Possible Hepatoprotective Effect of Tocotrienol-Rich Fraction Vitamin E in Non-alcoholic Fatty Liver Disease in Obese Children and Adolescents

Farah D R Al-Baiaty, Aziana Ismail, Zarina Abdul Latiff, Khairul Najmi Muhammad Nawawi, Raja Affendi Raja Ali, Norfilza Mohd Mokhtar

Front Pediatr . 2021 Jul 8;9:667247. doi: 10.3389/fped.2021.667247. eCollection 2021.

Abstract

Obesity has become a worldwide health concern among the pediatric population. The prevalence of non-alcoholic fatty liver disease (NAFLD) is growing rapidly, alongside the high prevalence of obesity. NAFLD refers to a multifactorial disorder that includes simple steatosis to non-alcoholic steatohepatitis (NASH) with or devoid of fibrosis. NAFLD is regarded as a systemic disorder that influences glucose, lipid, and energy metabolism with hepatic manifestations. A sedentary lifestyle and poor choice of food remain the major contributors to the disease. Prompt and timely diagnosis of NAFLD among overweight children is crucial to prevent the progression of the condition. Yet, there has been no approved pharmacological treatment for NAFLD in adults or children. As indicated by clinical evidence, lifestyle modification plays a vital role as a primary form of therapy for managing and treating NAFLD. Emphasis is on the significance of caloric restriction, particularly macronutrients (fats, carbohydrates, and proteins) in altering the disease consequences. A growing number of studies are now focusing on establishing a link between vitamins and NAFLD. Different types of vitamin supplements have been shown to be effective in treating NAFLD. In this review, we elaborate on the potential role of vitamin E with a high content of tocotrienol as a therapeutic alternative in treating NAFLD in obese children.

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Tocotrienols Activate Nrf2 Nuclear Translocation and Increase the Antioxidant- Related Hepatoprotective Mechanism in Mice Liver

Ahmed Atia, Nadia S Alrawaiq, Azman Abdullah

Curr Pharm Biotechnol . 2021;22(8):1085-1098. doi: 10.2174/1389201021666200928095950.

Abstract

Background: The most common preparation of tocotrienols is the Tocotrienol-Rich Fraction (TRF). This study aimed to investigate whether TRF induced liver Nrf2 nuclear translocation and influenced the expression of Nrf2-regulated genes.

Methods: In the Nrf2 induction study, mice were divided into control, 2000 mg/kg TRF and diethyl maleate treated groups. After acute treatment, mice were sacrificed at specific time points. Liver nuclear extracts were prepared and Nrf2 nuclear translocation was detected through Western blotting. To determine the effect of increasing doses of TRF on the extent of liver nuclear Nrf2 translocation and its implication on the expression levels of several Nrf2-regulated genes, mice were divided into 5 groups (control, 200, 500 and 1000 mg/kg TRF, and butylated hydroxyanisole-treated groups). After 14 days, mice were sacrificed and liver RNA was extracted for qPCR assay.

Results: 2000 mg/kg TRF administration initiated Nrf2 nuclear translocation within 30 min, reached a maximum level of around 1 h and dropped to half-maximal levels by 24 h. Incremental doses of TRF resulted in dose-dependent increases in liver Nrf2 nuclear levels, along with concomitant dosedependent increases in the expressions of Nrf2-regulated genes.

Conclusion: TRF activated the liver Nrf2 pathway resulting in increased expression of Nrf2-regulated cytoprotective genes.

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alpha-Tocopherol supplementation reduces inflammation and apoptosis in high cholesterol mediated nonalcoholic steatohepatitis

Tugce Demirel-Yalciner, Erdi Sozen, Esra Ozaltin, Ali Sahin, Nesrin Kartal Ozer

Biofactors . 2021 May;47(3):403-413. doi: 10.1002/biof.1700. Epub 2021 Jun 8.

