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Title: Phytosterols synergize with endotoxin to augment inflammation in Kupffer cells but alone have limited direct effect on hepatocytes

Author
item GUTHRIE, GREGORY - Children'S Nutrition Research Center (CNRC)
item TACKETT, BRYAN - Children'S Nutrition Research Center (CNRC)
item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item MARTIN, CAMILIA - Beth Israel Deaconess Medical Center
item OLUTOYE, OLUYINKA - Baylor College Of Medicine
item Burrin, Douglas - Doug

Submitted to: Journal of Parenteral and Enteral Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/30/2017
Publication Date: 8/1/2017
Publication URL: https://handle.nal.usda.gov/10113/5801873
Citation: Guthrie, G., Tackett, B., Stoll, B., Martin, C., Olutoye, O., Burrin, D.G. 2017. Phytosterols synergize with endotoxin to augment inflammation in Kupffer cells but alone have limited direct effect on hepatocytes. Journal of Parenteral and Enteral Nutrition. doi:10.1177/0148607117722752.

Interpretive Summary: Phytosterols are compounds found in the fat given to infants on intravenous nutrition supplementation. These phytosterols may cause liver disease if the infants receive them for a long period of time, though why the phytosterols cause liver disease is unclear. It is suggested phytosterols may inhibit clearance of bile acids from the liver or enhance inflammation, both factors that can lead to liver disease. To better examine these two mechanisms, we isolated cells from the liver involved in bile acid clearance (hepatocytes) and liver immune cells (macrophages). We treated both cell types with phytosterols in the presence or absence of an activator of inflammation (lipopolysaccharide [LPS]). We did not see any effect on transporters involved in bile acid clearance in hepatocytes from phytosterol treatment alone, but did see LPS reduced the levels of those transporters. The treatment of macrophages with phytosterols did not increase markers of inflammation. LPS did increase inflammation and the combination of LPS and phytosterols more than doubled the concentration of inflammatory markers compared to LPS alone. These results show that phytosterols can enhance inflammation in infants. This study adds a mechanism of action to support clinical observations on the potential danger of using phytosterol-containing intravenous fats long-term in infants.

Technical Abstract: Phytosterols are implicated in the development of parenteral nutrition–associated liver disease. A newly proposed mechanism for phytosterol-mediated parenteral nutrition–associated liver disease is through phytosterol-facilitated hepatic proinflammatory cytokine release following exposure to intestinally derived bacteria. Whether the proinflammatory effects are liver cell specific is not known. To determine if phytosterols cause inflammation in hepatocytes or Kupffer cells independently or require costimulation by lipopolysaccharide (LPS). In an in vivo study, neonatal piglets on parenteral nutrition for 11 days received an 8-hour infusion of LPS. In the in vitro studies, neonatal piglet Kupffer cells and hepatocytes were treated with media, media + 1 percent soy oil, or media + 1 percent soy oil + 100microM phytosterols. After 24-hour incubation, cells were treated with farnesoid X receptor (FXR) agonist obeticholic acid or liver X receptor (LXR) agonist GW3965 and challenged with LPS or interleukin 1beta. LPS administration in piglets led to transient increases in proinflammatory cytokines and suppression of the transporters bile salt export pump and ATP-binding cassette transporter G5. In hepatocytes, phytosterols did not activate inflammation. Phytosterol treatment alone did not activate inflammation in Kupffer cells but, combined with LPS, synergistically increased interleukin 1beta production. FXR and LXR agonists increased transporter expression in hepatocytes. GW3965 suppressed proinflammatory cytokine production in Kupffer cells, but obeticholic acid did not. In conclusion, LPS suppresses transporters that control bile acid and phytosterol clearance. Phytosterols alone do not cause inflammatory response. However, with costimulation by LPS, phytosterols synergistically maximize the inflammatory response in Kupffer cells.