Connections between: UVB, vitamin D, cholesterol ?

[Duer 157099]

So I'm researching the literature pretty heavily nowadays, looking at what's been happening over the past decade in vitamin D research, and I've got a question that maybe some of you can weigh in on.

The normal biological way to produce vitamin D in the body is via sunlight, where a certain molecule (7-dehydrocholesterol, 7DHC) interacts with UVB rays to form the first molecule in the vitamin D biosynthetic pathway (vitamin D3).

Well, it turns out that 7DHC is *also* the immediate precursor to cholesterol. In other words, 7DHC can be converted to vitamin D3 and cholesterol, depending on circumstances.

So what I'm wondering is how the balance works, like, if you don't get much sun/UVB exposure, does your body then convert more of the 7DHC to cholesterol? If this were true, you might see issues with high cholesterol in populations with high melanin content in skin (because melanin also competes for the UVB rays). Has anyone looked at this?

Likewise, if a population were to start blocking access of UVB to skin, would that population find itself dealing with high cholesterol issues?

I don't know what the balance is or what the factors are affecting it. It could be that they are so disproportionate that there is absolutely no relationship whatsoever. But, it could also be that they are in a definite balance and pushing the equation one way makes a difference.

So far I haven't found info about this, which is surprising to me. Or, I just haven't looked correctly.

Anyone?

[hedgehog]

1. I can't help you with cholesterol, but Vitamin D levels have been tied to

insulin metabolism, breast cancer rates, high blood pressure and breast cancer rates. Want to take a guess as to which populations in this country have higher rates of diabetes, prostate cancer, hypertension and breast cancer?

[Duer 157099]

7. ummm... does it have to do with melanin?

otherwise I don't know

[hedgehog]

9. Sorry - I've been such a nut on Vitamin D the last few years I forget other people haven't

read all the articles I have.

Blacks have higher rates of these conditions than do whites. Blacks, Hispanics and Native Americans have higher rates of diabetes than do whites.

It's not all about melanin - all people living in the Great Lakes region tend to have higher rates of Multiple sclerosis and arthritis. It's the cloud cover that does it.

Here's a disease I'm really interested in - lupus. Black women have the highest rate of lupus, which is an auto-immune disorder. Vitamin D is tied into the immune system. That sounds pretty straight forward,right? Yet exposure to the sun can cause a flare of lupus symptoms. I'd love to find out what all the connections are there.

[Duer 157099]

11. Right, yes, I know about some of those connections

And the connection to vitamin D levels makes sense because the melanin directly competes for the UVB rays, thus reducing the amounts of 7DHC that are converted to vitamin D3. But has anyone shown that this is also correlated with higher levels of cholesterol?

I haven't looked into lupus, but there are so many players in the immune response, and so many players even within the vitamin D metabolic pathways, and so many gene variants (polymorphisms) in each of the enzymes in the cascade(s) and in the receptor(s) ... ad almost infinitum ... that while at first glance it looks like there should be an obvious answer, it just rarely turns out to be simple (as I'm sure you know). Next time I'm digging for info, I'll take a tangent down the lupus path and see how it looks (but I bet it's very confusing!)

:hi:

[Duer 157099]

17. Regarding Lupus

Yikes, that's a whole ball of yarn in and of itself. I just briefly did a scan of the literature and there's tons.

But I did stumble upon one interesting clue (wrt your comment about the seeming paradoxical effect of sun) that has to do with another disease, SLOS. I've bolded the important points. While this has nothing to do with Lupus, it is an example of a case where the molecule needed for vitamin D3 biosynthesis (7DHC), which DOES NOT react to UVA radiation (but rather only to UVB) can be converted into another molecule, 9-DDHC, that *does* respond to UVA and indeed seems to be involved in symptoms of photosensitivity. Perhaps Lupus patients have a mutation in that enzyme such that it readily converts too much 7DHC into 9-DDHC? Dunno. Although, it seems that the photosensitivity in Lupus is to both UVA and UVB.

