Vitamin E sequestration by liver fat in humans.

Abstract

BACKGROUNDWe hypothesized that obesity-associated hepatosteatosis is a pathophysiological chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were used to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepatosteatosis versus healthy controls.METHODSCustom-synthesized deuterated α-tocopherols (d3- and d6-α-tocopherols) were administered to hospitalized healthy women and women with hepatosteatosis under investigational new drug guidelines. Fluorescently labeled α-tocopherol was custom-synthesized for cell studies.RESULTSIn healthy subjects, 85% of intravenous d6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d3- and d6-α-tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1 hour, indicating a key role of the liver in uptake and re-release. Compared with healthy subjects who received 2 mg, subjects with hepatosteatosis had similar d6-α-tocopherol entry rates into liver but reduced initial release rates (P < 0.001). Similarly, pharmacokinetics parameters were reduced in hepatosteatosis subjects, indicating reduced hepatic d6-α-tocopherol output. Reductions in kinetics and pharmacokinetics parameters in hepatosteatosis subjects who received 2 mg were echoed by similar reductions in healthy subjects when comparing 5- and 2-mg doses. In vitro, fluorescent-labeled α-tocopherol localized to lipid in fat-loaded hepatocytes, indicating sequestration.CONCLUSIONSThe unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepatosteatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepatosteatosis may similarly alter hepatic physiology of other fat-soluble vitamins.TRIAL REGISTRATIONClinicalTrials.gov, NCT00862433.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases and NIH grants DK053213-13, DK067494, and DK081761.

• Authors: Pierre-Christian Violet, Ifechukwude C Ebenuwa, Yu Wang, Mahtab Niyyati, Sebastian J Padayatty, Brian Head, Kenneth Wilkins, Stacey Chung, Varsha Thakur, Lynn Ulatowski, Jeffrey Atkinson, Mikel Ghelfi, Sheila Smith, Hongbin Tu, Gerd Bobe, Chia-Ying Liu, David W Herion, Robert D Shamburek, Danny Manor, Maret G Traber, Mark Levine
• Journal: JCI insight (JCI Insight) Vol. 5 Issue 1 (01 16 2020) ISSN: 2379-3708 [Electronic] United States
• PMID: 31821172 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lipids
• Lipoproteins
• Vitamin E
• alpha-Tocopherol

Topics

• Adolescent
• Adult
• Cell Line
• Fatty Liver (drug therapy)
• Female
• Hep G2 Cells
• Humans
• Kinetics
• Lipids
• Lipoproteins
• Liver (metabolism)
• Obesity
• Vitamin E (administration & dosage, pharmacokinetics)
• Young Adult
• alpha-Tocopherol (administration & dosage, pharmacokinetics)