1. Vitamin D Fat-soluble vitamin Sources Foods Supplements Sunlight
Naturally found in very few foods
Added to many foods on the market
Supplements
Sunlight
Vitamin D is a fat-soluble vitamin. This means that it can only be absorbed with fat. Vitamin D is not found in many foods. In fact, it is can be difficult to obtain required amounts of vitamin D from foods. Foods that naturally contain significant amounts of vitamin D are fatty fish and eggs. To increase intake of vitamin D, foods have been fortified. Milk is the most commonly consumed products that are fortified with vitamin D. Juices, breakfast cereals, breads, and yogurt are also fortified with vitamin D.
Dietary supplements are also consumed by many individuals to meet the daily requirements of vitamin D, there are many forms of supplements and I will discuss these later. Cholecalciferol is a form of vitamin D made naturally by the body when the skin is exposed to sunlight. However, most people do not get enough sunlight to satisfy their daily recommended intake through sunlight, especially in the winter. 1

2. Vitamin D Daily Recommended Intake
Current minimum intake recommendations
Birth-50 years = 200 IU
51-70 years = 400 IU
71+ years = 600 IU
Currently being debated
Recommended daily intakes are given in International Units which is abbreviated IU. One IU is equal to 40 micrograms. The recommendations are 200 IU from birth to 50 years of age, 400 IUs from years age, and 600 IUs for 71+ years of age. These recommendations meet the minimum requirements, mostly based on bone health.
Currently there is debate within the medical community about the daily recommended intake for vitamin D. The debate is about whether or not the current amounts are adequate for all of the functions vitamin D plays in the body. Current research suggests consuming amounts closer to 1000 IU may be needed to obtain all the potential benefits of vitamin D. 2

3. Food Sources of Vitamin D
3 oz smoked salmon = 583 IU
3 oz light tuna, canned in oil = 229 IU
1 large, whole egg = 29 IU
Some examples of vitamin D content in foods are shown here. Fish, including salmon and tuna are excellent sources. Egg also contains vitamin D, the highest concentration is in the yolk. Other good food sources include
3 oz Beef Liver which contains 42 IU, and 3 oz Pork spareribs which contains 88 IU 3

4. Foods Fortified with Vitamin D
8 oz skim milk = 115 IU 8 oz orange juice = 100 IU 1 cup Cheerios = 40 IU ½ cup yogurt = 40 IU
Some foods that are fortified with vitamin D are shown here. An 8 ounce glass of milk will contain 115 IU, and 8 ounces of fortified orange juice 100 IU of vitamin D. Cheerios are a good source, as are other fortified breakfast cereals. Yogurt is another dairy product that also provides vitamin D. 4

5. Definitions 7-dehydrocholesterol: provitamin D3
Previtamin D3: cholecalciferol
Vitamin D3: produced in the skin from irradiated 7-DHC, isomerized previtamin D3
Vitamin D2: from plants, from irradiated ergosterol

6. Vitamin D synthesis

7. Vitamin D3 is hydroxylated in the liver:
25 OH vitamin D: inactive, measured in serum as the biomarker of vitamin D status from all sources
Second hydroxylation:
1,25 (OH)2 vitamin D in the kidney
*** These hydroxylation steps can also occur in keratinocytes, prostate cells and others

8. Vitamin D3 can be obtained in diet, or derived from cholesterol in a reaction that requires UV light.
UV light
spontaneous
liver enzyme
25-hydroxylase
calcitriol
Vitamin D3

9. Vitamin D is also important for immune system function.
Vitamin D binds to a “vitamin D binding protein” (VDP) for transport to target organs.
Vitamin D is not active itself (it’s a prohormone); it is modified to yield biologically active forms, such as calcitriol.
Calcitriol (derived from vitamin D) is a transcription factor, influencing expression of proteins involved in calcium absorption and transport.
Vitamin D is also important for immune system function.
Deficiency causes rickets, bone loss.
Calcitriol, from vitamin D.

10. Vitamin D production requires UV light (sunlight).
Sometime after humans migrated north out of Africa about 50,000 years ago, mutations appeared that reduced melanin (pigment) production in the skin, permitting vitamin D production with less sunlight.
Disadvantages of less melanin production are skin that is easily damaged by the sun, skin cancer risk, and loss of folic acid due to UV damage.
The melanin-reducing mutations helped early humans make vitamin D in northern europe in winter.

