Regulation of vitamin D metabolism by metabolic state in mice and humans:discovery of molecular factors repressing vitamin D bioactivation and inducing deficiency in diabetes

Abstract Vitamin D deficiency, i.e., low circulating 25-hydroxyvitamin D (25(OH)D) level, has been consistently associated with the prevalence of metabolic diseases, including types 1 and 2 diabetes. However, the causal link between low vitamin D and metabolic disturbances remains uncertain. In the present thesis, I report novel findings indicating that vitamin D metabolism is under strict control by the metabolic state. Specifically, obesity represses the expression of cytochrome P450 (CYP) 2R1, the major vitamin D 25-hydroxylase responsible for the first bioactivation step in both mice and humans. Interestingly, in humans, weight loss induced by gastric bypass surgery increased CYP2R1 expression in the white adipose tissue. In mouse liver, Cyp2r1 and vitamin D bioactivation was suppressed by fasting, and both type 1 and type 2 diabetes. This may consequently cause low plasma 25(OH)D levels. On the other hand, fasting induced expression of the vitamin D catabolic enzyme CYP24A1 in the kidney. Mechanistically, we discovered that Cyp2r1 and vitamin D bioactivation are repressed by molecular pathways activated physiologically by fasting or pathologically in diabetes, namely, the peroxisome proliferator-activated receptor-gamma coactivator 1-α and estrogen-related receptor α (PGC-1α-ERRα), and the glucocorticoid receptor pathways. Moreover, the PGC-1α-ERRα pathway is crucial for mediating the Cyp24a1 induction by fasting in the kidney. In the current thesis, we uncover a molecular mechanism for the vitamin D deficiency observed in diabetic patients and reveal a novel negative feedback mechanism controlling the crosstalk between energy homeostasis and the vitamin D pathway. Importantly, our data propose that vitamin D deficiency is a consequence, and not the cause of diabetes.Tiivistelmä D-vitamiinin puutteen eli veren matalan 25-hydroksi-D-vitamiinin (25(OH)D) pitoisuuden on havaittu toistuvasti assosioituvan metabolisten sairauksien, kuten tyypin 1 ja 2 diabeteksen, ilmenemiseen. Tästä huolimatta D-vitamiinin puutteen ja metabolisten häiriöiden välinen kausaalinen yhteys on epävarma. Tässä väitöskirjatyössä raportoimme uusia löydöksiä, jotka osoittavat elimistön metabolisen tilan tehokkaasti säätelevän D-vitamiinin aineenvaihduntaa. Tarkemmin ottaen lihavuus repressoi sytokromi P450 (CYP) 2R1:ta, D-vitamiinin tärkeintä 25-hydroksylaasia ja ensimmäistä bioaktivaatiovaihetta sekä hiirissä että ihmisissä. Mielenkiintoinen havainto oli, että ihmisillä mahalaukun ohitusleikkaukseen liittyvä painonlasku sai aikaan CYP2R1:n ilmenemisen nousun valkeassa rasvakudoksessa. Hiiren maksassa sekä tyypin 1 ja 2 diabetes että paastoaminen vähensivät Cyp2r1:n ilmentymistä ja D-vitamiinin bioaktivaatiota. Tämä voi johtaa plasman 25(OH)D pitoisuuden alentumiseen. Toisaalta paastoaminen indusoi D-vitamiinin kataboliaentsyymiä, CYP24A1, munuaisessa. Mekanistisella tasolla havaitsimme, että Cyp2r1 ilmentymistä ja D-vitamiinin bioaktivaatiota estävät sellaiset molekylaariset säätelytiet, jotka aktivoituvat fysiologisesti paaston aikana ja patologisesti diabeteksessa. Tällaisia ovat peroksisomi-proliferaattori-aktivaattori-reseptori γ:n koaktivaattori 1 α:n ja estrogeeniin kaltainen reseptori α:n (PGC-1α-ERRα) sekä glukokortikoidireseptorin välittämät säätelytiet. PGC-1α-ERRα säätelee tämän lisäksi myös Cyp24a1:n induktiota munuaisessa paaston aikana. Tässä väitöskirjatyössä tunnistimme molekylaarisen mekanismin, joka selittää diabeetikoilla havaitun D-vitamiinin puutteen ja löysimme aiemmin tuntemattoman negatiivisen palautemekanismin, joka välittää energiahomeostaasin ja D-vitamiinijärjestelmän välistä vuorovaikutusta. Löydöksien perusteella voidaan tehdä tärkeä johtopäätös, että D-vitamiinin puutos on diabeteksen seuraus, ei syy

