Liver function following preterm birth: long-term implications for metabolic health

Preterm birth affects one in ten infants and represents one of the major early life insults with long-term health implications. Among the organs most disrupted is the liver, crucial for metabolism, detoxification and general systemic function. While the early clinical signs like neonatal cholestasis are well documented, the molecular mechanisms underlying hepatic dysfunction remain poorly characterised. In this review, we explore the potential hepatic molecular alterations associated with preterm birth that may influence early life programming of metabolic dysfunction. First, we present normal liver function and the potential effect of preterm birth on liver development and function. Second, we review metabolic adaptation in the neonatal period following preterm birth and highlight findings of perturbed circulating and tissue metabolites in both preterm human cohorts and animal models. These altered metabolites are associated with disruption of glucose and insulin homeostasis; alterations in lipid metabolism and lipoprotein profiles; impaired bile acid metabolism; perturbations in amino acid and protein metabolism; oxidative stress and antioxidant imbalance; as well as hormonal, growth factor and immune dysregulation. Finally, we examine whether these metabolic perturbations resolve or persist during maturation and consider their potential contribution to adverse metabolic outcomes later in life. Although many of the metabolic perturbations appear to normalise, evidence suggests persistent alterations in insulin signalling and lipid metabolism. Despite growing evidence across the life course following preterm birth, the molecular mechanisms linking early hepatic alterations with later adverse metabolic outcomes remain poorly defined. Epidemiological studies nevertheless demonstrate increased risks of insulin resistance, dyslipidaemia, metabolic dysfunction-associated steatotic liver disease, and type 2 diabetes in individuals born preterm.