11. + cells throughout the body
Vitamin D 25(OH)D 1,25(OH)D 26
+ cells throughout the body
Vertebrate steroids
Steroid hormones
Sex steroids are a subset of sex hormones that produce sex differences or support reproduction. They include androgens, estrogens, and progestagens.
Corticosteroids include glucocorticoids and mineralocorticoids. Glucocorticoids regulate many aspects of metabolism and immune function, whereas mineralocorticoids help maintain blood volume and control renal excretion of electrolytes.
Anabolic steroids are a class of steroids that interact with androgen receptors to increase muscle and bone synthesis. There are natural and synthetic anabolic steroids. In popular language the word "steroids" usually refers to anabolic steroids.
Cholesterol which modulates the fluidity of cell membranes and is the principle constituent of the plaques implicated in atherosclerosis.
Characterized by a carbon skeleton with four fused rings, generally arranged in a fashion
UVB photons
7-dehydrocholesterol

12. Vitamin D Functions Many uses in the body
Promotes absorption of calcium from the small intestine
Maintain blood levels of calcium and phosphate for bone formation, mineralization, growth, and repair
Improves muscle strength and immune function
Reduces inflammation
Vitamin D plays important roles in many process throughout the body. Probably the most well understood function that Vitamin D has is in the absorption of calcium from the small intestine. When vitamin D is inadequate calcium from the diet is poorly absorbed. Another well characterized and important role of vitamin D is to maintain appropriate levels of calcium and phosphate in the blood to ensure proper bone formation, mineralization, growth, and repair. Vitamin D has other roles that have been less well characterized. It is thought to improve muscle strength and immune function and reduce inflammation. 12

13. Noncalcemic Functions of 1,25-dihydroxyvitamin D
Cytokines
Noncalcemic functions of 1,25(OH)2 D.
Vitamin D coming from the photoproduction of previtamin D or coming from the diet is converted in the liver to 25(OH)D by the vitamin 25-OHase. 25(OH)D is converted in the kidneys by 1-OHase. 1,25(OH)2D not only regulates calcium and phosphorus metabolism but can stimulate the pancreas to produce insulin and to downregulate the renal production of renin. 1,25(OH)2D also interacts with its nuclear receptor (VDR) in a wide variety of tissues and cells and helps maintain normal cell proliferation and differentiation. 25(OH)D can also be converted to 1,25(OH)2D in a wide variety of cells, including colon, prostate, and breast, for the autocrine production of 1,25(OH)2D. It is believed that the autocrine production of 1,25(OH)2D is important for regulating cell growth and maturation, which decreases risk of the cell becoming malignant. 25(OH)D also is metabolized in macrophages by the 1-OHase to produce 1,25(OH)2D. The expression of the VDR and 1-OHase is upregulated when TLR2/1 is stimulated by LPS. This results in an increase in the expression of the VDR and the 1-OHase. The increase production of 1,25(OH)2D increases the nuclear expression of cathelicidin (CD) in the macrophage, which is a cationic peptide that causes the destruction of infective agents including M. tuberculosis.
Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor–null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] synthesis also led to an increase in renin expression, whereas 1,25(OH)2D3 injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)2D3 markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)2D3 is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
Adaptive
Innate
Immune modulation

14. Vitamin D Deficiency At risk populations Breastfed infants
Older adults
People with limited sun exposure
Darker skin pigments
Certain religious groups
People at risk for vitamin D deficiency include breastfed infants, older adults, people with limited sun exposure, people with dark skin, and people with fat malabsorption. People age 50 and older are at increased risk of developing vitamin D deficiency because as they age the skin looses its ability to synthesize vitamin D as efficiently and the kidneys also convert less to its active form. People living in the northern latitudes, homebound individuals, and women who wear long robes and head coverings for religious reasons may also not obtain adequate levels of vitamin D from sunlight. People with darker skin have more pigment melanin which reduces the skin’s ability to produce vitamin D after sun exposure. 14

15. Vitamin D Related Diseases
Rickets
Osteomalacia
Osteoporosis
Prolonged inadequate intake of vitamin D will lead to impaired bone metabolism. In children, under mineralization of bone causes soft and deformed bones and can lead to the condition known as rickets. Rickets is rare in the US today, but was fairly common as recently as 100 years ago. When children developed rickets, their legs were too weak to hold their weight, resulting in bowed legs, which often persisted into adulthood. Osteomalacia is the adult form of rickets, and leads to impaired mobility and bone fractures. And osteoporosis, a condition that leads to weak and porous bones. 15

16. Vitamin D Deficiency Rickets, Osteomalacia Influenza, Tuberculosis
MS, RA, SLE, Type I diabetes
Hypertension, CAD, PVD, CHF
Syndrome X, Type 2 Diabetes
Chronic Fatigue, SAD, Depression
Cataracts, Infertility
Osteoporosis
Cancer
Other autoimmune diseases: Crohn’s disease, Hashimoto’s disease

