Predisposition to Non Alcoholic Fatty Liver Disease in Preterm Guinea Pigs
Background: Preterm birth accounts for ~10% of all births and is now an established risk factor for the development of metabolic syndrome, a cluster of conditions responsible for significant morbidity and mortality in New Zealand. The mechanisms underlying the development of Non alcoholic fatty liver disease (NAFLD, the hepatic manifestation of metabolic syndrome) in the ex-preterm are unknown at present. This project investigated potential differences between term and preterm born guinea pigs in the biological pathways believed to be associated with non-alcoholic fatty liver disease, including metabolism, and molecular and physiologic changes within the liver. Methods: Guinea pigs were delivered spontaneously at term (~GA69days), or prematurely by pharmacological induction of labour (GA62; equivalent to 32 weeks in humans). Fasting blood sugar levels (BSL) were taken at birth, and weekly thereafter. At corrected postnatal age (CPNA) 28 days (equivalent to early childhood in humans), glucose tolerance tests were performed, followed by euthanasia and collection of tissues. The prevalence of NALFD at CPNA 28 days was investigated using a NAFLD activity score based on histological methods and stains to visualise steatosis (oil red o), fibrosis (Masson’s trichome) and inflammation (H&E) in the liver. To observe hepatic alterations at a molecular level, amino acid profiles were assessed by liquid chromotography-tandem mass spectroscopy (LC-MS/MS). Results: Lower BSL at birth was observed in preterms compared to terms (p=0.001), however, BSL was higher in preterms than term counterparts at TEA (p<0.001). Preterms had a significant increase in hepatic steatosis at CPNA 28 days (p=0.0428) Inflammation was not significantly increased in preterms (p=0.4823), and pathologic fibrosis was not observed in any individuals enrolled in the study. Decreased concentrations of essential amino acids associated with liver damage prevention were observed in preterms compared to terms, including tryptophan (p=0.0242) and leucine (p=0.0174). Preterm cohorts had increased concentrations of cysteine (p<0.001) an amino acid associated with hepatic steatosis. Conclusions: Prematurity results in significant changes to hepatic metabolic function in the neonate. This deficit is reduced upon reaching term equivalent age, however molecular and physiological changes within the liver persisted into early childhood. In identifying metabolic, molecular and physiological alterations in the preterm guinea pig this study has begun to elucidate the pathways involved in preterm susceptibility to NAFLD and provided a solid platform for treatment.
Advisor: Berry, Max; Dyson, Rebecca; Gray, Clint
Degree Name: Bachelor of Biomedical Sciences with Honours
Degree Discipline: Paediatrics and Child Health
Publisher: University of Otago
Keywords: Preterm birth; NAFLD; Non alcoholic fatty liver disease; Steatosis; Hepatocytes; Metabolic syndrome; guinea pig
Research Type: Thesis