The fat-soluble vitamins are arguably the most important micronutrients and have the broadest range of physiological implications. The term “fat-soluble” implies that these vitamins are found in fatty sources of food and require fat and bile acids in order to be absorbed in the small intestine. Deficiencies in these vitamins are linked to many deleterious symptoms and conditions that are preventable, if not reversible, with adequate nutrition. They are referred to as vitamins A, D, E, and K, and despite having interrelationships with each other, as they work synergistically, they each have distinct functions and benefits. Let’s review why these compounds are critical for good health. 

Vitamin A (retinoids)

Retinoids form the group of compounds referred to as vitamin A, however, retinol and retinyl esters are the most abundant forms of retinoid in the human body. All-trans-retinol, by definition, is vitamin A and retinyl esters, such as palmitic acid, oleic acid, stearic acid, and linoleic acid, act as storage forms of retinol. However, retinol needs to be enzymatically activated to retinoic acid, the bioactive form of vitamin A. Additionally, -carotene, the plant-based source of retinol, can be converted into retinoic acid but the conversion rate is relatively poor as humans don’t adequately produce the prerequisite enzyme (O’Byrne & Blaner, 2013).   

Vitamin A has several distinct implications on physiological processes, pertaining to immune function, the visual system, and early genetic activity such as;

• Pleiotropic (genetic influencing) roles in bone formation, reproduction, and organogenesis during embryonic development
  • Placental development and neural formation (Clagett-Dame & DeLuca, 2002)
• Formation of epithelial linings of the skin and mucosal tissue, forming part of the mucosal immunity
• Inducing lymphocyte (T and B cells) trafficking to intestinal mucosa and provide a substrate for gut-associated dendritic cells to metabolize vitamin A into retinoic acid
  • Promotes differentiation of regulatory T cells and Th2 cells and induction of immunoglobulin-A-antibody-secreting cells, which may have implications in mitigating and preventing autoimmune responses in the gut (Cassani et al, 2011) 
• Precursor to the photosensitive visual pigments (rhodopsin) that participate in the initiation of neural impulses from the photoreceptors, making it essential for visual function
  • Precursor to conjunctival epithelial cell RNA and glycoprotein synthesis, aiding conjunctival mucosa and corneal stroma (thickest layer of the cornea) maintenance (Smith & Steinemann, 2000)

Vitamin D (cholecalciferol)

I could dedicate an entire article on vitamin D as its functions affect every part of the body, but this will cover the essentials. Vitamin D is a unique compound in the sense that it is non-essential, meaning that it does not have to be obtained from the diet, as it can be formed via the breakdown of 7-dehydrocholesterol from the skin upon contact with ultraviolet radiation from the sun and subsequently converted into its bioactive form, 1,25-dihydroxyvitamin D3 in the liver and kidneys.  Secondly, referencing vitamin D as a vitamin is a misnomer because its primary mode of action in the body, binding to nuclear receptors that regulate transcription of genes in vitamin D target cells (over 1000 genes), makes it a prohormone (Jovičić et al, 2012).  

Given that a variety of cell types in the human body have receptors, it is evident that vitamin D is essential for life in higher animals. There are several well-researched physiological roles of vitamin D;

