Vitamin E sequestration by liver fat in humans

Violet PC, Ebenuwa IC, Wang Y, Niyyati M, Padayatty SJ, Head B, Wilkins K, Chung S, Thakur V, Ulatowski L, Atkinson J, Ghelfi M, Smith S, Tu H, Bobe G, Liu CY, Herion DW, Shamburek RD, Manor D, Traber MG, Levine M.

JCI Insight. 2019 Dec 10. pii: 133309. doi: 10.1172/jci.insight.133309.

Abstract

BACKGROUND We hypothesized that obesity-associated hepato-steatosis served as a pathophysiologic chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were utilized to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepato-steatosis vs healthy controls.METHODS Custom-synthesized deuterated α-tocopherols (d3- and d6-α-tocopherols) were administered to hospitalized healthy women and women with hepato-steatosis under IND guidelines. Serial samples obtained over 72 hours were analyzed by LC/MS. Fluorescent-labelled 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 6-8 hours. d3- and d6-α-Tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1h, indicating a key role of liver in rapid uptake and re-release into the circulation. Compared to healthy subjects, subjects with hepato-steatosis had similar d6-α-tocopherol entry rates into liver, but reduced initial release rates (p<0.001). Similarly, pharmacokinetics parameters of AUC and Maximum Concentration (Cmax) were reduced (AUC0-8 ,p<0.01;Cmax p<0.02) in hepato-steatosis subjects, indicating reduced hepatic d6-α-tocopherol output. Reduced kinetics and pharmacokinetics parameters (AUC and Cmax) in hepato-steatosis subjects who received 2 mg were mirrored by similar reductions in healthy subjects when comparing 5 and 2 mg doses. In vitro, fluorescent-labelled α-tocopherol localized specifically 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 hepato-steatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepato-steatosis may similarly alter hepatic physiology of other fat-soluble vitamins.

Fujiwara Y

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S34-S37. doi: 10.3177/jnsv.65.S34.

Abstract

The dietary fat intake of Japanese is thought to be more appropriate than in Western countries; however there is a range of differences of individuals in the amounts of fat intake and n-6/n-3 ratio. Therefore, it is important what kind of vegetable oils are used for cooking in order to consider the total balance of fat intake. Rice bran oil (RBO) is expected to reduce plasma cholesterol and be useful for prevention of cardiovascular disease because it contains several effective ingredients. RBO is rich in linoleic and oleic acid. RBO contains γ-oryzanol, which is well known to reduce plasma cholesterol levels. Furthermore, it contains tocotrienols, which are analogs of vitamin E, reported to have unique bioactivity different from that of α-tocopherol. The biological function of these components and their potential to prevent Japanese lifestyle-related diseases are discussed.

Ibrahim MA, Ibrahim HM, Mohamed AA, Tammam HG

Toxicol Mech Methods. 2019 Oct 29:1-12. doi: 10.1080/15376516.2019.1681043.

Abstract

Several deleterious effects of Tramadol including deaths were reported especially when used in large doses. Being metabolized mainly in the liver, Tramadol have serious hepatotoxic effects. This study investigates the effect of vitamin E on Tramadol-induced hepatotoxicity in rats by evaluating the antioxidant biochemical markers, the histopathological and immunohistochemical changes.Thirty adult mature male albino rats were divided into five groups (Gs); G1: negative control; G2: received Tramadol 150 mg/kg, G 3-5: received Tramadol plus vitamin E in concentrations of 50 mg/kg, 100 mg/kg and 200 mg/kg respectively. Liver function parameters and oxidative markers in liver tissue (CAT, SOD, GSH, and MDA) were estimated. Liver samples were processed for histopathological and immunohistochemical (Caspase 3 and TNF[Formula: see text]) examinations. The results indicated that Sub-chronic administration of Tramadol resulted in impaired liver functions, increased oxidative stress parameters with decreased antioxidant capacity of liver tissues, severe hepatocellular damage (hydropic degeneration, steatosis and apoptosis) and strong immunoexpression to TNF[Formula: see text] and Caspase 3. All these effects were ameliorated with concomitant administration of vitamin E especially with high doses. The co-treatment of Tramadol-intoxicated rats with Vitamin E, especially in high doses, protects against hepatic toxicity.

Lee H, Lim Y

Nutr Res Pract. 2019 Oct;13(5):377-383. doi: 10.4162/nrp.2019.13.5.377.

Abstract

BACKGROUND/OBJECTIVES:

Hyperglycemia-induced hepatic damage has been recognized as one of the major cause of complications in diabetes. Hepatic complications are associated with inflammation and oxidative stress in diabetes. In this study, we investigated the hypothesis that gamma-tocopherol (GT) supplementation ameliorates NLRP3 inflammasome associated hepatic inflammation in diabetes.

MATERIALS/METHODS:

Diabetes was induced by the intraperitoneal injection of alloxan (150 mg/kg. BW) in ICR mice. All mice were fed with a control diet (AIN-76A). After diabetes was induced (fasting glucose level ≥ 250 mg/dL), the mice were treated with tocopherol-stripped corn oil or GT-supplemented (35 mg/kg) corn oil, respectively, by gavage for 2 weeks.

