Vitamin E sequestration by liver fat in humans

Abstract

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 (d 3-and d 6-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 d 6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d 3-and d 6-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 d 6-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 d 6-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, fluorescentlabeled 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.

Cardiovascular and Metabolic Protection by Vitamin E: A Matter of Treatment Strategy?

“…Fatty liver disease is an inflammatory disease, and thus elevated oxidative stress levels decreased α-TOH plasma levels in NASH patients compared to healthy subjects (22.4 vs. 26.8 nmol/mL; p < 0.01), whereas γ-TOH remained unchanged [ 89 ]. This observation supports the hypothesis that α-TOH is the most active antioxidative form of vitamin E. A recent study of Violet et al showed alteration of α-TOH kinetics in women with obesity-associated hepatosteatosis compared to healthy controls, resulting in decreased release of α-TOH from the liver, consequently lowering the concentration of circulating α-TOH [ 91 ]. In addition, the authors postulate complex-like binding of α-TOH to lipids, which in the following avert α-TOH ROS-quenching properties and thus causing a worsening of the disease [ 91 ].…”

Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis

“…Furthermore, it is not clear that NAFLD is a vitamin E deficiency disorder or the result of local vitamin E deficiency. In fact, in NAFLD and possibly in hepatic steatosis in general, vitamin E appears to be sequestered in lipid droplets [ [52] , [53] , [54] ] which may prevent it from performing its physiological role in other subcellular compartments. Supplementation may be able to restore vitamin E concentration in other organelles although the appropriate dose needs to be elucidated in larger studies.…”

Alpha-Tocopherol Metabolites (The Vitamin E Metabolome) and Their Interindividual Variability during Supplementation

“…In fact, the age-related decline of physiological functions and the excess of fat depots appear to play a key role in determining the status and systemic availability of this vitamin [ 46 ], and highly prevalent ailments, such as obesity, metabolic syndrome, and non-alcoholic fatty liver disease, are all associated with sequestration, and impaired catabolism and turnover of tissue α-TOH [ 47 , 48 , 49 ]. Subclinical forms of these metabolic conditions (such as overweight, benign obesity, and fatty liver) are very common in apparently healthy people and could interfere with vitamin E metabolism, stimulating its free radical-mediated oxidation [ 36 ] and/or leading to reduced biotransformation throughout enzymatic pathways [ 48 ], thus representing potential factors of variability of this metabolome that are worth investigating in future clinical trials. Considering the anthropometric characteristics and baseline levels of α-TQ and lipid corrected levels of α-TOH, the presence of subclinical conditions of fatty liver [ 36 ] can be excluded in the heathy volunteers of this study.…”

“…The fact that blood lipids, subject age, and WC are among the factors that may contribute to the interindividual variability of α-TOH levels and metabolism is not surprising. In fact, the age-related decline of physiological functions and the excess of fat depots appear to play a key role in determining the status and systemic availability of this vitamin [46], and highly prevalent ailments, such as obesity, metabolic syndrome, and non-alcoholic fatty liver disease, are all associated with sequestration, and impaired catabolism and turnover of tissue α-TOH [47][48][49]. Subclinical forms of these metabolic conditions (such as overweight, benign obesity, and fatty liver) are very common in apparently healthy people and could interfere with vitamin E metabolism, stimulating its free radical-mediated oxidation [36] and/or leading to reduced biotransformation throughout enzymatic pathways [48], thus representing potential factors of variability of this metabolome that are worth investigating in future clinical trials.…”