• Calcium regulation and bone health 
  • When calcium levels drop, parathyroid hormone is produced to stimulate vitamin D production in the kidney, which then binds to vitamin d receptors in intestinal cells to up-regulate absorption of calcium.
  • Calcium is essential for the homeostatic processes in bones, re-mineralization, and vitamin D stimulates osteoblast function, aiding the conversion of preosteoclasts to osteoclasts (Laird et al, 2010)
• Innate and adaptive immune responses
  • Almost all immune cells carry vitamin D receptors and their expression is modulated by the presence of an infection. 
    • Vitamin D acts on monocytes and macrophages to increase the production of chemokines, which stimulate the recruitment of innate and adaptive immune cells to the site of infection, whilst also increasing the production of antimicrobial proteins (cathelicidin)
    • Antimicrobial proteins can disrupt microbial membranes and viral envelopes, arresting development and promoting apoptosis of viral and bacterial pathogens
    • Vitamin D also promotes the phagocytic (cell killing) activity of macrophages and dendritic cells, whilst reducing the production of pro-inflammatory cytokines, such as tumour necrosis factor-, INF-, interleukin-6 and interleukin-1 (Albergamo et al, 2022)
• Insulin secretion and metabolic health  
  • Vitamin D can act directly on genes in adipose tissue to interfere with adipocyte differentiation, thus inhibiting adipogenesis
  • Activating vitamin D receptors in brown adipose tissue results in thermogenesis through -oxidation, which leads to apoptosis of adipose tissue
  • Vitamin D deficiency is correlated with decreased insulin function but oppositely, vitamin D may improve pancreatic -cell function and insulin sensitivity (how receptive cells are to insulin) (Park et al, 2018)
• Heart function and blood pressure
  • Vitamin D binds to vitamin D receptors in cardiomyocytes (heart muscle cells) and suppresses the renin-angiotensin-system (RAS), involved in regulating electrolyte homeostasis and intravascular volume, resulting lowered blood pressure
  • As vitamin D is critical for calcium regulation, deficiency in calcium can lead to electrolyte abnormalities that interfere with blood pressure and heart rhythm (Brandenburg et al, 2012)
• Reproduction 
  • Vitamin D increases intracellular concentrations of calcium, which improves sperm-egg binding and increases acrosine (the enzyme that digests the outer wall of the ovum to allow sperm penetration and fertilization) activity 
  • Ovarian physiology and follicular recruitment are influenced by vitamin D and the endometrium may be less receptive for embryo implantation if a woman is vitamin D deficient, as vitamin D regulates growth factors and cytokine expression that influence endometrial receptivity (Heyden & Wimalawansa, 2018)
  • Placental vitamin D receptor expression is an important regulator of placental and foetal growth, as vitamin d regulates genes involved in early placental development
    • Increases the availability of vascular endothelial growth factor, which promotes adequate blood supply to the foetus and placenta (Luk et al, 2012) 

Vitamin E (tocopherol)

If you can put vitamin C aside, then you will realize that vitamin E is pound-for-pound the chief antioxidant in our food. Vitamin E is comprised of eight compounds divided between four tocopherols and four tocotrienols that are synthesized in several fat-rich plant sources, such as nuts and nut oils, wheat germ, avocados, olives and soya beans. The tocochromanols (vitamin E compounds) are the most effective group of lipophilic phenolic antioxidants because they mitigate lipid oxidation of cellular membranes and protect DNA from damage by neutralizing free radicals. Antioxidants essentially break the chain reaction of lipid peroxidation and simultaneously protect cell membranes by lipid repair and replacement (Colombo, 2010) & (Galli et al, 2017). 

Given vitamin E’s strong antioxidant properties, there is well-established research indicating that vitamin E plays novel roles in preventing and treating disease, as well as protective roles, such as;