Abstract

Inflammation and apoptosis signaling are crucial steps in the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Alpha-tocopherol, the most active form of vitamin E, is an important modulator of signaling mechanisms, but its involvement to cholesterol-induced NASH pathogenesis remains poorly defined. Herein we have reported a novel effect of α-tocopherol in the transition from hepatic steatosis to NASH. High cholesterol diet alone (without α-tocopherol) in rabbits elevated NASH development as indicated by increased inflammatory response, apoptotic activity and liver fibrosis. Such elevation results from induction of signaling mechanisms since the expressions of IL1β, phospho c-Jun/c-Jun ratio, JNK, caspase 9, CHOP and Bax were increased, and recruitment of macrophage, α-smooth muscle actin (α-SMA) and COL1A1 into the liver tissue were induced. Alpha-tocopherol supplementation inhibited inflammatory response, apoptosis and fibrosis development without affecting lipid accumulation in high cholesterol-induced NASH. Specifically, α-tocopherol lowered the inflammatory level as observed by reduced macrophage infiltration and JNK/c-Jun signaling. Lower inflammatory status co-occurred with the reduction of CHOP and Bax expressions as well as fibrosis-related COL1A1 and α-SMA levels. Taken together, α-tocopherol supplementation inhibits cholesterol-induced NASH development by lowering JNK/c-Jun/inflammation axis in addition to JNK/CHOP/apoptosis signaling, which might contribute to resistance against NAFLD/NASH transition.

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Dynamics of Serum Retinol and Alpha-Tocopherol Levels According to Non-Alcoholic Fatty Liver Disease Status

Dongsub Jeon, Minkook Son, Juhyun Shim

Nutrients . 2021 May 19;13(5):1720. doi: 10.3390/nu13051720.

Abstract

The available data on the association between micronutrients in the blood and non-alcoholic fatty liver disease (NAFLD) are limited. To investigate the clinical implications of this relationship, we sought to identify the difference in the serum levels of vitamins A and E according to NAFLD status using data from the seventh Korea National Health and Nutrition Examination Survey. In this cross-sectional study of the Korean population, NAFLD and its severity were defined using prediction models. Differences in the prevalence and severity of NAFLD were analyzed according to serum retinol (vitamin A) and alpha (α)-tocopherol (vitamin E) levels. Serum levels of retinol and α-tocopherol were positively correlated with the prevalence of NAFLD. In most prediction models of the NAFLD subjects, serum retinol deficiency was significantly correlated with advanced fibrosis, while serum α-tocopherol levels did not differ between individuals with or without advanced fibrosis. Similar trends were also noted with cholesterol-adjusted levels of α-tocopherol. In summary, while circulating concentrations of retinol and α-tocopherol were positively associated with the presence of NAFLD, advanced liver fibrosis was only correlated with serum retinol levels. Our findings could provide insight into NAFLD patient care at a micronutrient level.

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Endogenous vitamin E metabolites mediate allosteric PPARγ activation with unprecedented co-regulatory interactions

Sabine Willems, Leonie Gellrich, Apirat Chaikuad, Stefan Kluge, Oliver Werz, Jan Heering, Stefan Knapp, Stefan Lorkowski, Manfred Schubert-Zsilavecz, Daniel Merk

Cell Chem Biol . 2021 May 12;S2451-9456(21)00212-9. doi: 10.1016/j.chembiol.2021.04.019. Online ahead of print.

Abstract

Vitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARγ). Co-stimulation of PPARγ with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARγ-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARγ compared with canonical PPARγ agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARγ modulation as an alternative avenue to PPARγ targeting and suggest contributions of PPARγ activation by α-13-tocopherolcarboxylate to the pharmacological effects of vitamin E.

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The effects of tocotrienols intake on obesity, blood pressure, inflammation, liver and glucose biomarkers: a meta-analysis of randomized controlled trials

Fengxiang Li, Biao Xu, Samira Soltanieh, Fernando Zanghelini, Ahmed Abu-Zaid, Jian Sun

Crit Rev Food Sci Nutr . 2021 Apr 28;1-14. doi: 10.1080/10408398.2021.1911926. Online ahead of print.