Extranuclear sirtuins and metabolic stress

Abstract Significance: Extranuclear sirtuins in cytosol (SIRT2) and mitochondria (SIRT3, SIRT4, and SIRT5) are key regulators of metabolic enzymes and the antioxidative defense mechanisms. They play an important role in the adjustment of metabolic pathways in alterations of the nutritional status. Recent Advances: Recent studies have shown that in addition to lysine deacetylation, sirtuins catalyze several different lysine deacylation reactions, removal of lipid modifications, and adenosine diphosphate-ribosylation. Large-scale studies have revealed hundreds of target proteins regulated by different sirtuin modifications. Critical Issues: Sensing of the metabolic state and regulation of the sirtuin function and expression are critical components of the machinery, optimizing cellular functions in the switch from fed to fasting condition. Overfeeding, obesity, and metabolic diseases cause metabolic stress that dysregulates the sirtuins, which may play a role in the pathogenesis and complications of metabolic diseases such as type 2 diabetes, fatty liver disease, and cardiac diseases. In the current review, we will discuss the significance of the extranuclear sirtuins as metabolic regulators and in protection against the reactive oxygen species, and also how these sirtuins are regulated by metabolic status and their putative role in metabolic diseases. Future Directions: To efficiently utilize sirtuins as drug targets for treatment of the metabolic diseases, better understanding of the sirtuin functions, targets, regulation, and cross talk is needed. Furthermore, more studies in humans are needed to confirm the many observations mainly made in animal and cell models so far. Antioxid. Redox Signal. 28, 662–676

Streptozotocin-induced Diabetes Represses Hepatic CYP2R1 Expression but Induces Vitamin D 25-Hydroxylation in Male Mice

Abstract Vitamin D deficiency [ie, low plasma 25-hydroxyvitamin D (25-OH-D)] associates with the prevalence of metabolic diseases including type 1 diabetes; however, the molecular mechanisms are incompletely understood. Recent studies have indicated that both fasting and metabolic diseases suppress the cytochrome P450 (CYP) 2R1, the major hepatic vitamin D 25-hydroxylase. We specifically studied the effect of a mouse model of type 1 diabetes on the regulation of Cyp2r1 and vitamin D status. We show that streptozotocin-induced diabetes in mice suppresses the expression of the Cyp2r1 in the liver. While insulin therapy normalized the blood glucose levels in the diabetic mice, it did not rescue the diabetes-induced suppression of Cyp2r1. Similar regulation of Cyp2r1 was observed also in the kidney. Plasma 25-OH-D level was not decreased and was, in contrast, higher after 4 and 8 weeks of diabetes. Furthermore, the vitamin D 25-hydroxylase activity was increased in the livers of the diabetic mice, suggesting compensation of the Cyp2r1 repression by other vitamin D 25-hydroxylase enzymes. Cyp27b1, the vitamin D 1α-hydroxylase, expression in the kidney and the plasma 1α,25-dihydroxyvitamin D level were higher after 4 weeks of diabetes, while both were normalized after 13 weeks. In summary, these results indicate that in the mouse model of type 1 diabetes suppression of hepatic Cyp2r1 expression does not result in reduced hepatic vitamin D 25-hydroxylase activity and vitamin D deficiency. This may be due to induction of other vitamin D 25-hydroxylase enzymes in response to diabetes

Obesity represses CYP2R1, the vitamin D 25‐hydroxylase, in the liver and extrahepatic tissues