RESULTS:

GT supplementation reduced fasting blood glucose levels in diabetic mice relative to non-treated diabetic mice. Moreover, GT supplementation ameliorated hyperglycemia-induced hepatic damage by regulation of NOD-like receptor protein 3 (NLRP3)-inflammasome associated inflammation represented by NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain, caspase-1, nuclear factor-κB pathway as well as oxidative stress demonstrated by nuclear factor erythroid 2-related factor 2, NAD(P)H dehydrogenase quinone 1, catalase and glutathione-dependent peroxidase in diabetic mice.

CONCLUSION:

The findings suggested that GT supplementation ameliorated hepatic damage by attenuating inflammation and oxidative stress in alloxan-induced diabetic mice. Taken together, GT could be a beneficial nutrient that can ameliorate inflammatory responses associated with NLRP3 inflammasome in hyperglycemia-induced hepatic damage.

Sebastiani G, Saeed S, Lebouche B, de Pokomandy A, Szabo J, Haraoui LP, Routy JP, Wong P, Deschenes M, Ghali P, Klein M; LIVEHIV Study Group.

AIDS. 2019 Oct 16. doi: 10.1097/QAD.0000000000002412.

Abstract

OBJECTIVE:

Human immunodeficiency virus (HIV)-infected patients are at increased risk of nonalcoholic steatohepatitis (NASH). Vitamin E is recommended for treatment of NASH in the general population. However, its safety and efficacy among HIV-infected patients remain unknown.

DESIGN:

Single centre, phase IV, open-label, single arm clinical trial.

METHODS:

HIV mono-infected patients without significant alcohol intake or viral hepatitis coinfection were included. The diagnosis of NASH was based on the co-existence of fatty liver, diagnosed by controlled attenuation parameter (CAP) ≥ 248 dB/m, and significant hepatocyte apoptosis, defined by the serum biomarker cytokeratin 18 (CK-18) >130.5 U/L. Participants were treated with 800 IU daily of oral vitamin E (alpha-tocopherol) for 24 weeks, and followed for an additional 24 weeks post-discontinuation. Generalized linear mixed effects models were used to evaluate changes in ALT, CAP and CK-18 at the completion of treatment and end of follow-up, controlling for pre-treatment trends.

RESULTS:

A total of 27 patients were included. Four (15%) had a pretreatment liver biopsy, which confirmed the diagnosis of NASH in all cases. Compared to baseline, 24 weeks of vitamin E treatment improved ALT (-27 units/L; 95% confidence interval [CI] -37, –17), CAP scores (-22 dB/m; 95% CI -42, -1) and CK-18 (-123 units/L; 95% CI -201, -46). Conversely, there was no change in BMI. No serious adverse event was reported and no patient was lost to follow-up.

CONCLUSION:

In this first clinical trial, we showed that vitamin E is an effective and well-tolerated treatment for NASH in HIV-infected patients.

Eid RA, Al-Shraim M, Zaki MS, Kamar SS, Abdel Latif NS, Negm S, Al-Ani B, Haidara MA

Ultrastruct Pathol. 2019;43(4-5):199-208. doi: 10.1080/01913123.2019.1673860.

Abstract

Food additives such as nitrates and nitrites, and monosodium glutamate (MSG) used in the food industry increase the risk of certain cancers and inflict damage to vital organs. We sought to determine whether the antioxidant vitamin E can protect against liver injuries induced by a toxic dose of MSG in a rat model of MSG-induced acute liver injury. The model group of rats received a daily dose of MSG (4 gm/kg) for 7 days, whereas the protective groups were either received a 100 mg/kg vitamin E plus MSG or 300 mg/kg vitamin E plus MSG for 7 days. Rats were then sacrificed at day 8. Transmission and light microscopy images revealed substantial liver tissue damage induced by MSG in the model group as demonstrated by apoptotic hepatocytes with Pyknotic nuclei and irregular nuclear membrane, and cytoplasm displayed many vacuoles, swollen mitochondria, dilated endoplasmic reticulum, dilated blood sinusoids and bundles of collagen fibers in extracellular space. Treatment of the model group with vitamin E showed a substantial protection of liver tissue and hepatocellular architecture by 300 mg/kg vitamin E compared to a partial protection by 100 mg/kg vitamin E. In addition, MSG significantly (p < .05) modulated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), and glutathione peroxidase (GPx), which were significantly (p < .05) protected with vitamin E. Thus, vitamin E at 300 mg/kg effectively protects against MSG-induced acute liver injury in rats, possibly via the inhibition of inflammation, and up-regulation of endogenous antioxidants.

