- Central role in inflammation
- Increasing incidence of Vitamin D deficiency worldwide and as latitude increases
- Implicated in Diabetes, Cardiovascular Disease, Autoimmune Disease and Cancer
- Role in macrophage efficiency, particularly in cardiovascular disease.
- Generally Summer production when Fructose and Carbohydrate loads are high. Self managing inflammation naturally.
The Role of Vitamin D
The purpose of Vitamin D may be the suppression of the inflammatory reaction, before it overshoots the mark.
Uncontrolled, activated macrophages can cause severe damage to tissue.
Vitamin D may the internal control mechanism that stops runaway inflammation.
Vitamin D deficient states allow the body to not control it’s own ‘cleaning and clearing’ mechanisms.
The Link with Fructose, Carbohydrate and Polyunsaturated Oils and Inflammation
Explained on this page
Summary of Vitamin D and Vitamin K from Dr Mercola, March 2011
Get your Vitamin D levels up and keep up the Vitamin K intake with green leafy vegetables.
Both are fat soluble.
Summary of how much Vitamin D do you need.
Overview of Vitamin D
from Sunlight and Vitamin D – A global perspective for health 2013
Matthias Wacker and Michael F. Holick
Vitamin D is the sunshine vitamin that has been produced on this earth for more than 500 million years. During exposure to sunlight 7-dehydrocholesterol in the skin absorbs UV B radiation and is converted to previtamin D3 which in turn isomerizes into vitamin D3. Previtamin D3 and vitamin D3 also absorb UV B radiation and are converted into a variety of photoproducts some of which have unique biologic properties. Sun induced vitamin D synthesis is greatly influenced by season, time of day, latitude, altitude, air pollution, skin pigmentation, sunscreen use, passing through glass and plastic, and aging. Vitamin D is metabolized sequentially in the liver and kidneys into 25-hydroxyvitamin D which is a major circulating form and 1,25-dihydroxyvitamin D which is the biologically active form respectively. 1,25-dihydroxyvitamin D plays an important role in regulating calcium and phosphate metabolism for maintenance of metabolic functions and for skeletal health. Most cells and organs in the body have a vitamin D receptor and many cells and organs are able to produce 1,25-dihydroxyvitamin D. As a result 1,25-dihydroxyvitamin D influences a large number of biologic pathways which may help explain association studies relating vitamin D deficiency and living at higher latitudes with increased risk for many chronic diseases including autoimmune diseases, some cancers, cardiovascular disease, infectious disease, schizophrenia and type 2 diabetes. A three-part strategy of increasing food fortification programs with vitamin D, sensible sun exposure recommendations and encouraging ingestion of a vitamin D supplement when needed should be implemented to prevent global vitamin D deficiency and its negative health consequences.
Vitamin D deficiency: a worldwide problem with health consequences
Michael F Holick and Tai C Chen, 2008
Vitamin D deficiency is now recognized as a pandemic. The major cause of vitamin D deficiency is the lack of appreciation that sun exposure in moderation is the major source of vitamin D for most
humans. Very few foods naturally contain vitamin D, and foods that are fortified with vitamin D are often inadequate to satisfy either a child’s or an adult’s vitamin D requirement. Vitamin D deficiency
causes rickets in children and will precipitate and exacerbate osteopenia, osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. A circulating level of 25-hydroxyvitamin D of 75nmol/L, or 30ng/mL, is required to maximize vitamin D’s beneficial effects for health. In the absence of adequate sun exposure, at least 800–1000 IU vitamin D3/d may be needed to achieve this in children and adults. Vitamin D2 may be equally effective for maintaining circulating concentrations of 25-hydroxyvitamin D when given in physiologic concentrations.
