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Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth.


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Authors

Tarry-Adkins, Jane L 
Fernandez-Twinn, Denise S 
Hargreaves, Iain P 
Neergheen, Viruna 
Aiken, Catherine E 

Abstract

BACKGROUND: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. OBJECTIVES: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. DESIGN: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction. RESULTS: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). CONCLUSIONS: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.

Description

Keywords

accelerated postnatal growth, coenzyme Q, developmental programming, liver disease, low birth weight, Animals, Anti-Inflammatory Agents, Non-Steroidal, Cytokines, Diet, Protein-Restricted, Dietary Supplements, Female, Fetal Development, Fetal Growth Retardation, Hepatitis, Hyperinsulinism, Liver, Liver Cirrhosis, Male, Malnutrition, Maternal Nutritional Physiological Phenomena, Oxidative Stress, Pregnancy, Pregnancy Complications, Rats, Wistar, Specific Pathogen-Free Organisms, Ubiquinone, Weaning

Journal Title

Am J Clin Nutr

Conference Name

Journal ISSN

0002-9165
1938-3207

Volume Title

103

Publisher

Elsevier BV
Sponsorship
British Heart Foundation (None)
Medical Research Council (MC_UU_12012/4)
Medical Research Council (MC_UU_12012/5)
British Heart Foundation (None)
Medical Research Council (MC_PC_12012)
This work was supported by The British Heart Foundation [PG/09/037/27387, FS/09/029/27902]; and The Medical Research Council [MC_UU_12012/4]. Serum analysis was performed by The Wellcome Trust Supported Cambridge Mouse Laboratory, UK. SEO is a member of the MRC Metabolic Diseases Unit. IPH is supported by the Department of Health’s NIHR Biomedical Research Centers funding scheme at UCLH/UCL.