Vitamin E sequestration by liver fat in humans.

Autor:	Violet PC; Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA., Ebenuwa IC; Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA., Wang Y; Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA., Niyyati M; Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA., Padayatty SJ; Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA., Head B; Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA., Wilkins K; Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA., Chung S; Department of Pharmacology and Department of Nutrition, School of Medicine, Case Western Reserve University and the Case Comprehensive Cancer Center, Cleveland, Ohio, USA., Thakur V; Department of Pharmacology and Department of Nutrition, School of Medicine, Case Western Reserve University and the Case Comprehensive Cancer Center, Cleveland, Ohio, USA., Ulatowski L; Department of Pharmacology and Department of Nutrition, School of Medicine, Case Western Reserve University and the Case Comprehensive Cancer Center, Cleveland, Ohio, USA., Atkinson J; Department of Chemistry, Brock University, Saint Catharines, Ontario, Canada., Ghelfi M; Department of Chemistry, Brock University, Saint Catharines, Ontario, Canada., Smith S; Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA., Tu H; Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA., Bobe G; Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA., Liu CY; Radiology and Imaging Sciences and., Herion DW; Clinical Research Informatics, Clinical Center, NIH, Bethesda, Maryland, USA., Shamburek RD; Cardiovascular Branch, Intramural Research Program, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA., Manor D; Department of Pharmacology and Department of Nutrition, School of Medicine, Case Western Reserve University and the Case Comprehensive Cancer Center, Cleveland, Ohio, USA., Traber MG; Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA., Levine M; Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2020 Jan 16; Vol. 5 (1). Date of Electronic Publication: 2020 Jan 16.
DOI:	10.1172/jci.insight.133309
Abstrakt:	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.
Databáze:	MEDLINE
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