• Cardiovascular disease
  • Vitamin E protects fats from oxidizing by donating hydrogen to lipid peroxide radicals and neutralizing them.
    • -tocopherol increases the resistance of LDL (low-density lipoprotein) to oxidation and decreases cytotoxicity of oxidized LDL toward endothelial cells, which plays a pivotal role in the atherogenetic process 
    • Factors that influence coronary artery disease, such as reduced plaque rupture, platelet adhesion, and vasospasm are added benefits from protection of LDL against oxidation
  • Antioxidative effects of vitamin E decrease inflammation, through the increase of endothelial nitric oxide (NO), which supresses the expression of inflammatory molecule genes (Kirmizis & Chatzidimitriou, 2009)
• Neuroprotection
  • Vitamin E is known to cross the blood-brain barrier and affect different areas of the brain, such as protection of Purkinje neurons (component of the cerebellar cortex with a critical role in motor output)
    • Tocotrienols have been implicated in neuronal protection after ischemic stroke, as the brain is a fat-dense organ and polyunsaturated fatty acids are structural components of neurons, therefore vitamin E protects neurons against oxidation and influences other mechanisms behind neuronal death, including autophagy, apoptosis and necrosis
• Immunomodulation
  • Supplementation with vitamin E has shown to enhance cell-mediated and humoral (macromolecule-mediated, such as antibodies) immune responses 
    • Increased lymphocyte penetration, immunoglobulin production, antibody responses, natural killer (NK) cell activity, and interleukin-2 production (Lee & Han, 2018)
    • Tocopherol supplementation during allergen sensitization and challenge regulates the development of allergic disease early in life, implying that vitamin E supplantation during pregnancy may decrease the chances of a newborn from developing allergic disease (Galli et al, 2017) 
• Cancer
  • Tocotrienols possess antiproliferative and apoptotic activities on cancer cells via mitochondria-mediated pathway and to cell cycle arrest due to suppression of cyclin D (a protein involved in regulating cell cycle progression) (Colombo, 2010)
• Non-alcoholic fatty liver disease 
  • Vitamin E improves metabolic and inflammatory abnormalities associated with non-alcoholic fatty liver disease, such as insulin resistance, lipid accumulation, and liver cell toxicity
    • Significant decreases in serum aminotransferase (liver enzyme) levels, hepatic steatosis (fat accumulation), and lobular inflammation 
  • The hepato-protective effects of vitamin E can be attributed to the preservation of the seleno-enzyme (contains selenium), glutathione peroxidase, that coverts glutathione (a major antioxidant), by neutralizing radical-dependent peroxidatic reactions (Galli et al, 2017)

Vitamin K (quinones) 

Vitamin K exists in two forms, phylloquinone, referred to as K1 and menaquinone, which are referred to as K2 and includes MK-4 and MK-7. Phylloquinone is the plant-based form of vitamin K, primarily found in leafy-green vegetables and needs to be converted into MK-4 by liver enzymes for it to become bioactive, whereas K2 can be synthesized by intestinal flora and is found in animal sources, including fermented cheese, meat, egg yolk, milk, and natto, a fermented soy product. The primary function of vitamin K is acting as an enzyme cofactor for gamma-glutamyl carboxylase (GGCX) that activates a series of vitamin K-dependent proteins (VKPD).

Vitamin-K-dependent proteins have various roles in physiological processes, which include;

• Blood coagulation and cardiovascular health 
  • Proteins involved in the coagulation cascade, including coagulation factors II, VII, IX, X, and anticoagulation proteins C, S, and Z are all vitamin K dependent (Fusaro et al, 2022).
  • Carboxylated matrix Gla protein (a VKDP) has a strong inhibitory effect on vascular calcification, indicating that vitamin K may aid in the prevention of cardiovascular disease (Halder et al, 2019)
• Bone homeostasis 
  • Osteocalcin is a vitamin-k-dependent protein that is produced by osteoblasts during bone formation and represents the primary noncolageneous protein in bone and also functions as a regulator of bone mineral maturation  
  • (Gla)-rich protein, another VKDP, is highly expressed in bone and cartilage and regulates extracellular calcium
    • Periostin is a matricellular protein that is expressed in collagen-rich connective tissues, including bone (Booth, 2009) 
• Other physiological roles 
  • Increases beta cell proliferation and insulin production and reduces the risk of diabetes type 1
  • Neuroprotective effects partially due to vitamin K2 enzymes being expressed in the brain
  • Improves renal artery function and decreases vascular calcification in chronic kidney disease

References

Albergamo, A., Apprato, G. & Silvagno, F. (2022). The role of vitamin D in supporting health in the COVID-19 era. International Journal of Molecular Sciences, 23(7), 3621. https://doi.org/10.3390/ijms23073621