The Role of the Intraplaque Vitamin D System in Atherogenesis
Vitamin D has been shown to play critical activities in several physiological pathways not involving the calcium/phosphorus homeostasis. The ubiquitous distribution of the vitamin D receptor that is expressed in a variety of human and mouse tissues has strongly supported research on these “nonclassical” activities of vitamin D. On the other hand, the recent discovery of the expression also for vitamin D-related enzymes (such as 25-hydroxyvitamin D-1α-hydroxylase and the catabolic enzyme 1,25-dihydroxyvitamin D-24-hydroxylase) in several tissues suggested that the vitamin D system is more complex than previously shown and it may act within tissues through autocrine and paracrine pathways. This updated model of vitamin D axis within peripheral tissues has been particularly investigated in atherosclerotic pathophysiology. This review aims at updating the role of the local vitamin D within atherosclerotic plaques, providing an overview of both intracellular mechanisms and cell-to-cell interactions. In addition, clinical findings about the potential causal relationship between vitamin D deficiency and atherogenesis will be analysed and discussed.
Type 2 Diabetes, PUFAs, and Vitamin D: Their Relation to Inflammation
J Immunol Res. 2014; 2014: 860703.
Chronic diseases have become one of the most important public health problems, due to their high costs for treatment and prevention. Until now, researchers have considered that the etiology of Type 2 diabetes mellitus (T2DM) is multifactorial. Recently, the study of the innate immune system has offered an explanation model of the pathogenesis of T2DM. On the other hand, there is evidence about the beneficial effect of polyunsaturated fatty acids (PUFA) n-3 and n-6 in patients with chronic inflammatory diseases including diabetes. Furthermore, high vitamin D plasmatic concentrations have been associated with the best performance of pancreatic β cells and the improving of this disease. In conclusion, certain fatty acids in the adequate proportion as well as 25-hydroxivitamin D can modulate the inflammatory response in diabetic people, modifying the evolution of this disease.
1,25(OH)2 vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients.
Reduced monocyte infiltration into the vessel wall and increased macrophage cholesterol efflux are critical components in atherosclerotic plaque regression. During inflammation, monocyte chemotactic protein 1 (MCP-1) signaling activation and cholesterol deposition in macrophages induce endoplasmic reticulum (ER) stress, which promotes an increased inflammatory response. Increased macrophage ER stress shifts macrophages into an M2 macrophage phenotype with increased cholesterol uptake and deposition. In type 2 diabetes, a population with elevated baseline risk of cardiovascular disease (CVD), vitamin D deficiency doubles that risk. We have found that 1,25-dihydroxy vitamin D [1,25(OH)2D] prevents foam cell formation during macrophage differentiation by suppressing ER stress. However, it is unknown whether suppression of ER stress by 1,25(OH)2D decreases monocyte infiltration and reverses atherogenic cholesterol metabolism in previously differentiated, vitamin D-deplete macrophages. We collected peripheral monocytes from type 2 diabetic patients and differentiated them into macrophages under vitamin D-deplete or 1,25(OH)2D-supplemented conditions. 1,25(OH)2D supplementation suppressed macrophage migration in response to MCP-1 and mRNA expression of chemokine (C-C motif) receptor 2 (CCR2), the MCP-1 receptor, compared to vitamin D-deplete cells. Furthermore, inhibition of ER stress with phenyl butyric acid resulted in similar effects even in vitamin D-deplete cells, while induction of ER stress with Thapsigargin under 1,25(OH)2D-supplemented conditions increased macrophage migration and CCR2 expression, suggesting that the effects of vitamin D on migration are mediated through ER stress suppression. To determine whether the detrimental pattern of macrophage cholesterol metabolism in vitamin D depletion is reversible, we assessed cholesterol uptake in macrophages differentiated under vitamin D-deplete conditions as described above, then supplemented with 1,25(OH)2D or maintained in vitamin D-deplete conditions. Cholesterol uptake was decreased in 1,25(OH)2D-supplemented compared to vitamin D-deplete cells, suggesting slowed cholesterol deposition with active vitamin D. 1,25(OH)2D supplementation also suppressed cholesteryl ester formation and enhanced cholesterol efflux in M2 macrophages compared to vitamin D-deplete cells, suggesting facilitation of cholesterol egress in the presence of 1,25(OH)2D. We thus provide further evidence that active vitamin D is an ER stress reliever that may have a role in atherosclerotic plaque regression.
“Vitamin D inhibits the uptake of cholesterol by cells called macrophages,” says principal investigator Carlos Bernal-Mizrachi, M.D., a Washington University endocrinologist at Barnes-Jewish Hospital. “When people are deficient in vitamin D, the macrophage cells eat more cholesterol, and they can’t get rid of it. The macrophages get clogged with cholesterol and become what scientists call foam cells, which are one of the earliest markers of atherosclerosis.”