Abstract Low plasma level of 25‐hydroxyvitamin D (25‐OH‐D), namely vitamin D deficiency, is associated with obesity and weight loss improves 25‐OH‐D status. However, the mechanism behind obesity‐induced vitamin D deficiency remains unclear. Here, we report that obesity suppresses the expression of cytochrome P450 (CYP) 2R1, the main vitamin D 25‐hydroxylase, in both mice and humans. In humans, weight loss induced by gastric bypass surgery increased the expression of CYP2R1 in the s.c. adipose tissue suggesting recovery after the obesity‐induced suppression. At the same time, CYP27B1, the vitamin D 1α‐hydroxylase, was repressed by the weight loss. In a mouse (C57BL/6N) model of diet‐induced obesity, the plasma 25‐OH‐D was decreased. In accordance, the CYP2R1 expression was strongly repressed in the liver. Moreover, obesity repressed the expression of CYP2R1 in several extrahepatic tissues, the kidney, brown adipose tissue, and testis, but not in the white adipose tissue. Obesity had a similar effect in both male and female mice. In mice, obesity repressed expression of the vitamin D receptor in brown adipose tissue. Obesity also upregulated the expression of the vitamin D receptor and CYP24A1 in the s.c. adipose tissue of a subset of mice; however, no effect was observed in the human s.c. adipose tissue. In summary, we show that obesity affects CYP2R1 expression both in the mouse and human tissues. We suggest that in mouse the CYP2R1 repression in the liver plays an important role in obesity‐induced vitamin D deficiency. Currently, it is unclear whether the CYP2R1 downregulation in extrahepatic tissues could contribute to the obesity‐induced low plasma 25‐OH‐D, however, this phenomenon may affect at least the local 25‐OH‐D concentrations

Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes

Low 25-hydroxyvitamin D levels correlate with the prevalence of diabetes; however, the mechanisms remain uncertain. Here, we show that nutritional deprivation-responsive mechanisms regulate vitamin D metabolism. Both fasting and diabetes suppressed hepatic cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase responsible for the first bioactivation step. Overexpression of coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), induced physiologically by fasting and pathologically in diabetes, resulted in dramatic downregulation of CYP2R1 in mouse hepatocytes in an estrogen-related receptor alpha (ERR alpha)-dependent manner. However, PGC-1 alpha knockout did not prevent fasting-induced suppression of CYP2R1 in the liver, indicating that additional factors contribute to the CYP2R1 repression. Furthermore, glucocorticoid receptor (GR) activation repressed the liver CYP2R1, suggesting GR involvement in the regulation of CYP2R1. GR antagonist mifepristone partially prevented CYP2R1 repression during fasting, suggesting that glucocorticoids and GR contribute to the CYP2R1 repression during fasting. Moreover, fasting upregulated the vitamin D catabolizing CYP24A1 in the kidney through the PGC-1 alpha-ERR alpha pathway. Our study uncovers a molecular mechanism for vitamin D deficiency in diabetes and reveals a novel negative feedback mechanism that controls crosstalk between energy homeostasis and the vitamin D pathway

Fasting-induced transcription factors repress vitamin D bioactivation, a mechanism for vitamin D deficiency in diabetes

Abstract Low 25-hydroxyvitamin D levels correlate with the prevalence of diabetes; however, the mechanisms remain uncertain. Here, we show that nutritional deprivation–responsive mechanisms regulate vitamin D metabolism. Both fasting and diabetes suppressed hepatic cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase responsible for the first bioactivation step. Overexpression of coactivator peroxisome proliferator–activated receptor γ coactivator 1-α (PGC-1α), induced physiologically by fasting and pathologically in diabetes, resulted in dramatic downregulation of CYP2R1 in mouse hepatocytes in an estrogen-related receptor α (ERRα)–dependent manner. However, PGC-1α knockout did not prevent fasting-induced suppression of CYP2R1 in the liver, indicating that additional factors contribute to the CYP2R1 repression. Furthermore, glucocorticoid receptor (GR) activation repressed the liver CYP2R1, suggesting GR involvement in the regulation of CYP2R1. GR antagonist mifepristone partially prevented CYP2R1 repression during fasting, suggesting that glucocorticoids and GR contribute to the CYP2R1 repression during fasting. Moreover, fasting upregulated the vitamin D catabolizing CYP24A1 in the kidney through the PGC-1α-ERRα pathway. Our study uncovers a molecular mechanism for vitamin D deficiency in diabetes and reveals a novel negative feedback mechanism that controls crosstalk between energy homeostasis and the vitamin D pathway