TY - JOUR AU - Violet, Pierre-Christian AU - Ebenuwa, Ifechukwude C. AU - Wang, Yu AU - Niyyati, Mahtab AU - Padayatty, Sebastian J. AU - Head, Brian AU - Wilkins, Kenneth AU - Chung, Stacey AU - Thakur, Varsha AU - Ulatowski, Lynn AU - Atkinson, Jeffrey AU - Ghelfi, Mikel AU - Smith, Sheila AU - Tu, Hongbin AU - Bobe, Gerd AU - Liu, Chia-Ying AU - Herion, David W. AU - Shamburek, Robert D. AU - Manor, Danny AU - Traber, Maret G. AU - Levine, Mark T1 - Vitamin E sequestration by liver fat in humans PY - 2020/01/16/ AB - BACKGROUND We 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.METHODS Custom-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.RESULTS In 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.CONCLUSIONS The 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 REGISTRATION ClinicalTrials.gov, NCT00862433.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases and NIH grants DK053213-13, DK067494, and DK081761. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.133309 VL - 5 IS - 1 UR - https://doi.org/10.1172/jci.insight.133309 PB - The American Society for Clinical Investigation ER -