Which just emphasizes again how complex it is, and that so much more work needs to be done to figure it all out. I don't think vitamin D will be the silver bullet for all of these diseases, but I *do* believe that it plays a role, and that low vitamin D levels just cannot be helping anyone (except pathogens).

Free Radic Biol Med. 2006 Jul 15;41(2):339-46. Epub 2006 Apr 30.
Ultraviolet A sensitivity in Smith-Lemli-Opitz syndrome: Possible involvement of cholesta-5,7,9(11)-trien-3 beta-ol.

Chignell CF, Kukielczak BM, Sik RH, Bilski PJ, He YY.

Laboratory of Pharmacology and Chemistry, NIEHS/NIH, Research Triangle Park, NC 27709, USA. [e-mail]

Smith-Lemli-Opitz syndrome (SLOS) is a severe developmental disorder caused by mutations in the DHCR7 gene coding for 7-dehydrocholesterol (7-DHC) reductase, the enzyme involved in the last step of cholesterol biosynthesis. SLOS homozygotes exhibit marked deficiency of cholesterol in plasma and tissues with concomitant increase in 7-DHC. Ultraviolet A (UVA) photosensitivity has been recognized as part of SLOS with maximal response occurring at 350 nm. 7-DHC itself has no UVA absorption and so cannot be the direct cause of SLOS photosensitivity. However, cholesta-5,7,9(11)-trien-3beta-ol (9-DDHC), a metabolite of 7-DHC, has been detected in plasma from SLOS patients. Because 9-DDHC has strong absorption in the UVA range (approximately 15,000 @ 324 nm), we have examined its photobiology to determine whether it could be involved in SLOS photosensitivity. High levels of 7-DHC (0.65 mg/100 g wet weight) and measurable amounts of 9-DDHC (0.042 mg/100 g wet weight) were found in skin lipids extracted from CD-1 mice treated with AY9944 (trans-1,4-bis(2-chlorobenzylaminomethyl)cyclohexane dihydrochloride), an inhibitor of 7-DHC reductase. Human HaCaT keratinocytes treated with 9-DDHC (10 microM) and then immediately exposed to UVA (15 J/cm2) exhibited an 88% decrease in viability (compared to dark controls). No damage was observed in cells exposed to 7-DHC/UVA or UVA alone. However, HaCaT keratinocytes treated with 7-DHC (5 microM) for 15 h and then exposed to UVA (30 J/cm2) were damaged. 9-DDHC was detected in keratinocytes incubated with 7-DHC. Reactive oxygen species were detected in 9-DDHC/UVA-exposed cells using the fluorescent probe 5-(and 6-)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester. Singlet oxygen was generated when 9-DDHC was UVA irradiated in CCl4. UVA irradiation of 9-DDHC in acetonitrile generated superoxide and carbon-centered and alkoxyl radicals which were trapped by 5,5-dimethyl-1-pyrroline N-oxide. These findings suggest that reactive oxygen species generated by 9-DDHC may play a role in the UVA skin photosensitivity of SLOS patients. Furthermore, several statin drugs inhibit 7-DHC reductase, in addition to hydroxymethylglutaryl-CoenzymeA reductase, so that 9-DDHC may also be responsible for statin-derived photosensitivity, dermatoses, and cataract formation. Finally, we have previously detected 9-DDHC in skin lipids from normal subjects, so this sterol may also be the skin chromophore responsible for skin photoaging and UV-induced skin cancer.

[postulater]

2. I don't know but keep us posted if you find anything.

I wasn't aware of the chemistry. Wouldn't that be something if the solution to cholesterol / heart / circulation problems turns out to be cheap Vit D instead of the statins? That would take a bite out of the health care expense right there. And piss off the pharma companies.

[Duer 157099]

6. That's sort of what I'm thinking

Also, if you consider that the statins inhibit the synthesis of cholesterol way upstream of 7DHC, it would make sense that it also limits the amount of 7DHC available for UVB conversion to vitamin D.

