Cyclic infusion mitigates liver dysfunction associated with continuous total parenteral nutrition in a novel murine model

Parenteral nutrition (PN) is a lifesaving intervention for patients unable to feed enterally but is often associated with parenteral nutrition-associated liver disease (PNALD), also called intestinal failure-associated liver disease (IFALD). This disease is characterized by steatosis, cholestasis, and elevated liver stress markers. Continuous PN induces hepatic injury through mechanisms including insulin resistance, lipotoxicity, systemic inflammation, and oxidative stress. Infusion cycling is known to ameliorate clinical markers of liver injury, but metabolic underpinnings have not been thoroughly investigated. Therefore, we modeled PN-induced liver injury in mice to investigate how differential infusion patterns impacted hepatic metabolism. Intermittent infusions protected against increased circulating alanine aminotransferase levels and improved histopathology to more closely resemble chow controls. Transcriptomic analyses revealed 804 differentially expressed genes between PN groups, highlighting pathways related to peroxisome proliferator-activated receptor signaling, fatty acid metabolism, and peroxisomes. Relative to the continuous group, intermittent PN infusion specifically downregulated <i>Acaa1b</i>, <i>Aldh3a2</i>, <i>Inmt</i>, and <i>Acot4</i>; transcripts involved in peroxisomal lipid oxidation, dicarboxylic acid synthesis, and one-carbon metabolism. This study suggests that infusion cycling may attenuate metabolic burden induced by alternate lipid oxidation pathways. Future work can therapeutically leverage these metabolic pathways to deepen our understanding of PNALD/IFALD and guide PN treatments to improve patient outcomes.<b>NEW & NOTEWORTHY</b> This work demonstrated that the infusion schedule, independent of nutrient and caloric concentration, is a modulator of hepatic lipid metabolism in a novel murine model of parenteral nutrition. This cyclic infusion paradigm attenuated transcripts involved in microsomal and peroxisomal lipid oxidation, which were upregulated in the continuous infusion group. These data support the clinical use of cyclic infusion to improve hepatic parameters known to be adversely affected by parenteral nutrition.