Abstract

The objective of this study is to accomplish a systematic review and meta-analysis of all randomized controlled trials that dissected the influence of tocotrienol supplementation on various anthropometric and cardiometabolic indices in all individuals, irrespective of health condition. This research was carried out in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. 17 eligible articles were included in the final quantitative analysis. Current study revealed that tocotrienol consumption was not associated with CRP, WC, MDA, BMI, IL-6, HbA1C, ALT, AST, creatinine TNF-α, FPG, BW, DBP, and SBP. We did observe an overall increase in BW (SMD: 0.063 kg, 95% CI: -0.200, 0.327, p = 0.637) and DBP (SMD: 0.249 mmHg, 95% CI: 0.053, 0.446, p = 0.013). In addition, a significant reduction in SBP was observed (SMD: -0.616 mmHg, 95% CI: -1.123, -0.110, p = 0.017). In summary, our meta-analysis revealed that tocotrienol consumption was associated with increase in BW and DBP and decrease in SBP. Significant associations were not observed for other outcomes.

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Vitamin E and Lactobacillus Provide Protective Effects Against Liver Injury Induced by HgCl 2: Role of CHOP, GPR87, and mTOR Proteins

Ahlam Alhusaini, Shahad Alghilani, Waad Alhuqbani, Iman H Hasan

Dose Response . 2021 Apr 26;19(2):15593258211011360. doi: 10.1177/15593258211011360. eCollection Apr-Jun 2021.

Abstract

Background and objective: Mercury is one of the most harmful heavy metals and its toxicity causes severe multi-organ dysfunction. This study was designed to explore novel molecular pathways involved in the hepatoprotective effect of vitamin E (Vit-E) and Lactobacillius plantarum (Lac-B) against mercury toxicity.

Method: Acute hepatotoxicity was induced by administration of high dose of mercuric chloride (HgCl2) in male rats, Vit-E or/and Lac-B were given along with HgCl2 for 2 weeks. The effects of those antioxidants were studied focusing on their anti-apoptotic, anti-oxidative stress and anti-inflammatory eficacies. Histopathological examinations were also conducted.

Results: The administration of HgCl2 induced liver injury which manifested by elevation in serum ALT and AST. Liver MDA, caspase-3 and TNF-α levels were markedly increased; whereas, GSH level and SOD activity were declined. HgCl2 significantly elevated the expressions of hepatic CHOP, GPR87, NF-κB and mTOR. Histopathological examination revealed massive hepatocyte degeneration following HgCl2 administration. Treatment with Vit-E or/and Lac-B restored the normal levels of the previously mentioned parameters, as well as improved hepatic architecture.

Conclusion: Vit-E and Lac-B provided protective effect against HgCl2-induced hepatotoxicity via reduction of oxidative stress and inflammation, and downregulation of CHOP, GPR87, NF-κB and mTOR proteins’ expressions.

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The Combination of Berberine, Tocotrienols and Coffee Extracts Improves Metabolic Profile and Liver Steatosis by the Modulation of Gut Microbiota and Hepatic miR-122 and miR-34a Expression in Mice

Valentina Cossiga, Vincenzo Lembo, Cecilia Nigro, Paola Mirra, Claudia Miele, Valeria D'Argenio, Alessia Leone, Giovanna Mazzone, Iolanda Veneruso, Maria Guido, Francesco Beguinot, Nicola Caporaso, Filomena Morisco

Nutrients . 2021 Apr 13;13(4):1281. doi: 10.3390/nu13041281.

Abstract

Non-alcoholic-fatty liver disease (NAFLD) is spreading worldwide. Specific drugs for NAFLD are not yet available, even if some plant extracts show beneficial properties. We evaluated the effects of a combination, composed by Berberis Aristata, Elaeis Guineensis and Coffea Canephora, on the development of obesity, hepatic steatosis, insulin-resistance and on the modulation of hepatic microRNAs (miRNA) levels and microbiota composition in a mouse model of liver damage. C57BL/6 mice were fed with standard diet (SD, n = 8), high fat diet (HFD, n = 8) or HFD plus plant extracts (HFD+E, n = 8) for 24 weeks. Liver expression of miR-122 and miR-34a was evaluated by quantitativePCR. Microbiome analysis was performed on cecal content by 16S rRNA sequencing. HFD+E-mice showed lower body weight (p < 0.01), amelioration of insulin-sensitivity (p = 0.021), total cholesterol (p = 0.014), low-density-lipoprotein-cholesterol (p < 0.001), alanine-aminotransferase (p = 0.038) and hepatic steatosis compared to HFD-mice. While a decrease of hepatic miR-122 and increase of miR-34a were observed in HFD-mice compared to SD-mice, both these miRNAs had similar levels to SD-mice in HFD+E-mice. Moreover, a different microbial composition was found between SD- and HFD-mice, with a partial rescue of dysbiosis in HFD+E-mice. This combination of plant extracts had a beneficial effect on HFD-induced NAFLD by the modulation of miR-122, miR-34a and gut microbiome.

