Stigmasterol, a Soy Lipid–Derived Phytosterol, Is an Antagonist of the Bile Acid Nuclear Receptor FXR

Carter, Beth A.; Taylor, Olga A.; Prendergast, Daniel R; Zimmerman, Tracy L.; Furstenberg, Richard von; Moore, David D.; Karpen, Saul J.

doi:10.1203/pdr.0b013e3181256492

Cited by 253 publications

(199 citation statements)

References 40 publications

(34 reference statements)

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“…Although TPN is lifesaving in providing nutrition to extremely low-birth weight infants and infants with serious gastrointestinal surgical conditions, it has serious side effects, with PNALD being the foremost among them (3,8). Until recently, infants with PNALD lacked effective modes of treatment, but the recent emergence of FOLE has shown a significant reduction in the mortality and morbidity associated with established PNALD (17,18).…”

Section: Discussionmentioning

confidence: 99%

“…However, evidence accumulated over the past few decades strongly suggests the lipid component of TPN as the most probable cause of PNALD. Both animal and human research during the past decade has implicated phytosterols and v-6 (n-6) fatty acids as the most likely components in the current lipid formulations as primary reasons for PNALD (8)(9)(10)(11)(12). In contrast, fish oil-based lipid emulsions (FOLEs) have been shown to be associated with full resolution of PNALD (13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Fish Oil–Based Lipid Emulsions in the Treatment of Parenteral Nutrition-Associated Liver Disease: An Ongoing Positive Experience

Premkumar

Carter

Hawthorne

et al. 2014

Advances in Nutrition

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We previously reported the beneficial effect of fish oil-based lipid emulsions (FOLEs) as monotherapy in the treatment of parenteral nutritionassociated liver disease (PNALD). In this report, we share our ongoing experience at Texas Children's Hospital, Houston, Texas in the use of FOLE in treatment of PNALD as presented at the 2013 Experimental Biology meeting. We describe the findings of a single center, prospective, observational study of infants <6 mo of age with PNALD who received parenteral FOLE as monotherapy. A total of 97 infants received FOLE under the compassionate-use protocol for the treatment of PNALD. Eighty-three (86%) survived with resolution of cholestasis and 14 (14%) died. The median conjugated bilirubin (CB) concentration at the initiation of FOLE therapy was 4.8 mg/dL (range 2.1-26). The median time to resolution of cholestasis was 40 d (range 3-158). Compared with infants with mild cholestasis (CB of 2.1-5 mg/dL at the initiation of FOLE), nonsurvivors were significantly more premature and took longer to resolve their cholestasis. Gestational age at birth correlated inversely with CB at the beginning of FOLE and peak CB. Infants with an initial CB >10 mg/dL had a higher mortality rate than infants with an initial CB <5 mg/dL (35% vs. 6%; P < 0.05). Our experience with the use of FOLE in PNALD continues to be encouraging. Prematurity continues to be a major determinant in mortality and severity of cholestasis. This calls for further controlled studies designed to optimize dose and timing of intervention in the use of FOLE in neonates. Adv. Nutr. 5: 65-70, 2014.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fish Oil–Based Lipid Emulsions in the Treatment of Parenteral Nutrition-Associated Liver Disease: An Ongoing Positive Experience

Premkumar

Carter

Hawthorne

et al. 2014

Advances in Nutrition

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“…Significantly higher ratios of serum phytosterols (stigmasterol, sitosterol, and avenasterol) were found associated with direct bilirubin in infants with IFALD, compared with those without IFALD [9]. The factors associated with IFALD in patients receiving high intakes of n-6 polyunsaturated fatty acids (n-6 PUFA) with soybean oil-based IVLE are the formation of n-6 arachidonic acid, a proinflammatory mediator, the high provision of phytosterols, and the limited supply of alpha tocopherol relative to PUFA supply [1,8,10].…”

Section: Introductionmentioning

confidence: 99%

Parenteral nutrition-associated cholestasis and triglyceridemia in surgical term and near-term neonates: A pilot randomized controlled trial of two mixed intravenous lipid emulsions