17. System and Tissue Distribution of Nuclear Vitamin D Receptors (VDR)
System Tissue
Immune Thymus, bone marrow, macrophages, B cells, T cells
Gastrointestinal Esophagus, stomach, small intestine, colon, rectum
Cardiovascular Endothelial cells, smooth muscle cells, myocytes
Respiratory Lung alveolar cells
Hepatic Liver parenchyma cells
Renal Proximal and distal tubules, collecting duct
Endocrine Parathyroid, thyroid, pancreatic beta cells
Exocrine Parotid gland, sebaceous gland
CNS Brain neurons, astrocytes, microglia
Epidermis/appendage Skin, breast, hair follicles
Musculoskeletal Osteoblasts, osteocytes, chondrocytes, striated muscle
Connective Tissue Fibroblasts, stroma
Reproductive Testis, ovary, placenta, uterus, endometrium, yolk sac

18. Diverse Structure of Ligands for Nuclear Receptors

20. Nutrigenomics Vitamin D
Wood and colleagues analyzed vitamin D-induced gene expression in a human colon cancer cell line. They identified 12 genes that exhibited statistically significant increase in expression, two of which are known to have anti-proliferative effects.
Physiological Genomics 17: (2004) /04 $5.00 © 2004 American Physiological Society
DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line
Richard J. Wood1, Laurie Tchack1, Giana Angelo1, Richard E. Pratt2 and Larry A. Sonna3,4
Note fallout prep if have no KI
Confirmatory PCR for 1,25-dihydroxyvitamin D-regulated genes found by Affymetrix GeneChip transcriptional profiling
Wood RJ, Tchack L, Angelo G, etal. DNA Microarray Analysis of Vitamin D-induced Gene Expression in a Human Colon Carcinoma Cell Line. Physiological Genomics 2004;17:

21. Vitamin D and Cancer Roles in prevention of Colon cancer Breast cancer
There is recent evidence that adequate levels of vitamin D in the diet may play a role in the prevention of certain cancers. Thus far, the best studied role for vitamin D has been found in cancers of the colon and breast. In general, vitamin D plays a role in maintaining healthy cells, and when vitamin D levels are low these protective effects may be compromised. 21

22. Human Migration Out of Africa
Mutation in one rung in the 3 billion rungs on the DNA double-helix ladder – only a change in one base pair
35° S
Lamson Rl, etal. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 2005;310:

24. Early studies that correlated cancer incidence with sun exposure rates in populations began the search for a role for vitamin D in cancer.
This map illustrates the colon cancer mortality rates in men throughout the United States. Areas shown in red have the highest colon cancer mortalities, while those in blue have the lowest. It is fairly clear that states in the north and eastern parts of the US, those with the longest winters, have the higher colon cancer mortality rates.
Vitamin D may have a role in cancer prevention. The graph above came from an epidemiologic study and shows geographic correlation. An inverse relationship was found between sunlight exposure levels and the rates of incidence and death for certain cancers. Individuals living in northern latitudes were found to have higher rates of incidence and death for these cancers than those living at southern latitudes. The researchers hypothesize that this is because UVB rays from sunlight are necessary to synthesize vitamin D. 24

25. This map illustrates the mortality of white females due to breast cancer from As shown here, there is a correlation between the northern, northeastern, and some western states and increased rates of breast cancer. Again, areas shown in red have the highest breast cancer mortalities, while those in blue have the lowest. Most of the southern states are bright blue suggesting much lower incidence of breast cancer. The graph above came from the same epidemiologic study as shown on the previous slide, and again shows the geographic correlation. An inverse relationship was found between sunlight exposure levels and the rates of incidence and death for certain cancers. 25

26. Vitamin D and Cancer How it prevents Promotes cellular differentiation
Decreases cancer cell growth
Stimulates cell deaths
The exact role of vitamin D in cancer prevention is still unclear, however researchers know that vitamin D plays and integral role in cellular differentiation. Increased levels of vitamin D decrease the growth of cancer cells and stimulates cell death. 26

27. Vitamin D Cancer Research
Mostly observational studies, only show correlation
Food frequency questionnaires
Interviews
Diet records
Most Vitamin D cancer research that has been done is observational and more epidemiological studies are needed to support the findings that have been made. Observational studies include things like food frequency questionnaires, interviews, and recording dietary intakes which are all subject to a large amount of misinformation and error. Epidemiological studies are aimed, where possible, at revealing unbiased relationships between exposures such as biological agents, stress, or chemicals to mortality or morbidity. In this case epidemiological studies would be searching for the link between Vitamin D and cancer mortality and/or morbidity. The identification of causal relationships between these exposures and outcomes is an important aspect of epidemiology. Let’s take a look at some of the research that has been done. 27

