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

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 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.

Muscle FOXO-Specific Overexpression and Endurance Exercise Protect Skeletal Muscle and Heart from Defects Caused by a High-Fat Diet in Young Drosophila

“…In addition, Activation of cardiac Nmnat/NAD+/SIR2 pathways by expressing Nmnat gene resists the lipotoxic cardiomyopathy induced by a HFD in flies [56]. A HFD decreases SOD activity, Sirt1 level, and FOXO signaling pathways and increased MDA level in liver [57,58].…”

The Role of Oxidative Stress and Cellular Senescence in the Pathogenesis of Metabolic Associated Fatty Liver Disease and Related Hepatocellular Carcinoma

“…In another murine mode developed by Keshavjee et al, reduced protein intake in pregnant mice led to higher amounts of visceral adiposity, MAFLD, and insulin resistance in adult male mice offspring [ 81 ]. This MS phenotype was only observed in male individuals and was linked with a variety of premature senescence markers, such as p21 and p16, in the context of a high OS environment (high superoxide anion levels, DNA damages, decreased Cu/Zn SOD, increased catalase protein expression, increased nfr2 and decreased keap1 mRNA expression) [ 81 ]. Furthermore, Kondo et al developed another mouse model that shows SMP-30/SOD1 double knockout individuals developed OS-related MAFLD, possibly secondary to OS-impaired VLDL (very low-density lipoprotein) transport [ 82 ].…”

Resveratrol Reverses Endothelial Colony-Forming Cell Dysfunction in Adulthood in a Rat Model of Intrauterine Growth Restriction

“…The animal model used in this study was described previously [9,11,60]. Briefly, a rat model of IUGR was induced by an altered maternal diet during gestation.…”

“…Finally, as resveratrol exerts positive effects on reproductive processes, it would be of interest to test in vivo whether an LP diet supplemented with resveratrol during gestation could prevent ECFC dysfunctions in the offspring and thereby delay/prevent the development of the cardiovascular and metabolic disorders that we previously observed in IUGR males during adulthood [9,11]. Funding: This research was funded by a grant from the "Association pour l'information et la recherche sur les maladies rénales génétiques" (AIRG-Suisse) and the Swiss Heart Foundation.…”

“…Impaired number and functionality of ECFCs have been associated with several cardiometabolic disorders such as arterial hypertension and CVDs, obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver diseases (NAFLD) [3]. In low birth weight (LBW) newborns and in a rat model of IUGR with cardiometabolic disorders at adulthood [7][8][9], the ECFCs isolated from, respectively, the cord blood and bone marrow, had an impairment in proliferation, vascular network formation, and angiogenic capabilities associated with oxidative stress and stress-induced premature senescence (SIPS) [10,11].…”