Parenteral nutrition emulsion inhibits CYP3A4 in an iPSC derived liver organoids testing platform

ObjectivesParenteral nutrition (PN) is used for patients of varying ages with intestinal failure to supplement calories. Premature newborns with low birth weight are at a high risk for developing PN associated liver disease (PNALD) including steatosis, cholestasis, and gallbladder sludge/stones. To optimize nutrition regimens, models are required to predict PNALD.MethodsWe have exploited induced pluripotent stem cell derived liver organoids to provide a testing platform for PNALD. Liver organoids mimic the developing liver and contain the different hepatic cell types. The organoids have an early postnatal maturity making them a suitable model for premature newborns. To mimic PN treatment we used medium supplemented with either clinoleic (80% olive oil/20% soybean oil) or intralipid (100% soybean oil) for 7 days.ResultsHomogenous HNF4a staining was found in all organoids and PN treatments caused accumulation of lipids in hepatocytes. Organoids exhibited a dose dependent decrease in CYP3A4 activity and expression of hepatocyte functional genes. The lipid emulsions did not affect overall organoid viability and glucose levels had no contributory effect to the observed results.ConclusionsLiver organoids could be utilized as a potential screening platform for the development of new, less hepatotoxic PN solutions. Both lipid treatments caused hepatic lipid accumulation, a significant decrease in CYP3A4 activity and a decrease in the RNA levels of both CYP3A4 and CYP1A2 in a dose dependent manner. The presence of high glucose had no additive effect, while Clinoleic at high dose, caused significant upregulation of interleukin 6 and TLR4 expression. image What is Known Infants receiving parenteral nutrition (PN) are at risk of developing PN associated liver disease (PNALD) which include steatosis, cholestasis, and gallbladder sludge/stones. Composition of lipid emulsions affect risk of PNALD.What is New Induced pluripotent stem cell (iPSC) derived liver organoids can provide a testing platform for PN. High concentrations of both intralipid and clinoleic decreased Cytochrome P450 3A4 (CYP3A4) activity. High concentrations of intralipid and clinoleic reduced the expression of CYP1A2 and CYP3A4 RNA. High concentrations of clinoleic caused significant upregulation of interleukin 6 expression.