Neonatal nutrition may influence early-life susceptibility to steatotic liver disease (SLD), yet the relative physiological contributions of dietary medium-chain fatty acids (MCFA) and long-chain fatty acids (LCFA) remain unclear. Prior work could not distinguish whether MCFA-induced steatosis was driven by MCFA themselves or by the high-energy density of typical MCFA-rich formulas. We hypothesized that MCFAs directly promote hepatic steatosis independent of caloric load. Newborn pigs were fed isonitrogenous formulas differing in fat source (MCFA vs LCFA) and energy density (high vs low, 120 vs 80 % of requirements) for 20 days. Body weight and feed intake did not differ among groups, indicating that hepatic outcomes were not driven by differences in growth or nutrient intake. Liver weight as a percentage of body weight was greater in MCFA-fed pigs compared with LCFA-fed pigs (5.2 ± 0.152 % vs 3.5 ± 0.159 %; P < 0.0001) and in high- compared with low-energy pigs (4.8 ± 0.152 % vs 4.0 ± 0.159 %; P < 0.01). Absolute hepatic fat mass was 77 grams (g) greater in MCFA-fed pigs than LCFA-fed pigs (146 ± 11.99 vs 69 ± 12.8 g; P < 0.0001) and 61 g greater in high- compared with low-energy pigs (138 ± 11.98 vs 77 ± 10.7 g; P < 0.0001). Fat represented a greater proportion of liver mass in MCFA-fed pigs compared with LCFA-fed pigs (31 ± 1.45 % vs 24 ± 1.35 %; P < 0.0001). Oil Red O staining confirmed greater lipid accumulation in MCFA livers (P < 0.01). Steatosis was panacinar in all pigs, but most severe in those fed MCFA. Hepatic fatty acid composition reflected dietary source, with MCFA-fed pigs accumulating more C12:0, C14:0, and C16:0, whereas LCFA-fed pigs accumulated more C18:1n-9 and C18:2n-6. High energy density upregulated expression of genes related to lipid uptake, synthesis, and oxidation (FABP1, FATP5, SREBP-1c, FASN, PPARα, MCAD, LCAD), while MCFA feeding selectively increased MCAD and CPT-1α expression. Despite this transcriptional activation, functional ex vivo oxidation of C8:0 and C12:0 was not affected by diet, whereas C18:1n-9 oxidation was significantly reduced by high-energy feeding (P = 0.006), indicating an energy-dependent suppression of LCFA oxidative capacity. In conclusion, the data support our hypothesis that MCFAs, rather than caloric density, drive hepatic steatosis in neonatal pigs. MCFA-rich formulas produce greater liver fat accumulation and distinct hepatic lipid signatures and also induce lipid metabolic genes without enhancing functional oxidation of C8:0 and C12:0. Together, these findings identify dietary fat type as a key determinant of early-life hepatic lipid handling and implicate substrate overload as a mechanism of neonatal steatosis. This research received no external funding. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Shafron et al. (Fri,) studied this question.