczyk
Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland
Metabolic syndrome (MetS) refers to cardiometabolic risk factors, such as visceral obesity, dyslipidemia, hyperglycemia/insulin resistance, arterial hypertension and non-alcoholic fatty liver disease (NAFLD). Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing metabolic/hepatic disorders later in life. Oxidative stress and cellular senescence have been associated with MetS and are observed in infants born following IUGR. However, whether these mechanisms could be particularly associated with the development of NAFLD in these individuals is still unknown. IUGR was induced in rats by a maternal low-protein diet during gestation versus. a control (CTRL) diet. In six-month-old offspring, we observed an increased visceral fat mass, glucose intolerance, and hepatic alterations (increased transaminase levels, triglyceride and neutral lipid deposit) in male rats with induced IUGR compared with the CTRL males; no differences were found in females. In IUGR male livers, we identified some markers of stress-induced premature senescence (SIPS) (lipofuscin deposit, increased protein expression of p21WAF, p16INK4a and Acp53, but decreased pRb/Rb ratio, foxo-1 and sirtuin-1 protein and mRNA expression) associated with oxidative stress (higher superoxide anion levels, DNA damages, decreased Cu/Zn SOD, increased catalase protein expression, increased nfe2 and decreased keap1 mRNA expression). Impaired lipogenesis pathways (decreased pAMPK/AMPK ratio, increased pAKT/AKT ratio, SREBP1 and PPARγ protein expression) were also observed in IUGR male livers. At birth, no differences were observed in liver histology, markers of SIPS and oxidative stress between CTRL and IUGR males. These data demonstrate that the livers of IUGR males at adulthood display SIPS and impaired liver structure and function related to oxidative stress and allow the identification of specific therapeutic strategies to limit or prevent adverse consequences of IUGR, particularly metabolic and hepatic disorders.
