Modulation of Hepatic Lipid Metabolism by Dietary Fats in Neonatal Pigs: Implications for Steatotic Liver Disease

Abstract

Steatotic liver disease (SLD) is increasingly recognized in pediatric populations, yet its nutritional origins and development are poorly understood. Using a neonatal pig model, we conducted three nutritional based studies to evaluate how dietary lipid composition influences the onset, progression, and metabolic regulation in SLD. In Study Ia, we demonstrated that steatosis develops as early as day 7 in pigs fed medium-chain fatty acid (MCFA)-rich formulas and rapidly progresses to steatohepatitis by day 14, independent of whole-body adiposity. In Study Ib, we identified a paradoxical metabolic state characterized by simultaneous upregulation of lipolytic and lipogenic pathways in MCFA-fed pigs, in where increased fatty acid oxidation failed to prevent hepatic lipid accumulation. In Study II, we compared distinct lipid sources and found that laurate/myristate-rich coconut oil exacerbated steatosis and lipogenesis, while caprylate/caprate-rich medium-chain triglyceride (MCT) oil was hepatoprotective, despite no measurable increase in oxidation. In Study III, we tested animal- and plant-based formula fats and found that lard and butter supported growth but promoted mild steatosis, coconut oil induced severe steatosis and central adiposity, and MCT oil reduced formula intake and prevented progression to steatohepatitis. Altogether, this dissertation work reveals that early-life dietary lipid composition exerts differential effects on hepatic outcomes, independent of obesity, and that MCFA species confer divergent metabolic and histopathological consequences. These findings highlight the need to reconsider infant formula lipid blends not only for growth and energy but also for their long-term implications in metabolic programming and pediatric liver health.