SUN-555 Vitamin E Sequestration by Liver Fat in Vitro and in Women with Hepato-Steatosis

Abstract BACKGROUND: The global obesity epidemic has sobering consequences to human health. Especially concerning is obesity-associated hepato-steatosis (HS), a common cause of chronic liver disease in the Americas and Western Europe that precedes non-alcoholic steatohepatitis (NASH). Maintenance of normal body weight is the only current means to prevent HS and NASH. We hypothesized that excess liver fat in obesity-associated HS could act as a pathophysiologic chemical depot for fat-soluble vitamins and alter normal physiology. Because clinical trials with Vitamin E (α-T) have shown that NASH partially responds to this supplement, we selected α-T as a model vitamin to test the sequestration hypothesis. INTERVENTIONS: Under an IND and IRB-approved protocol, two deuterium-labeled α-tocopherols (d3-α-T and d6-α-T) were administered orally and intravenously, respectively, to 10 healthy women and 6 women with HS. Serial blood samples obtained over 72 h were analyzed by LC-MS/MS. In parallel, we performed studies in hepatocytes in cell culture and mouse model. RESULTS: In healthy women who received oral d3- and intravenous d6-α-T, 85% of the initial plasma peak d6-α-T disappeared within 20 minute and reappeared in the plasma peaking between 6-8 h. Compared to healthy subjects, subjects with HS had similar d6-α-T entry rates into liver, but reduced release rates into plasma (p<0.001). Similarly, pharmacokinetics parameters (AUC and Maximum Concentration [Cmax]), were reduced (AUC0-8,p<0.01;Cmax p<0.02) in HS subjects, indicating reduced hepatic d6-α-T output. Consistently, livers of mice fed with a high fat diet (42% fat) had more vitamin E compared to controls diet (5% fat), with both diets having the same α-T content CONCLUSION: These findings suggest the unique role of the liver in vitamin E physiology which is dysregulated by excess liver fat (measured by magnetic resonance spectroscopy). Considered together, the findings imply that obesity-associated HS may produce unrecognized hepatic α-T sequestration, which might subsequently drive liver disease. The data here raise the intriguing possibility that timely α-T supplementation might attenuate progression of HS to NASH, perhaps by correcting an unrecognized fat-induced, localized, hepatic vitamin E deficiency prior to onset of inflammation, hepatitis, and fibrosis. Additionally, our findings raise the possibility that HS may similarly alter hepatic physiology of other fat-soluble vitamins.

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