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Tocotrienols activate Nrf2 nuclear translocation and increase the antioxidant-related hepatoprotective mechanism in mice liver

Ahmed Atia, Nadia Salem Al-Rawaiq, Azman Abdullah

Curr Pharm Biotechnol . 2020 Sep 27. doi: 10.2174/1389201021666200928095950. Online ahead of print.

Abstract

Background: The most common preparation of tocotrienols is the tocotrienol-rich fraction (TRF). This study aimed to investigate whether TRF induced liver Nrf2 nuclear translocation and influenced the expression of Nrf2-regulated genes.

Methods: In the Nrf2 induction study, mice were divided into control, 2000 mg/kg TRF and diethyl maleate treated groups. After acute treatment, mice were sacrificed at specific time points. Liver nuclear extracts were prepared and Nrf2 nuclear translocation was detected through Western blotting. To determine the effect of increasing doses of TRF on the extent of liver nuclear Nrf2 translocation and its implication on the expression levels of several Nrf2-regulated genes, mice were divided into 5 groups (control, 200, 500 and 1000 mg/kg TRF, and butylated hydroxyanisole-treated groups). After 14 days, mice were sacrificed and liver RNA extracted for qPCR assay.

Results: 2000 mg/kg TRF administration initiated Nrf2 nuclear translocation within 30 min, reached maximum level around 1 h and dropped to half-maximal levels by 24 h. Incremental doses of TRF resulted in dose-dependent increases in liver Nrf2 nuclear levels, along with concomitant dose-dependent increases in the expressions of Nrf2-regulated genes.

Conclusion: TRF activated the liver Nrf2 pathway resulting in increased expression of Nrf2-regulated cytoprotective genes.

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4-HNE Immunohistochemistry and Image Analysis for Detection of Lipid Peroxidation in Human Liver Samples Using Vitamin E Treatment in NAFLD as a Proof of Concept

Maren C Podszun, Joon-Yong Chung, Kris Ylaya, David E Kleiner, Stephen M Hewitt, Yaron Rotman

J Histochem Cytochem . 2020 Sep;68(9):635-643. doi: 10.1369/0022155420946402.

Abstract

Lipid peroxidation is a common feature of liver diseases, especially non-alcoholic fatty liver disease (NAFLD). There are limited validated tools to study intra-hepatic lipid peroxidation, especially for small specimen. We developed a semi-quantitative, fully automated immunohistochemistry assay for the detection of 4-hydroxynoneal (4-HNE) protein adducts, a marker of lipid peroxidation, for adaptation to clinical diagnostics and research. We used Hep G2 cells treated with 4-HNE to validate specificity, sensitivity, and dynamic range of the antibody. Staining and semi-quantitative automated readout were confirmed in human needle-biopsy liver samples from subjects with NAFLD and normal liver histology. The ability to detect changes in lipid peroxidation was tested in paired liver biopsies from NAFLD subjects, obtained before and after 4 weeks of treatment with the antioxidant vitamin E (ClinicalTrials.gov NCT01792115n=21). The cellular calibrator was linear and NAFLD patients had significantly higher levels of 4-HNE adducts compared to controls (p=0.02). Vitamin E treatment significantly decreased 4-HNE (p=0.0002). Our findings demonstrate that 4-HNE quantification by immunohistochemistry and automated image analysis is feasible and able to detect changes in hepatic lipid peroxidation in clinical trials. This method can be applied to archival and fresh samples and should be considered for use in assessing NAFLD histology.

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