But again, it all depends on the balance and the relative values involved, about which I know nothing, so it's all wag'ing (wild ass guessing) at this point

[dixiegrrrrl]

3. It'slate, I 'm tired, please help me understand..

Are you saying there is a possible correlation between LOW vit. D levels and the other health issues
or
HIGH Vit. D. levels and the health issues?

[SPedigrees]

4. Low vitamin D. We humans don't get enough of it anymore...

to our detriment.

[Duer 157099]

5. It's almost impossible to get too much vitamin D

More specifically what's I'm suggesting is that if the 7DHC is not converted to vitamin D via UVB (sun), then more 7DHC is available for conversion to cholesterol.

I have no question that low vitamin D levels are associated with all sorts of disease states, non whatsoever.

[dixiegrrrrl]

8. So Vit. D supplements would be helpful ?

[Duer 157099]

10. I think supplements are all but critical, yes

But supplementing vitamin D still would not influence what happens with the 7DHC in the body that is not being converted to vitamin D via the sun/UVB, which is the angle that I'm wondering about, and whether that contributes to a rise in blood cholesterol levels. It may or may not, I don't know. Or, it may be so tightly regulated that it's irrelevent to the big picture. I would think that somebody knows, but I haven't seen the answer yet.

[SPedigrees]

13. I think that the links I posted in my reply #12 may address this.

Vitamin D has a protective effect on cardiovascular function. I've seen quite a few articles about the link between heart disease and low levels of vitamin D.

[Duer 157099]

14. Yes, I know that many studies show an association

but so far the mechanisms are still being untangled. Do you know of any study/link that specifically talks about a link between low UVB and increased cholesterol as a result of lower utilization of 7DHC for vitamin D3 synthesis? Know what I mean?

If 7DHC, the immediate precursor to BOTH vitamin D3 and cholesterol, were itself induced by UVB, then you could argue that no, there should not be an effect on cholesterol levels (and in fact, might even lower cholesterol if you avoided sunshine). But I haven't seen any indication that 7DHC is upregulated by UVB. So, absent other mitigating factors, that leaves more 7DHC available for conversion to cholesterol.

Let's say that you have 100 molecules of 7DHC circulating in your blood. If you go into the sun, let's say 70 of those get converted via the UVB rays into vitamin D3, and 30 remain and are converted to cholesterol.

(Yes, this is an absurdly simplistic view, but it illustrates my point)

Now, if you had not gone into the sun, all 100 of those molecules would be available to be converted to cholesterol.

I'd be very surprised if the answer is not known; I just have not been able to find it.

[SPedigrees]

16. I admit it all goes over my head, but I expect the connection or

mechanism you are wondering about may surface in the research in the near future if your theory is correct.

[SPedigrees]

12. Vitamin D3 is the best form to take.

Vitamin D is actually a hormone, so its effects on bodily functions are many. This list of links to articles in chronological order describe the many benefits of vitamin D, along with articles about health problems attributed to a lack of this vitamin. I have the full text to all these articles that I can email to anyone if requested, if a link doesn't work. The last article on this list is perhaps the most interesting as it involves the very recent discovery of the exact mechanism by which the vitamin works. Here are the links to articles :

Insufficient vitamin D causes weight gain and stunts growth in girls
Published: Wednesday, 10-Dec-2008
http://www.news-medical.net/?id=44058

Low Vitamin D Levels May Increase Cold Risk
By John Gever, Senior Editor, MedPage Today
Published: February 27, 2009
http://www.medpagetoday.com/InfectiousDisease/URItheFlu/13061?utm_source=mSpoke&utm_medium=email&utm_campaign=DailyHeadlines&utm_content=GroupB&userid=76027&impressionId=1235935156932

Cognitive Impairment in Older Persons Linked to Vitamin D Deficiency
By Kristina Fiore, Staff Writer, MedPage Today
http://www.medpagetoday.com/Geriatrics/GeneralGeriatrics/12594

