Vitamin D, Lipid Metabolism and Prostate Cancer

Abstract

Tutkimuksen tarkoituksena oli selvittää D-vitamiinin vaikutuksia rasva-aineenvaihduntaan ja tämän yhteyksiä eturauhassyövän kehittymiseen. Työ on jatkoa tutkimusryhmän aikaisemmille tuloksille, joiden mukaan D-vitamiini säätelee suoraan rasvahappojen tuottoa soluissa. Koska D-vitamiini syntyy kolesterolista, haluttiin selvittää, voisiko D-vitamiini säädellä myös kolesterolin aineenvaihduntaa.

Tutkimuksesa löydettiin entsyymi, kolesteroli-25-hydroksylaasi, joka estää kolesterolin tuotantoa. Havaittiin myös, että D-vitamiini toimii yhdessä LX-reseptorin kanssa säätelemällä kolesterolin soluun siirtymistä. Nämä samat mekanismit näyttivät säätelevän myös eturauhasen solujen kasvua ja siten saattavat vaikuttaa eturauhasen syövän kehitykseen. Lisäksi D-vitamiini vaikutti sukupuolihormonien aineenvaihduntaan säätelemällä niitä tuottavaa entsyymiä.

Tutkimuksessa käytettiin myös hiiriä, joilta oli tuhottu D-vitamiini reseptori. Näillä hiirillä oli lievä seerumin kokonaiskolesterolin nousu. Yhteenvetona voitiin todeta, että D-vitamiini säätelee kolesterolin aineenvaihduntaa ja voi myös sitä kautta suojata verenkiertoelimistön kalkkeutumiselta.

Derived from 7-dehydrocholesterol in the skin or in taken from foods, vitamin D3 is further modified and the most hormonally active form is 1,25-dihydroxyvitamin D3 (calcitriol). The functions of vitamin D have been mainly fulfilled via its regulation of gene expression after binding to vitamin D receptor (VDR). Classical functions of vitamin D are mediation of calcium and phosphate balance in our body. Other functions include controlling of the cell proliferation, suppression of adaptive immunity, acting as a neuroactive hormone and so on. VDR deficient mice models have been generated and used in research for better understanding the role of vitamin D in physiological and pathological processes. Low concentration of vitamin D in blood has been suggested to associate with the development of prostate cancer and the increase of blood cholesterol. The studies of vitamin D in relation to prostate cancer have been carried out for years and different mechanisms have been described. However, only few studies deal with the effects of vitamin D on lipid related aspects. Especially, during cancer cell growth, large amount of lipids are needed, because the membrane of the cells are made mainly of cholesterol and other types of lipids. In our laboratory, Qiao et al. found that calcitriol inhibited the expression of an enzyme for fatty acids production and this played a role in the suppression of prostate cancer cell growth. In the present study, I further investigated the role of vitamin D in prostate cells with lipid-related aspect as a focus.

We identified ch25h (cholesterol 25-hydroxylase) and abca1 (ATP-binding cassette transporter A1) as novel calcitriol regulated genes with ch25h being up-regulated whereas abca1 was down-regulated. CH25H is an enzyme that can reduce cholesterol production. abca1 is regulated by liver X receptor (LXR) which is involved in cholesterol balance. Our study indicated both of these two regulations partly contribute to calcitriol-mediated control of prostate cell growth, indicating a role of these regulations in prostate cancer, where androgen plays an important role. Interestingly, our study suggests that the VDR, AR (androgen receptor) and LXR system interacts with each other by mutual and overlapping regulation of their target genes. For example, LXR agonist induced the expression of 25-hydroxyvitamin D3-24-hydroxylase (CYP24), a target gene of VDR, whereas VDR ligand, calcitriol, down-regulated ABCA1, which is a target of LXR. It also suggests that VDR system interact that of AR ! (androgen receptor) and LXR in controlling of androgen production.

Our in vivo studies showed mice lacking of VDR, which had been on high calcium containing foods, had higher total serum cholesterol level, but only male mice displayed a higher level of high-density lipoprotein-bound cholesterol (HDL-C). On the other hand, in another strain of mice where wild-type (WT) mice were switched to high calcium foods 3 weeks before sampling, KO female mice (male not studied) had similar levels of both total serum cholesterol and HDL-C. In the former strain, VDR-KO female mice had lower mRNA expression of SREBP2 in comparison to WT. However, VDR-KO male mice had higher levels of LXRâ and ApoAI than WT mice. SREBP2, LXR and ApoAI are involved in lipid metabolism. This suggests that the altered lipid profile may result from changing of the related gene expression where gender plays a role, and it can be rescued by special food containing high calcium.

Taken together, the results suggest that calcitriol/VDR is directly or indirectly involved in lipid metabolism via regulation of specific gene expression, which is implicated in the control of prostate stromal and prostate cancer cell growth. VDR, AR and LXR ligands interact and can individually control corresponding target signaling, including androgen production. It provides further information for drug discovery in the treatment of prostate cancer via VDR mediated signaling systems.