Concurrent increase in fatty acid oxidation and fatty acid synthesis: a unique metabolic state in a pig model of pediatric steatotic liver disease.

Abstract

Steatotic liver disease (SLD) is a spectrum of chronic and progressive disorders. Although often associated with obesity, it can afflict individuals without obesity, including infants. We previously reported that neonatal pigs fed formulas enriched with medium-chain fatty acids (MCFAs), rather than long-chain fatty acids (LCFAs), developed steatosis byand steatohepatitis by. Here, we examined hepatic regulation of lipolytic and lipogenic pathways and associated metabolic outcomes. Neonatal pigs (= 18) were fed isocaloric formulas containing MCFAs or LCFAs for 7, 14, or 21 days. Transcript abundance of most lipolytic and lipogenic genes was greater in MCFA- than in LCFA-fed pigs, independent of feeding duration. Upregulation of lipolytic genes of MCFA-fed pigs corresponded with greater lauric (= 0.04) and palmitic (= 0.03) acid oxidation, and greater plasma &#x3b2;-hydroxybutyrate concentrations than LCFA counterparts (= 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 (< 0.05), and greater de novo lipogenic index at all time points (< 0.001) compared with the LCFA group. Principal component and partial least squares analyses indicated that MCFA-fed pigs clustered with upregulated lipogenic, lipolytic, and transport genes, and were 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 overwhelm the liver's oxidative or export capacity, causing net lipid accumulation.We identify a distinct metabolic state in neonatal pigs with SLD. Contrary to the prevailing paradigm, disease development and progression to the more severe steatohepatitis occur despite enhanced hepatic fatty acid oxidation and the concurrent upregulation of both lipolytic and lipogenic gene expression. This paradoxical metabolic state, where increased fatty acid oxidation fails to prevent progressive steatosis, provides new insights into early-life SLD pathophysiology.