Vitamin D Linked to Decrease in All-Cause Mortality
Published: September 10, 2007
LYON, France, Sept. 10 -- Vitamin D, widely touted for its ability to improve bone health, may also reduce all cause mortality by a small but statistically significant degree.
http://www.medpagetoday.com/Pediatrics/PreventiveCare/6637
Low Vitamin D Linked to High Mortality Risk
Published: June 23, 2008
http://www.medpagetoday.com/PrimaryCare/DietNutrition/9906
Low vitamin D levels substantially increase risk of death
http://www.news-medical.net/?id=40626

Women with low levels of vitamin D have an increased risk of hip fracture
Published: Sunday, 23-Sep-2007
Women with low levels of vitamin D have an increased risk of hip fracture, according to a study led by the University of Pittsburgh Graduate School of Public Health presented this week at the 29th annual meeting of the American Society for Bone and Mineral Research at the Hawaii Convention Center.
http://www.news-medical.net/?id=30172

Low Vitamin D Plus Hypertension May Worsen Cardiovascular Risks
http://www.medpagetoday.com/Cardiology/MyocardialInfarction/7877

Vitamin D Benefits from Sun Exposure Outshine Cancer Risk
By Crystal Phend, Staff Writer, MedPage Today
Published: January 08, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.
UPTON, N.Y., Jan. 8 -- Overall health benefits from increased sun exposure may outweigh the risk of skin cancer, researchers here said.
http://www.medpagetoday.com/HematologyOncology/SkinCancer/7888


Breast Cancer Survival Linked to Vitamin D
The Independent - London
05-20-08

Women with a vitamin D deficiency when they are diagnosed with breast cancer have an increased risk of dying within 10 years, research has found.

Patients whose levels of the vitamin are below average are twice as likely to see the cancer spread, and 73 per cent more likely to die within a decade of diagnosis, according to a study due to be presented next month by the American Society of Clinical Oncology.

While the correlation between low levels of vitamin D and the increased risk of breast, prostate, pancreas, oesophagus and colon cancer is well documented, no previous attempt has been made until now to link it to patients' prognosis after the disease is discovered.

"This is the first study to look at the impact of vitamin D on outcomes of breast cancer," said the lead author, Dr Pamela Goodwin, an oncologist at Mount Sinai Hospital in New York and professor of medicine at the University of Toronto.

The researchers studied 512 women diagnosed with localised breast cancer between 1989 and 1995....
http://www.lef.org/news/LefDailyNews.htm?NewsID=6857&Section=VITAMINS

ASCO: Vitamin D May Play Role in Breast Cancer Survival
Published: May 16, 2008
http://www.medpagetoday.com/MeetingCoverage/ASCO/9490

Vitamin D isn't just for bones anymore
Published: Thursday, 21-Feb-2008
Researchers at The Rockefeller University Hospital have begun a clinical study to explore a possible connection between vitamin D deficiency and insulin resistance.
The hypothesis, that raising blood vitamin D levels in an obese, insulin-resistant population will improve the subjects' ability to metabolize sugar, could have eventual implications for patients with type 2 diabetes and their doctors.
http://www.news-medical.net/?id=35463

ATVB: Too Little Vitamin D May Increase Risk of Peripheral Arterial Disease
http://www.medpagetoday.com/PrimaryCare/DietNutrition/9156

Low blood levels of vitamin D may be associated with depression in seniors
http://www.news-medical.net/?id=38049
http://www.news-medical.net/?id=38083

Vitamin D linked to reduced mortality rate in chronic kidney disease
Published: Wednesday, 7-May-2008
http://www.news-medical.net/?id=38163

Colon Cancer Mortality Risk Drops as Vitamin D Levels Rise
Published: June 19, 2008
http://www.medpagetoday.com/HematologyOncology/ColonCancer/9871

Chronic pain among women may be down to low levels of vitamin D
http://www.news-medical.net/?id=40652