1,25(OH)2Vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes
Cardiovascular disease is the leading cause of death among diabetics. Vitamin D deficiency is associated with increased risk of cardiovascular disease in this population. To determine the mechanism by which vitamin D deficiency mediates accelerated cardiovascular disease in patients with diabetes, we investigated the effects of active vitamin D on macrophage cholesterol deposition.
Methods and Results
We obtained macrophages from 76 obese, diabetic, hypertensive patients with vitamin D deficiency (25-hydroxyvitamin D < 80 nmol/L)(group A) and four control groups: obese, diabetic, hypertensive patients with normal vitamin D (group B, n=15), obese, non-diabetic, hypertensive patients with vitamin D deficiency (group C, n=25), and non-obese, non-diabetic, non-hypertensive patients with vitamin D deficiency (group D, n=10) or sufficiency (group E, n=10). The same patient’s macrophages from all groups were cultured in vitamin D-deficient or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH)2D3 suppressed foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptake in diabetics only. Conversely, deletion of the vitamin D receptor in macrophages from diabetic patients accelerated foam-cell formation induced by modified LDL. 1,25(OH)2D3 downregulation of c-Jun N-terminal kinase activation reduced PPARγ expression, suppressed CD36 expression, and prevented oxLDL-derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1expression, and prevented oxLDL and AcLDL-derived cholesterol uptake.
These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam-cell formation and accelerated cardiovascular disease in diabetics.
It is estimated that one billion people around the world are vitamin D deficient. Vitamin D deficiency has been linked to various inflammatory diseases. However, the mechanism by which vitamin D reduces inflammation remains poorly understood. In this study, we investigated the inhibitory effects of physiologic levels of vitamin D on lipopolysaccharide (LPS)-stimulated inflammatory response in human blood monocytes, and explored potential mechanisms of vitamin D action. We observed that two forms of the vitamin D, 1,25(OH)2D3, and 25(OH)D3, dose dependently inhibited LPS-induced p38 phosphorylation at physiologic concentrations, IL-6 and TNF-α production by human monocytes. Upon vitamin D treatment, the expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) was significantly upregulated in human monocytes and murine bone marrow-derived macrophages (BMM). Increased binding of the vitamin D receptor and increased histone H4 acetylation at the identified vitamin D response element of the murine and human MKP-1 promoters were demonstrated. Moreover, in BMM from MKP1−/− mice, the inhibition of LPS-induced p38 phosphorylation by vitamin D was completely abolished. Vitamin D inhibition of LPS-induced IL-6 and TNF-α production by BMM from MKP-1−/− mice was significantly reduced as compared to wild type mice. In conclusion, this study identified the upregulation of MKP-1 by vitamin D as a novel pathway by which vitamin D inhibits LPS-induced p38 activation and cytokine production in monocytes/macrophages.
Multiple epidemiological studies link vitamin D deficiency to increased cardiovascular disease (CVD), but causality and possible mechanisms underlying these associations are not established. To clarify the role of vitamin D-deficiency in CVD in vivo, we generated mouse models of diet-induced vitamin D deficiency in two backgrounds (LDL receptor- and ApoE-null mice) that resemble humans with diet-induced hypertension and atherosclerosis. Mice were fed vitamin D-deficient or -sufficient chow for 6 weeks and then switched to high fat (HF) vitamin D-deficient or –sufficient diet for 8–10 weeks. Mice with diet-induced vitamin D deficiency showed increased systolic and diastolic blood pressure, high plasma renin, and decreased urinary sodium excretion. Hypertension was reversed and renin was suppressed by returning chow-fed vitamin D-deficient mice to vitamin D-sufficient chow diet for 6 weeks. On a HF diet, vitamin D-deficient mice had ∼2-fold greater atherosclerosis in the aortic arch and ∼2–8-fold greater atherosclerosis in the thoracic and abdominal aorta compared to vitamin D-sufficient mice. In the aortic root, HF-fed vitamin D-deficient mice had increased macrophage infiltration with increased fat accumulation and endoplasmic reticulum (ER) stress activation, but a lower prevalence of the M1 macrophage phenotype within atherosclerotic plaques. Similarly, peritoneal macrophages from vitamin D-deficient mice displayed an M2-predominant phenotype with increased foam cell formation and ER stress. Treatment of vitamin D-deficient mice with the ER stress reliever PBA during HF feeding suppressed atherosclerosis, decreased peritoneal macrophage foam cell formation, and downregulated ER stress proteins without changing blood pressure. Thus, we suggest that vitamin D deficiency activates both the renin angiotensin system and macrophage ER stress to contribute to the development of hypertension and accelerated atherosclerosis, highlighting vitamin D replacement as a potential therapy to reduce blood pressure and atherosclerosis.
