Dietary Vitamin E intake is associated with a reduced risk of developing digestive diseases and NAFLD

Eleonora Scorletti, Kate Townsend Creasy, Marijana Vujkovic, Mara Vell, Inuk Zandvakili, Daniel J Rader, Kai Markus Schneider, Carolin V Schneider

Am J Gastroenterol . 2022 Mar 14. doi: 10.14309/ajg.0000000000001726. Online ahead of print.


Introduction: Vitamin E supplementation is recommended for the treatment of non-alcoholic fatty liver disease (NAFLD) for nondiabetic patients, but its preventative effects are unclear.

Methods: We assessed dietary Vitamin E intake with disease phenotypes and evaluated Vitamin E levels with the development of NAFLD.

Results: Data from >210,000 participants demonstrate that increased dietary Vitamin E associates with reduced rates of several gastrointestinal diseases and reduced overall mortality. Diabetic and overweight subjects with increased Vitamin E intake have fewer NAFLD diagnoses.

Conclusion: Our findings reveal the relevance of Vitamin E consumption for several gastrointestinal diseases and warrant further mechanistic and therapeutic investigations.

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Effect of tocotrienol on the primary progression of nonalcoholic steatohepatitis in a mouse model

Jun Noichi, Tomoko Ishiakawa, Ikuyo Ichi, Yoko Fujiwara

J Clin Biochem Nutr . 2022 Mar;70(2):140-146. doi: 10.3164/jcbn.21-69. Epub 2021 Oct 2.


Tocotrienol (T3), a vitamin E (Vit E) isoform, is known to have both biological and antioxidant effects. Although alpha-tocopherol (α-Toc), another isoform of Vit E is suggested to be a useful treatment against nonalcoholic steatohepatitis (NASH), the effect of T3 on NASH is unclear. This study aimed to comparatively evaluate the effects of T3 and α-Toc on NASH in the early stage of NASH progression, using a recently established NASH mouse model induced by a choline-deficient l-amino acid-defined high-fat diet (CDAHFD). Six-week-old male mice were divided into four groups (n = 6 per group) and fed the CDAHFD for 1 week. The first group was given no other treatment (Pre). The other three groups continued the CDAHFD plus daily oral administration of Vit E-free corn oil (Control), corn oil containing α-Toc, or corn oil containing T3 for additional 2 weeks. Neither Vit E treatment changed the histologic features of NASH, but T3 significantly reduced the mRNA expression of several genes related to inflammation and fibrosis and α-Toc did not. These results suggested that oral T3 treatment was more effective than α-Toc at suppressing hepatic inflammation and fibrosis in the early stage of NASH progression in CDAHFD model mice.

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Hepatic retinaldehyde dehydrogenases are modulated by tocopherol supplementation in mice with hepatic steatosis

Amanda D'Espessailles, Valeria Campos, Nevenka Juretić, Gladys S Tapia, Paulina Pettinelli

Nutrition . 2022 Feb;94:111539. doi: 10.1016/j.nut.2021.111539. Epub 2021 Nov 17.


Objectives: An altered retinol metabolism might play a role in the development of nonalcoholic fatty liver disease (NAFLD). Tocopherols (TF) modulate metabolic pathways and have been proposed as a complementary treatment of obesity-induced metabolic alterations. Moreover, there is evidence suggesting that TF may modulate retinol metabolism. The aim of this study was to evaluate whether the dietary supplementation of α- and γ-TF modulates the expression of hepatic retinaldehyde dehydrogenases, RALDH1, RALDH2, and RALDH3 (involved in retinol metabolism) and, lipogenic factors sterol regulatory element binding protein-1c (SREBP-1c) and cluster differentiation 36 (CD36) in an animal model of diet-induced NAFLD.

Methods: Male C57BL/6J mice were divided into four groups: a control diet (CD) group (10% fat, 20% protein, 70% carbohydrates); a CD + TF group (α-tocopherol: 0.7 mg·kg·d-1, γ-tocopherol: 3.5 mg·kg·d-1); a high-fat diet (HFD) group (60% fat, 20% protein, 20% carbohydrates); and a HFD + TF group (0.01 mL·g body weight·d-1), for 12 wk. General parameters (body-adipose tissue weight, glucose-triacylglyceride serum levels), liver steatosis (histology, liver triacylglycerides content), and hepatic RALDH1, RALDH2, RALDH3, SREBP-1c and CD36 (qPCR, quantitative polymerase chain reaction; IHQ, immunohistochemistry) were measured.

Results: TF supplementation in HFD-fed mice decreased the presence of lipid vesicles (90%) and total lipid content (75%) and downregulated the expression of RALDH1, RALDH3, SREBP-1c, and CD36.

Conclusions: The present study demonstrated that α- and γ-TF (1:5 ratio) might play a role in modulating retinol metabolism in the prevention of NAFLD induced by a HFD.

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Palm tocotrienol rich fraction with palm kernel oil supplementation prevents development of liver steatosis in high fat diet ICR mice

Mohd Danial Mohd Efendy Goon, Nur Izzati Zulkanain, Siti Hamimah Sheikh Abdul Kadir, Sharaniza Ab Rahim, Musalmah Mazlan, Normala Abd Latip, Mardiana Abdul Aziz, Norizal Mohd Noor

Transl Gastroenterol Hepatol . 2022 Jan 25;7:2. doi: 10.21037/tgh.2020.02.20. eCollection 2022.


Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) in Asian countries is increasing at concerning level. Currently, no specific treatment available to prevent its oxidative stress and progression except for diet and lifestyle changes. Vitamin E such as tocotrienol-rich fraction (TRF) has a promising potential in preventing NAFLD progression. TRF is a potent antioxidant but has low bioavailability due to the use of long-chain triglycerides (LCT) as its carrier. Testing of potential therapeutic agents such as TRF are commonly carried out using animal models. These animal models are often costly due to limited access to the supply especially Asian countries and predisposed to high transportation cost. Lower expenditure of NAFLD model should be investigated without forfeiting the outcome of study. Therefore, this study addresses the gap by utilizing the ICR mice as NAFLD model through dietary modification and testing on the newly formulated TRF with combination of palm kernel oil (PKO) as a medium-chain triglycerides (MCT) carrier.

Methods: Fifteen ICR strain mice were randomly group into two control and one treatment group. Control groups received high-fat diet (HFD) only and standard diet while treatment group was given HFD with TRF (200 mg/kg/day). Study was carried out for 10 weeks. Weights were recorded twice a week. At the end of study, all mice were euthanized and data such weights, waist circumference and random blood glucose were recorded. Liver from each mouse were prepared for histology assessment.

Results: Mice mean weights and random blood sugar showed no difference between group (P>0.05) while significance waist circumference was larger in HFD and TRF groups compared to SD (P<0.05). Histology assessment showed steatosis in TRF group had lower severity compared to HFD group. NAFLD activity score (NAS) was lower in treatment group compared to HFD group.

Conclusions: TRF showed promising potential as an agent to reduce NAFLD progression in ICR mice. Further study at gene and protein levels are required to fully elucidate the mechanism of this new TRF formulation in reducing NAFLD progression.

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Role of vitamin E in the treatment of non-alcoholic steatohepatitis

Yoshio Sumida, Masato Yoneda, Yuya Seko, Hirokazu Takahashi, Nagisa Hara, Hideki Fujii, Yoshito Itoh, Masashi Yoneda, Atsushi Nakajima, Takeshi Okanoue , Japan Study Group of NAFLD (JSG-NAFLD)

Free Radic Biol Med . 2021 Oct 26;S0891-5849(21)00767-X. doi: 10.1016/j.freeradbiomed.2021.10.017. Online ahead of print.


Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD), can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure/liver transplantation. Indeed, NASH will soon be the leading cause of HCC and liver transplantation. Lifestyle intervention represents the cornerstone of NASH treatment, but it is difficult to sustain. However, no pharmacotherapies for NASH have been approved. Oxidative stress has been implicated as one of the key factors in the pathogenesis of NASH. Systematic reviews with meta-analyses have confirmed that vitamin E reduces transaminase activities and may resolve NASH histopathology without improving hepatic fibrosis. However, vitamin E is not recommended for the treatment of NASH in diabetes, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. Nevertheless, vitamin E supplementation may improve clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Further studies are warranted to confirm such effects of vitamin E and that it would reduce overall mortality/morbidity without increasing the incidence of cardiovascular events. Future clinical trials of the use of vitamin E in combination with other anti-fibrotic agents may demonstrate an additive or synergistic therapeutic effect. Vitamin E is the first-line pharmacotherapy for NASH, according to the consensus of global academic societies.

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Untargeted serum metabolites profiling in high-fat diet mice supplemented with enhanced palm tocotrienol-rich fraction using UHPLC-MS

Danial Efendy Goon, Sharaniza Ab-Rahim, Amir Hakimi Mohd Sakri, Musalmah Mazlan, Jen Kit Tan, Mardiana Abdul Aziz, Norizal Mohd Noor, Effendi Ibrahim, Siti Hamimah Sheikh Abdul Kadir

Sci Rep . 2021 Oct 25;11(1):21001. doi: 10.1038/s41598-021-00454-9.


Excessive high fat dietary intake promotes risk of developing non-alcoholic fatty liver disease (NAFLD) and predisposed with oxidative stress. Palm based tocotrienol-rich fraction (TRF) has been reported able to ameliorate oxidative stress but exhibited poor bioavailability. Thus, we investigated whether an enhanced formulation of TRF in combination with palm kernel oil (medium-chain triglycerides) (ETRF) could ameliorate the effect of high-fat diet (HFD) on leptin-deficient male mice. All the animals were divided into HFD only (HFD group), HFD supplemented with ETRF (ETRF group) and HFD supplemented with TRF (TRF group) and HFD supplemented with PKO (PKO group). After 6 weeks, sera were collected for untargeted metabolite profiling using UHPLC-Orbitrap MS. Univariate analysis unveiled alternation in metabolites for bile acids, amino acids, fatty acids, sphingolipids, and alkaloids. Bile acids, lysine, arachidonic acid, and sphingolipids were downregulated while xanthine and hypoxanthine were upregulated in TRF and ETRF group. The regulation of these metabolites suggests that ETRF may promote better fatty acid oxidation, reduce oxidative stress and pro-inflammatory metabolites and acts as anti-inflammatory in fatty liver compared to TRF. Metabolites regulated by ETRF also provide insight of its role in fatty liver. However, further investigation is warranted to identify the mechanisms involved.

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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.


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.


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.


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.


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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