Few Americans Get Enough Vitamin D
Published: March 23, 2009
http://www.medpagetoday.com/Endocrinology/Osteoporosis/13383?utm_source=mSpoke&utm_medium=email&utm_campaign=DailyHeadlines&utm_content=GroupB&userid=76027&impressionId=1237860386608
U.S. Children Lack Vitamin D
http://www.medpagetoday.com/Pediatrics/GeneralPediatrics/15359?userid=76027&impressionId=1249360355055&utm_source=mSpoke&utm_medium=email&utm_campaign=DailyHeadlines&utm_content=Group1

Low Vitamin D Called a Major Culprit in CV (Cardiovascular) Death Disparities
Published: January 07, 2010
http://www.medpagetoday.com/Cardiology/Atherosclerosis/17849?utm_content=GroupC&utm_medium=email&impressionId=1262922386135&utm_campaign=DailyHeadlines&utm_source=mSpoke&userid=76027

Low Vitamin D Worsens Asthma
By John Gever, Senior Editor, MedPage Today
Published: January 28, 2010
http://www.medpagetoday.com/Pulmonology/Asthma/18187?utm_content=GroupCL&utm_medium=email&impressionId=1264747405539&utm_campaign=DailyHeadlines&utm_source=mSpoke&userid=76027

Low Vitamin D Linked to Hip OA
Published: February 09, 2010
http://www.medpagetoday.com/Rheumatology/Arthritis/18379?utm_content=GroupCL&utm_medium=email&impressionId=1265784449196&utm_campaign=DailyHeadlines&utm_source=mSpoke&userid=76027

AAN: High Intake of Vitamin D Linked to Lower MS Risk
Published: February 10, 2010
http://www.medpagetoday.com/MeetingCoverage/AAN/18406?utm_content=GroupCL&utm_medium=email&impressionId=1265870682251&utm_campaign=DailyHeadlines&utm_source=mSpoke&userid=76027

Study suggests vitamin D supplements may decrease insulin resistance, fight depression
4. March 2010 01:00
http://www.news-medical.net/news/20100304/Study-suggests-vitamin-D-supplements-may-decrease-insulin-resistance-fight-depression.aspx

Scientists find why "sunshine" vitamin D is crucial
http://www.reutershealth.com/archive/2010/03/08/eline/links/20100308elin009.html

[Duer 157099]

15. Here's another clue

So there's a disease that is caused by a problem with the enzyme (7DHC reductase, aka DHCR7) that converts 7DHC to cholesterol.

The disease is called Smith-Lemli-Opitz syndrome.

These patients have low levels of blood cholesterol, and abnormally high levels of 7DHC.

Interestingly, they treated this patient with a combination of cholesterol and simvastatin. So, here's a case where they deliberately use simvastatin to reduce levels of 7DHC! The very precursor that's needed for vitamin D3 synthesis. (granted, in these patients it's a problem because they seem to have too much 7DHC.) So then, I wonder if the doctors who prescribe statins ALSO routinely put their patients on vitamin D supplement? Betcha they don't all.

While this doesn't directly support my hypothesis, it also does not refute it. I wonder if exposure of these patients to UVB reduces their levels of 7DHC?

Eur J Pediatr. 2010 Jan;169(1):121-3. Epub 2009 Apr 14.

A patient with Smith-Lemli-Opitz syndrome: novel mutation of the DHCR7 gene and effects of therapy with simvastatin and cholesterol supplement.

Szabó GP, Oláh AV, Kozak L, Balogh E, Nagy A, Blahakova I, Oláh E.

Pediatrics Department, Medical and Health Science Center, Debrecen University, Nagyerdei krt. 98, 4012 Debrecen, Hungary.

