Vitamin E sequestration by liver fat in humans

• Published in: JCI insight 2020-01, Vol.5 (1)
• Main Authors: Violet, Pierre-Christian, Ebenuwa, Ifechukwude C, Wang, Yu, Niyyati, Mahtab, Padayatty, Sebastian J, Head, Brian, Wilkins, Kenneth, Chung, Stacey, Thakur, Varsha, Ulatowski, Lynn, Atkinson, Jeffrey, Ghelfi, Mikel, Smith, Sheila, Tu, Hongbin, Bobe, Gerd, Liu, Chia-Ying, Herion, David W, Shamburek, Robert D, Manor, Danny, Traber, Maret G, Levine, Mark
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; alpha-Tocopherol - administration & dosage; alpha-Tocopherol - pharmacokinetics; Cell Line; Clinical Medicine; Fatty Liver - drug therapy; Female; Hep G2 Cells; Humans; Kinetics; Lipids; Lipoproteins; Liver - metabolism; Obesity; Vitamin E - administration & dosage; Vitamin E - pharmacokinetics; Young Adult
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.133309

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.