Attending Neonatologist Goryeb Children's Hospital, Atlantic Health System Morristown, New Jersey, United States
Background: Vegetable oil-based lipid emulsions (LE) contain high concentrations of plant cholesterols, known as phytosterols (PS). Newborns receiving short-term parenteral nutrition (PN) have PS levels 2-5-fold higher than normal, while those receiving long-term PN have PS levels comparable to patients with congenital sitosterolemia (>10 fold). PS are structurally similar to cholesterol and have been shown to directly affect the expression of genes involved in cholesterol homeostasis. Data on the cellular mechanisms by which cerebral and hepatic PS accumulation alters cholesterol metabolism in developing neonates is lacking. Objective: To characterize cortical and hepatic gene expression of key proteins involved in cholesterol metabolism and to describe plasma lipid profiles in rat pups exposed to PS. Design/Methods: β-sitosterol, campesterol, and stigmasterol were dissolved in 2-hydroxypropyl-β-cyclodextrin (vehicle) to create a PS solution. Sprague-Dawley rat pups received daily intraperitoneal injections of PS solution from P0-P13 at a dose approximating PS content in 2 g/kg/d Intralipid (n=11). Animals were euthanized and brains/livers were extracted. Vehicle exposed pups (n=11) and saline injected pups (n=4) served as controls. Expression of cholesterol synthetic gene (Hmgcr), cell surface receptors (Ldlr, Lrp1, Scarb1/Sr-b1), efflux transporters (Abcg5/8), and nuclear receptors/transcription factors (Srebf1, Srebf2, Mbtps1/S1p, Nr1h3/LXR, Pparα) were measured using custom QuantiGene assays (ThermoFisher) and normalized to Sdha expression. Plasma lipid levels (cholesterol, LDL, HDL) were analyzed in representative subsets of rats by IDEXX BioAnalytics. Results were compared by ANOVA; differences between groups were considered significant if p< 0.05. Results: Cortical and hepatic expression of the selected genes and plasma lipid levels showed no significant differences in PS-exposed pups. A noticeable downward trend was observed in the expression of cortical Hmgcr and cortical Ldlr (Fig 1).
Conclusion(s): This is the first study characterizing the independent effects of PS exposure on cholesterol metabolism in the brains, livers, and plasma of a neonatal animal model. Though not statistically significant, our results suggest that short-term exposure of PS may alter cortical cholesterol metabolism and reduce endogenous cholesterol synthesis and cellular uptake. Given that up to 70% of the most vulnerable neonates admitted to the NICU receive parenteral nutrition, further mechanistic and clinical studies elucidating this potential alteration are warranted.
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