BACKGROUND: The Smith-Lemli-Opitz (SLO) syndrome is a multiple congenital anomaly with mental retardation due to a decreased or lack of activity of 7-dehydrocholesterol reductase as a consequence of mutations of the DHCR7 gene. This paper describes a special patient with SLO syndrome. Laboratory examination showed low cholesterol (2.77 mmol/L) and increased 7-dehydrocholesterol level (102 mg/L). Molecular genetic analysis revealed a compound heterozygosity c.964-1G>C/p.G366V (c.G1370T) of the proband. The p.G366V is a novel mutation of the DHCR7 gene with guanine by thymine nucleotide exchange resulting in glycin by valin amino acid exchange in the dehydrocholesterol reductase enzyme. Simvastatin (0.2 mg/kg/day) and cholesterol replacement therapy (150-250 mg/kg/day) led to significant improvement in the patient's laboratory findings (7-dehydrocholesterol, cholesterol) as well as in his behavior and gross motor function. CONCLUSION: Our patient demonstrates that the c.964-1G>C/p.G366V (c.G1370T) genotype of combined heterozygosity is associated with a typical form of SLO syndrome along with moderately altered laboratory findings and a favorable biochemical response to cholesterol and simvastatin treatment.

[Chemisse]

18. This has been a fascinating discussion

I would be very interested to see any further information you find about this. Please keep us posted.

[Duer 157099]

19. Here's just a small personal anecdote

not related to cholesterol.

So I've been taking high doses of vitamin D for over a month now, and assuming that I process it normally, my blood levels should be fairly high right now.

The other day I cut my thumb while washing dishes. A pretty deep cut (by a food processor blade) that bled like crazy, of course.

I bandaged it up (and had to stop washing dishes, awwwww) and was minorly irritated because it was my right thumb (surface) and I knew it would hinder some things I had planned to do over the next few days.

The next day, I changed the bandage, applied neosporin as I usually do with wounds. It still hurt like hell.

The next day: pain was completely gone. I could press down on it completely with absolutely no pain. No redness. Nada. Aside from a tiny flap of skin that I can still see on the surface, the wound itself is completely closed and healed.

That *never* ever happens that quickly, especially in an area like that where it's impossible to leave it alone.

I'm stongly suspecting that it is directly related to the vitamin D.

[Duer 157099]

20. Looks like I'm not imagining things. Check this out:

Exp Dermatol. 2009 Oct 28.

Topical treatment with the vitamin D analogue calcipotriol enhances the upregulation of the antimicrobial protein hCAP18/LL-37 during wounding in human skin in vivo.

Heilborn JD, Weber G, Grönberg A, Dieterich C, Ståhle M.

Dermatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

Please cite this paper as: Topical treatment with the vitamin D analogue calcipotriol enhances the upregulation of the antimicrobial protein hCAP18/LL-37 during wounding in human skin in vivo. Experimental Dermatology 2009.Abstract: Cathelicidin antimicrobial protein, hCAP18, is the sole cathelin protein in human. Its C-terminal peptide, which is released enzymatically from the holoprotein, has broad antimicrobial activity but also has effects on eukaryotic cells. hCAP18 is present in leukocytes and is produced at epithelial interfaces as part of the innate immune system. In normal intact skin, there is low constitutive expression of hCAP18, which is rapidly upregulated upon injury. Accumulating evidence indicates that hCAP18/LL-37 may serve a key role in protecting the integrity of the epithelium and also actively promote re-epithelialization and tissue repair. Molecular mechanisms responsible for controlling hCAP18 gene expression in vivo are only partly understood. Vitamin D(3) and its analogue calcipotriol were recently found to directly induce transcription of the hCAP18 gene via functional vitamin D responsive elements in the hCAP18 gene promoter. Skin is the major source for vitamin D(3) in human, where its production is dependent on ultraviolet B (UVB) radiation. We have shown that exposure to UVB, sufficient to produce vitamin D(3), upregulates hCAP18 in human skin in vivo. In the present study, we demonstrate that the upregulation of hCAP18/LL-37 following acute skin injury is further enhanced, at both hCAP18 mRNA and protein levels, after topical treatment with the vitamin D(3) analogue calcipotriol. In chronic ulcers, calcipotriol treatment upregulated hCAP18 mRNA, whereas no consistent upregulation of hCAP18 protein was detected. Our results further support the role of vitamin D(3) as a key physiologic regulator of hCAP18/LL-37 in human skin.

http://www.ncbi.nlm.nih.gov/pubmed/19878298