28. Vitamin D & Colon Cancer Research
Third National Health and Nutrition Examination Survey
Epidemiologic study
16,818 participants
Examined blood levels of vitamin D
Results
Blood levels 80nmol/L or higher reduced risk by 72%
The Third National Health and Nutrition Examination Survey published in _______ by _________ is one of very few epidemiologic studies on vitamin D and colon cancer. The researchers looked at 16, 818 participants and examined blood levels of vitamin D. Individuals with blood levels of 80 nmol/L or higher of vitamin D reduced their risk of colon cancer by 72% compared to individuals with blood levels below 50 nmol/L. 28

29. Vitamin D Cancer Research
American Cancer Society’s Cancer Prevention Study II Nutrition Cohort
Studied 120,000 men and women
Analyzed diet, medical history, and lifestyle
Results
Men with intakes of 520 IU or higher from both diet and supplementation slightly lowered risk
No effect in women
The American Cancer Society’s Cancer Prevention Study II Nutrition Cohort published in _______ by ________ showed a slightly lower risk of colorectal cancer in men but the women in the study did not show this same effect. This group of researchers studied a group of 120,000 men and women and analyzed their diet, medical history, and lifestyle. The study found that men with intakes of 520 IU or higher of vitamin D through their combined diet and supplementation had a slightly lower risk of colon cancer. 29

30. Vitamin D & Breast Cancer Research
In the same study of the American Cancer Society on Cancer Prevention Study II Nutrition Cohort, researchers also singled out postmenopausal women who had no family history of breast cancer. These 68,567 women were then given a questionnaire on dietary intake, medical history, and supplement use. Researchers looked specifically at calcium, vitamin D, and dairy consumption in their diets. The study concluded that women who consumed higher amounts of calcium and vitamin D from dairy sources decreased their risk of breast cancer.
Vitamin D & Breast Cancer Research
Cancer Prevention Study II Nutrition Cohort
Participants
68,567 postmenopausal women
Completed questionnaire on dietary intake, family history, and supplement use
Results
Women who consumed higher amounts of vitamin D and calcium from dairy products reduced their risk of breast cancer 30

31. Multiple Sclerosis in World War II Veterans by Latitude and State of Residence
Multiple Sclerosis Prevalence of U.S. WW II Veterans at Time of Entry into the Armed Forces vs. Latitude
according to latitude and state of residence in the U.S. at entry into active duty (EAD):
Wallin MT, etal. Multiple sclerosis in US veterans… Ann Neurol 2004;55:65-71

32. Tuberculosis Treated with Sunshine
Tuberculosis patients lie in beds on the porch of a building at the Jewish consumptives
Relief Sanatorium, 1600 Pierce Street, Lakewood, CO.  This facility later became the American Medical Center and then the AMC Cancer Research Center.
Vitamin D acts as a potent immune modulator. It induces a Toll-Like Receptor (TLR) gene which in turn promotes production of human cathelicidin antimicrobial peptide (CAMP) by white blood cells. [ii] This CAMP stuff is part of the innate immune system and provides a rapid response used to repel assaults from numerous infectious organisms including bacteria, viruses, fungi, and parasites and tuberculosis. [iii] [iv] It is our first line of defense against infection.

33. Preop Vitamin D3 levels in 73 Veterans Undergoing Heart Surgery at the Seattle VA Hospital
No. of
Patients
History of Cancer
25-hydroxyvitamin D3
Level (ng/ml)
7 (9.6 %)
1 (colon)
< 8 (severely deficient)
41 (56.2%) 6*
(deficient)
9 (12.3%)
(insufficient)
13 (17.8%)
(sufficient)
3 (4.1%)
(optimal)
From Dec 2006 to July 2007
Our low rate of wound infections and post-pericardiotomy syndrome
* Prostrate cancer – 3; Colon cancer – 1; Tonsillar cancer – 1; Melanoma -- 1
Surgery performed December 2006 – July 2007

34. Benefits of Vitamin D Skeletal-muscular Infections Cancer
Strong muscles and bones
Infections
Prevent influenza, treat tuberculosis
Cancer
Prevent breast, colon, and prostate cancer
? Suppress metastasizes
Autoimmune Diseases
Prevent multiple sclerosis and type 1 diabetes
Cardiovascular Disease
Slow progression of atherosclerosis
Treat hypertension and congestive heart failure
Neuropsychiatric Disorders
Prevent schizophrenia and relieve depression