Pereira‐da‐Silva

Nóbrega

Rosa

et al. 2017

Clinical Nutrition ESPEN

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s u m m a r yBackground: Cholestasis is a common complication in infants receiving prolonged parenteral nutrition (PN). We studied the effects of two intravenous lipid emulsions composed with either 30% soybean oil, 30% medium-chain triglycerides (MCT), 25% olive oil, and 15% fish oil (SMOF) or with 50% MCT and 50% soybean oil n-6 (MCT/SOY) on the incidence of cholestasis in surgical term and near-term neonates. Methods: A single-center, double-blinded, randomized controlled trial compared the incidence of cholestasis using either SMOF or MCT/SOY in neonates born at gestational age !34 weeks undergoing major surgery. The primary outcome was the incidence of conjugated serum bilirubin >1 mg/dL. Other liver enzymes were assessed as secondary outcomes. A post-hoc analysis assessed serum triglycerides levels. Odds ratios were estimated by mixed-effects regression models. Results: Enrollment was prematurely interrupted because the MCT/SOY became unavailable, thus 49 infants (SMOF 22, MCT/SOY 27) completed the study. The exposure (time on PN, cumulative dose of lipids) was similar in both groups. Similar cumulative incidence rates were found for elevated conjugated bilirubinemia and other liver enzymes. Hypertriglyceridemia >250 mg/dL (12/49) was more frequent in MCT/SOY (37.0%, 95% CI 21.53e55.77) than in SMOF (9.1%, 95% CI 2.53e27.81, p ¼ 0.024). Triglyceridemia at the first assessment (median 8 postnatal days) was significantly higher with MCT/SOY than with SMOF (181 vs. 134 mg/dL, p ¼ 0.006). Over the whole study period, mean triglyceride concentration was 36.5 mg/dL higher with MCT/SOY compared with SMOF (p ¼ 0.013). Conclusion: Both emulsions had similar effects on the incidence of cholestasis and markers of liver integrity, but MCT/SOY induced higher serum triglyceride concentrations. Trial registration: ClinicalTrials.gov, NCT02633384

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“…A recent study investigating the role of different phytosterols (sitosterol, campesterol, and stigmasterol) in the induction of liver damage has shown that stigmasterol is a potent antagonist of the nuclear farnesoid X receptor FXR and the ligand-activated pregnane X receptor (a member also of the NR superfamily involved in the bile acid metabolism and inflammation), while sitosterol and campesterol had minimal or insignificant inhibitory effects in a human-derived liver cell line HepG2 (15). In addition to the agonist action of the liver X receptors (LXRs) (highly expressed in the liver, adipose tissue, intestine, kidney, and macrophages with involvement in sterol transport, fatty acid metabolism, glucose regulation, immunity , and cellular response), stigmasterol also interferes with the processing of sterol response element binding protein-2 (SREBP-2), which is a central regulatory factor in cholesterol metabolism.…”

Section: Discussionmentioning

confidence: 99%

Phytosterols and Lack of Occurrence of Cholestasis in Rats Nourished Parenterally or Orally

Forchielli¹,

Bersani²,

Talà³

et al. 2012

Cholestasis

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Stigmasterol, a Soy Lipid–Derived Phytosterol, Is an Antagonist of the Bile Acid Nuclear Receptor FXR

Cited by 253 publications

References 40 publications

Fish Oil–Based Lipid Emulsions in the Treatment of Parenteral Nutrition-Associated Liver Disease: An Ongoing Positive Experience

Fish Oil–Based Lipid Emulsions in the Treatment of Parenteral Nutrition-Associated Liver Disease: An Ongoing Positive Experience

Parenteral nutrition-associated cholestasis and triglyceridemia in surgical term and near-term neonates: A pilot randomized controlled trial of two mixed intravenous lipid emulsions

Phytosterols and Lack of Occurrence of Cholestasis in Rats Nourished Parenterally or Orally

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