Concurrent Increase in Fatty Acid Oxidation and Fatty acid Synthesis: A Unique Metabolic State in a Pig Model of Pediatric Steatotic Liver Disease

Steatotic liver disease (SLD) is a spectrum of chronic and progressive disorders. While often associated with obesity, it can afflict individuals without obesity, including infants. We previously reported that neonatal pigs fed formulas enriched with medium- (MCFA), rather than long-chain (LCFA) fatty acids, developed steatosis by day 7 and steatohepatitis by day 14. Here, we examined hepatic regulation of lipolytic and lipogenic pathways and associated metabolic outcomes. Neonatal pigs ( n=18) were fed isocaloric formulas containing MCFA or LCFA for 7, 14 or 21 days. Transcript abundance of most lipolytic and lipogenic genes was greater in MCFA- than LCFA-fed pigs, independent of feeding duration. Upregulation of lipolytic genes of MCFA fed pigs corresponded with greater lauric ( P = 0.04) and palmitic ( P = 0.03) acid oxidation, and greater plasma β-hydroxybutyrate concentrations than LCFA counterparts ( P = 0.06). Upregulation of lipogenic genes in the MCFA group coincided with greater hepatic medium- (C12:0, C14:0) and long- (C16:0, C16:1) chain fatty acid concentrations ( P < 0.05), and greater de novo lipogenic index at all time points ( P < 0.001) compared with LCFA group. Principal component and partial least squares analyses indicated that MCFA-fed pigs clustered with upregulated lipogenic, lipolytic, and transport genes, and associated with greater medium-chain fatty acids, and hepatic fat. However, LCFA-fed pigs clustered with greater polyunsaturated fatty acids and reduced transcript abundance of these genes. These findings demonstrate that pediatric SLD pathophysiology involves metabolic adaptations where fatty acid uptake and synthesis overwhelms the liver's oxidative or export capacity, causing net lipid accumulation.