Amanullah I, Khan YH, Anwar I, Gulzar A, Mallhi TH, Raja AA

Postgrad Med J. 2019 Aug 21. pii: postgradmedj-2018-136364. doi: 10.1136/postgradmedj-2018-136364. [Epub ahead of print]

Abstract

The efficacy of vitamin E among patients with non-alcoholic fatty liver disease (NAFLD) is unclear. The current qualitative and quantitative analyses aimed to ascertain the efficacy of vitamin E on clinical outcomes of patients with NAFLD. A systematic search of randomised controlled trials (RCTs) was performed using databases (PubMed, ProQuest, Scopus, EBSCOhost and Ovid) from inception to July 2018. Trials meeting the inclusion criteria were subjected to quality assessment using the Jadad Scoring. All trials meeting the prerequisites information for meta-analysis were subjected to quantitative synthesis of results. Nine RCTs (five in adults and four in children) were included. Four of the five RCTs on adults demonstrated significant improvements in alanine transaminase and other liver function surrogates in patients with NAFLD. On the other hand, only one of the four RCTs conducted on children showed significant improvements in liver functions with the use of vitamin E. Although quantitative synthesis of available data revealed insignificant differences between vitamin E and placebo, still the use of vitamin E improves the level of alanine transaminase and aspartate transaminase by -1.96 and -0.59, with heterogeneity of I²=67% and I²=0%, respectively. Adjuvant vitamin E therapy provides significant biochemical and histological improvements in adult patients with NAFLD, while paediatric patients showed insignificant efficacy compared with placebo. Lifestyle interventions along with vitamin E can provide much better results. Data, including the impact of vitamin E on hepatic histology, are still lacking. Moreover, the short duration of trials limits the conclusion on the safety and efficacy of proposed treatments.

Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, Tio F, Suman A, Orsak BK, Hecht J, Cusi K

Diabetes Care. 2019 Aug;42(8):1481-1488. doi: 10.2337/dc19-0167. Epub 2019 May 21.

Abstract

OBJECTIVE:

While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without diabetes, information on patients with type 2 diabetes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH.

RESEARCH DESIGN AND METHODS:

This was a proof-of-concept, randomized, double-blind, placebo-controlled trial conducted from 2010 to 2016. Patients with T2DM and biopsy-proven NASH (n = 105) were randomized to vitamin E 400 IU b.i.d., vitamin E 400 IU b.i.d. plus pioglitazone 45 mg/day, or placebo. Eighty-six patients completed the 18-month study. The primary end point was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fibrosis. Secondary outcomes were resolution of NASH without worsening of fibrosis, individual histological scores, and metabolic parameters.

RESULTS:

More patients on combination therapy achieved the primary outcome versus placebo (54% vs. 19%, P = 0.003) but not with vitamin E alone (31% vs. 19%, P = 0.26). Both groups showed improvements in resolution of NASH compared with placebo (combination group: 43% vs. 12%, P = 0.005; vitamin E alone: 33% vs. 12%, P = 0.04). While steatosis assessed by histology improved with combination therapy (P < 0.001) and vitamin E alone (P = 0.018), inflammation (P = 0.018) and ballooning (P = 0.022) only improved with combination therapy. No improvement in fibrosis was observed in any group.

CONCLUSIONS:

In this proof-of-concept study, combination therapy was better than placebo in improving liver histology in patients with NASH and T2DM. Vitamin E alone did not significantly change the primary histological outcome.

Fell GL, Anez-Bustillos L, Dao DT, Baker MA, Nandivada P, Cho BS, Pan A, O'Loughlin AA, Nose V, Gura KM, Puder M

PLoS One. 2019 Jul 11;14(7):e0217155. doi: 10.1371/journal.pone.0217155. eCollection 2019.

Abstract

Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.

Ivancovsky-Wajcman D, Fliss-Isakov N, Salomone F, Webb M, Shibolet O, Kariv R, Zelber-Sagi S

Dig Liver Dis. 2019 Jul 4. pii: S1590-8658(19)30662-0. doi: 10.1016/j.dld.2019.06.005. [Epub ahead of print]

Abstract

BACKGROUND & AIMS:

Although antioxidants have a protective potential in nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), there is limited evidence regarding the role of dietary intake of antioxidants. The aim was to test the association between dietary vitamins E and C intake and NAFLD, NASH and fibrosis markers.

METHODS:

Cross-sectional study of a large cohort of subjects undergoing colonoscopy. The presence of NAFLD was evaluated by ultrasonography. The level of steatosis was defined using SteatoTest, moderate-severe NASH using new quantitative NashTest and borderline-significant fibrosis ≥ F1-F2 using FibroTest. Nutritional intake was measured by food frequency questionnaire (FFQ).

RESULTS:

Overall, 789 subjects were included (52.6% men, age 58.83 ± 6.58 years), 714 had reliable FibroMax. Adjusting for BMI, dietary and lifestyle factors, the upper tertile of vitamin E intake/1000 Kcal was associated with lower odds of NASH (OR = 0.64, 0.43-0.94, P = 0.024). There was an inverse association between reaching the recommended vitamin E intake and NASH (OR = 0.48, 0.30-0.77, P = 0.002). The upper tertile of vitamin C intake/1000 Kcal was associated with lower odds of NAFLD and NASH (OR = 0.68, 0.47-0.99, P = 0.045; OR = 0.57, 0.38-0.84, P = 0.004, respectively). Both vitamins were related with the level of steatosis according to SteatoTest.

CONCLUSION:

Vitamin E and C intake may be protective from NAFLD-related liver damage.