Brandenburg, V.M., Vervloet, M.G. & Marx, N. (2012). The role of vitamin D in cardiovascular disease: from present evidence to future perspectives. Atherosclerosis, 225(2), 253-263. https://doi.org/10.1016/j.atherosclerosis.2012.08.005

Booth, S.L. (2009). Roles for vitamin K beyond coagulation. Annual review of nutrition, 29, 89-110. https://doi.org/10.1146/annurev-nutr-080508-141217

Cassani, B., Villablanca, E.J., De Calisto, J., Wang, S., et al. (2011). Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Molecular aspects of medicine, 33(1), 63-76. https://doi.org/10.1016%2Fj.mam.2011.11.001

Clagett-Dame, M. & DeLuca, H.F. (2002). The role of vitamin A in mammalian reproduction and embryonic development. Annual review of nutrition, 22, 347-381. https://doi.org/10.1146/annurev.nutr.22.010402.102745E

Colombo, M.L. (2010). An update on vitamin E, tocopherol and tocotrienol-perspectives. Molecules, 15(4), 2103-2113. https://doi.org/10.3390/molecules15042103

Fusaro, M., Tondolo, F., Gasperoni, L., Tripepi, G., et al. (2022). The role of vitamin K in CKD-MBD. Current osteoporosis reports, 20(1), 65-77. https://doi.org/10.1007%2Fs11914-022-00716-z

Galli, F., Azzi, A., Birringer, M., Cook-Mills, J.M., et al. (2017). Vitamin E: emerging aspects and new directions. Free radical biology and medicine, 102, 16-36, https://doi.org/10.1016/j.freeradbiomed.2016.09.017.

Halder, M., Petsophonsakul, P., Akbulut, A.C., Pavlic, A., et al. (2019). Vitamin K: double bonds beyond coagulation insights into differences between vitamin K1 and K2 in health and disease. International journal of molecular sciences, 20(4), 896. https://doi.org/10.3390/ijms20040896

Heyden, E.L. & Wimalawansa, S.J. (2018). Vitamin D: effects on human reproduction, pregnancy, and fetal well-being. Journal of steroid biochemistry and molecular biology, 180, 41-50. https://doi.org/10.1016/j.jsbmb.2017.12.011

Jovičić, S., Ignjatović, S. & Majkić-Singh, N. (2012). Biochemistry and metabolism of vitamin D. Journal of medical biochemistry, 31(4), 309-315. https://farfar.pharmacy.bg.ac.rs/bitstream/handle/123456789/1667/1665.pdf?sequence=1&isAllowed=y

Kirmizis, D. & Chatzidimitriou, D. (2009). Antiatherogenic effects of vitamin E: the search for the Holy Grail. Vascular health and risk management, 5, 767-774. https://www.tandfonline.com/doi/full/10.2147/vhrm.s5532?scroll=top&needAccess=true&role=tab

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Lee, G.Y. & Han, S.N. (2018). The role of vitamin E in immunity. Nutrients, 10(11), 1614. https://doi.org/10.3390/nu10111614

Luk, J., Torrealday, S., Perry, G.N. & Pal, L. (2012). Relevance of vitamin D in reproduction. Human Reproduction, 27(10), 3015–3027. https://doi.org/10.1093/humrep/des248

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Park, J.E., Pichiah, P.B.T. & Cha, Y.S. (2018). Vitamin D and metabolic diseases: growing roles of vitamin D. Journal of obesity and metabolic syndrome, 27(4), 223-232. https://doi.org/10.7570%2Fjomes.2018.27.4.223

Smith, J. & Steinemann, T.L. (2000). Vitamin A deficiency and the eye. International ophthalmology clinics, 40(4), 83-91. https://www.researchgate.net/profile/Thomas-Steinemann/publication/12261939_Vitamin_A_Deficiency_and_the_Eye/links/63b2405f03aad5368e5a4923/Vitamin-A-Deficiency-and-the-Eye.pdf