Vitamin D regulates macrophage cholesterol metabolism in diabetes.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). In type 2 diabetics, the prevalence of vitamin D deficiency is 20% higher than in non-diabetics, and low vitamin D levels nearly double the relative risk of developing CVD compared to diabetic patients with normal vitamin D levels. However, the mechanism(s) by which vitamin D deficiency leads to an increased susceptibility to atherosclerosis in these patients is unknown. We studied the effects of vitamin D replacement on macrophage cholesterol metabolism and foam cell formation in obese, hypertensive diabetics and non-diabetic controls. We found that 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] suppressed foam cell formation by reducing acetylated low density lipoprotein (AcLDL) and oxidized low density lipoprotein (oxLDL) cholesterol uptake in diabetics only. 1,25(OH)2D3 downregulation of c-Jun N-terminal kinase activation reduced PPARgamma and CD36 expression, and prevented oxLDL-derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1 expression, and prevented oxLDL- and AcLDL-derived cholesterol uptake. The results of this research reveal novel insights into the mechanisms linking vitamin D signaling to foam cell formation in diabetics and suggest a potential new therapeutic target to reduce cardiovascular risk in this population.
Gene study supports link between vitamin D deficiency and disease
Scientists have mapped the points at which vitamin D interacts with our DNA – and identified over 200 genes directly influenced by vitamin D. The results are published in the journal Genome Research.
It is estimated that 1 billion people worldwide do not have sufficient vitamin D. This deficiency is thought to be largely due to insufficient exposure to the sun and in some cases to poor diet.
As well as being a well-known risk factor for rickets, there is a growing body of evidence that vitamin D deficiency also increases an individual’s susceptibility to autoimmune conditions such as multiple sclerosis (MS), rheumatoid arthritis and type 1 diabetes, as well as certain cancers and even dementia.
Hypovitaminosis D Correction and High-Sensitivity C-Reactive Protein Levels in Hypertensive Adults
Perm J. 2013 Fall; 17(4): 19–21.
Comment by Gary Fettke
Oral supplementation did not change inflammatory markers. There has been suggestion that sunlight driven Vitamin D is more effective than oral regimes.
Hypovitaminosis D has been implicated as a possible risk factor for the development of cardiovascular disease. High-sensitivity C-reactive protein (hs-CRP) has been one of the most extensively studied biomarkers for cardiovascular inflammation as an indicator of disease and event risk, independent of traditional risk factors. To date, it is unclear if correction of hypovitaminosis D leads to a reduction of hs-CRP in human subjects.
To assess laboratory validity of 25-hydroxyvita-min D (25-OH-vitamin D) and hs-CRP measurements and to determine whether hs-CRP levels in adults with well-controlled hypertension and comorbid low vitamin D levels changed after hypovitaminosis D correction to a serum 25-OH-vitamin D level greater than 30 ng/mL.
Prospective study using an unblinded design.
One hundred eight subjects who were vitamin D insufficient or deficient completed this study. The mean 25-OH-vitamin D level was 20.07 ng/mL before treatment and 43.92 ng/mL after treatment. Posttreatment vitamin D levels were in the normal range for 91% of the subjects. No statistically significant changes in hs-CRP level were detected after the vitamin D treatment was administered and a posttreatment vitamin D level above 30 ng/mL was confirmed.
We did not detect a statistically significant difference in hs-CRP after correction of hypovitaminosis D. Twelve weekly oral doses of 50,000 IU of ergocalciferol corrected the hypovitaminosis D in more than 90% of cases.