α-Tocopherol transfer protein (α-TTP)

Hiroyuki Arai, Nozomu Kono

Free Radic Biol Med . 2021 Sep 24;176:162-175. doi: 10.1016/j.freeradbiomed.2021.09.021. Online ahead of print.

Abstract

α-Tocopherol transfer protein (α-TTP) is so far the only known protein that specifically recognizes α-tocopherol (α-Toc), the most abundant and most biologically active form of vitamin E, in higher animals. α-TTP is highly expressed in the liver where α-TTP selects α-Toc among vitamin E forms taken up via plasma lipoproteins and promotes its secretion to circulating lipoproteins. Thus, α-TTP is a major determinant of plasma α-Toc concentrations. Familial vitamin E deficiency, also called Ataxia with vitamin E deficiency, is caused by mutations in the α-TTP gene. More than 20 different mutations have been found in the α-TTP gene worldwide, among which some missense mutations provided valuable clues to elucidate the molecular mechanisms underlying intracellular α-Toc transport. In hepatocytes, α-TTP catalyzes the vectorial transport of α-Toc from the endocytotic compartment to the plasma membrane (PM) by targeting phosphatidylinositol phosphates (PIPs) such as PI(4,5)P2. By binding PIPs at the PM, α-TTP opens the lid covering the hydrophobic pocket, thus facilitating the release of bound α-Toc to the PM.

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From fat to bilayers: Understanding where and how vitamin E works

Jeffrey Atkinson, Drew Marquardt, Mitchell DiPasquale, Thad Harroun

Free Radic Biol Med . 2021 Sep 20;176:73-79. doi: 10.1016/j.freeradbiomed.2021.09.015. Online ahead of print.

Abstract

Vitamin E was one of the last fat-soluble vitamins to be discovered. We provide here an historical review of the discovery and the increasingly more detailed understanding of the role of α-tocopherol both as an antioxidant and as a structural component of phospholipid bilayer membranes. Despite the detailed descriptions now available of the orientation, location, and dynamics of α-tocopherol in lipid bilayers, there are still gaps in our knowledge of the effect of α-tocopherol and its potential receptors than control gene transcription.

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Tocopherols and Tocotrienols-Bioactive Dietary Compounds; What Is Certain, What Is Doubt?

Kacper Szewczyk, Aleksandra Chojnacka, Magdalena Górnicka

Int J Mol Sci . 2021 Jun 9;22(12):6222. doi: 10.3390/ijms22126222.

Abstract

Tocopherols and tocotrienols are natural compounds of plant origin, available in the nature. They are supplied in various amounts in a diet, mainly from vegetable oils, some oilseeds, and nuts. The main forms in the diet are α- and γ-tocopherol, due to the highest content in food products. Nevertheless, α-tocopherol is the main form of vitamin E with the highest tissue concentration. The α- forms of both tocopherols and tocotrienols are considered as the most metabolically active. Currently, research results indicate also a greater antioxidant potential of tocotrienols than tocopherols. Moreover, the biological role of vitamin E metabolites have received increasing interest. The aim of this review is to update the knowledge of tocopherol and tocotrienol bioactivity, with a particular focus on their bioavailability, distribution, and metabolism determinants in humans. Almost one hundred years after the start of research on α-tocopherol, its biological properties are still under investigation. For several decades, researchers’ interest in the biological importance of other forms of vitamin E has also been growing. Some of the functions, for instance the antioxidant functions of α- and γ-tocopherols, have been confirmed in humans, while others, such as the relationship with metabolic disorders, are still under investigation. Some studies, which analyzed the biological role and mechanisms of tocopherols and tocotrienols over the past few years described new and even unexpected cellular and molecular properties that will be the subject of future research.

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Pharmacology and Pharmacokinetics of Vitamin E: Nanoformulations to Enhance Bioavailability

Anis Syauqina Mohd Zaffarin, Shiow-Fern Ng, Min Hwei Ng, Haniza Hassan, Ekram Alias

Int J Nanomedicine . 2020 Dec 8;15:9961-9974. doi: 10.2147/IJN.S276355. eCollection 2020.

Abstract

Vitamin E belongs to the family of lipid-soluble vitamins and can be divided into two groups, tocopherols and tocotrienols, with four isomers (alpha, beta, gamma and delta). Although vitamin E is widely known as a potent antioxidant, studies have also revealed that vitamin E possesses anti-inflammatory properties. These crucial properties of vitamin E are beneficial in various aspects of health, especially in neuroprotection and cardiovascular, skin and bone health. However, the poor bioavailability of vitamin E, especially tocotrienols, remains a great limitation for clinical applications. Recently, nanoformulations that include nanovesicles, solid-lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and polymeric nanoparticles have shown promising outcomes in improving the efficacy and bioavailability of vitamin E. This review focuses on the pharmacological properties and pharmacokinetics of vitamin E and current advances in vitamin E nanoformulations for future clinical applications. The limitations and future recommendations are also discussed in this review.

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Pharmacokinetics and Pharmacodynamics of Ursodeoxycholic Acid in an Overweight Population With Abnormal Liver Function

Yoon S, Lee H, Ji SC, Yoon SH, Cho JY, Chung JY

Clin Pharmacol Drug Dev. 2020 Mar 19. doi: 10.1002/cpdd.790. [Epub ahead of print]

Abstract

Ursodeoxycholic acid (UDCA) is a secondary bile acid that is used to treat primary biliary cholangitis. Although UDCA has a hepatoprotective effect in some diseases, its benefit in nonalcoholic fatty liver disease (NAFLD) remains controversial. We aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of UDCA in overweight subjects with elevated liver enzymes after multiple administrations of UDCA and compare these changes with vitamin E treatment. Overweight subjects (body mass index, 25-30 kg/m2 ) with elevated alanine aminotransferase (ALT) level (40-200 IU/L) were enrolled. Subjects received one of the following three 8-week treatments: UDCA 300 mg twice daily UDCA 300 mg twice daily for 4 weeks followed by UDCA 300 mg twice daily and metformin 500 mg twice daily for 4 weeks, and vitamin E 400 IU twice daily. PK and PD (liver function, lipid profiles, insulin sensitivity, and miR-122) analyses were performed. Thirty subjects were enrolled; 1 subject withdrew his consent during the study. The PK characteristics were similar to those of healthy volunteers. The ALT and miR-122 levels decreased in the UDCA groups, whereas the ALT and aspartate aminotransferase levels decreased in the vitamin E group. The lipid profiles and insulin sensitivity did not show significant changes among the groups. There was no serious adverse event, and the safety profiles were similar among the treatment groups. The liver enzyme and miR-122 levels were decreased by UDCA. Considering UDCA and vitamin E have a hepatoprotective effect and different mechanisms of action, combination therapy could be an option for NAFLD.

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