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

doi:10.3390/antiox11091695

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

Antioxidants (Basel). 2022 Aug 29;11(9):1695. doi: 10.3390/antiox11091695.

Authors

Basile Keshavjee¹, Valentine Lambelet¹, Hanna Coppola¹, David Viertl², John O Prior², Laurent Kappeler^{3

4}, Jean-Baptiste Armengaud¹, Jean-Pierre Chouraqui⁵, Hassib Chehade¹, Paul-Emmanuel Vanderriele⁶, Manon Allouche¹, Anne Balsiger¹, Alexandre Sarre¹, Anne-Christine Peyter⁷, Umberto Simeoni¹, Catherine Yzydorczyk¹

Affiliations

¹ Department of Woman-Mother-Child, Division of Pediatrics, DOHaD Laboratory, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland.
² Department of Nuclear Medicine and Molecular Imaging, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland.
³ INSERM, Centre de Recherche St Antoine, CRSA, Sorbonne Université, 75000 Paris, France.
⁴ IHU-ICAN Institute of Cardiometabolism and Nutrition, Sorbonne Université, 75000 Paris, France.
⁵ Department of Woman-Mother-Child, Pediatric Nutrition and Gastroenterology Unit, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland.
⁶ Department of Biomedical Sciences, University of Lausanne, National Center of Competence in Research Kidney, 1011 Lausanne, Switzerland.
⁷ Department Woman-Mother-Child, Neonatal Research Laboratory, Clinic of Neonatology, University of Lausanne and Lausanne University Hospital, 1011 Lausanne, Switzerland.

Abstract

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 p21^WAF, p16^INK4a 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.

Keywords: cellular senescence; developmental programming; intrauterine growth restriction; metabolic syndrome; nonalcoholic fatty liver disease; oxidative stress.

Grants and funding

10172/AIRG