Overview of the pathways for vitamin D synthesis, bioactivation, and inactivation. Part of the Fig. was drawn with the help of Servier Medical Art (www.servier.com).

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... CYP enzymes play critical roles in vitamin D bioactivation and degradation, namely CYP2R1, CYP27B1, and CYP24A1. Both CYP2R1 and CYP27B1 are responsible for bioactivation of vitamin D, while the CYP24A1 is responsible for the catabolism of vitamin D (Fig. ...

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... and is located in the mitochondria (Jones G, Prosser, & Kaufmann, 2014). CYP24A1 has been established as the key enzyme responsible for vitamin D catabolism. Though it was initially thought to catalyze the 24-hydroxylation of both 25(OH)D3 and 1α,25(OH) 2 D3, it is now shown to catalyze also the hydroxylation reaction at Carbon 23 ( Fig. 2) (Knutson & DeLuca, 1974;Prosser & Jones, 2004). Additionally, CYP24A1 catalyzes the hydroxylation of vitamin D2 to produce polyhydroxylated products (Masuda, Strugnell, Knutson, St-Arnaud, & Jones, 2006). CYP24A1 controls the amount of active vitamin D by reducing the amount of 1α,25(OH) 2 D when there is an elevated level in the ...

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... there was a tendency for a decrease in the VDR expression in three patients, the effect did not reach statistical significance (II, Fig. 1D). Moreover, we did not observe any effect of the weight loss on any of the known VDR target genes in the adipose tissue, such as PPARG, acetyl-CoA carboxylase alpha (ACACA) and uncoupling protein (UCP) 1 and UCP2, (Matthews, D'Angelo, Drelich, & Welsh, 2016;Saini, Zhao, Petit, Gori, & Demay, 2017) (II, Supplemental Fig. 2). ...

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... agreement with our hypothesis, Cyp2r1 was downregulated by PGC-1α overexpression strongly and dose-dependently in mouse primary hepatocytes (I, Fig. 2A). In fact, PGC-1α is a transcriptional coactivator and does not possess the ability to bind to DNA directly. Instead, PGC-1α must co-activate other nuclear receptors and transcription factors. Therefore, to explore the mechanism in more detail, we have transduced two PGC-1α mutants, i.e., PGC-1α-2X9 and PGC-1α-L2L3, into mouse ...

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... i.e., PGC-1α-2X9 and PGC-1α-L2L3, into mouse hepatocytes. The PGC-1α-2X9 mutant could activate specific nuclear receptors, namely HNF-4α and ERRα only, while the PGC-1α-L2L3 mutant cannot bind or activate any nuclear receptor ( Gaillard et al., 2006). Overexpression of PGC-1α-2X9 significantly repressed Cyp2r1, similar to the wildtype PGC-1α (I, Fig. 2B). On the other hand, PGC-1α-L2L3 did not affect Cyp2r1 and even caused a modest induction (I, Fig. ...

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... nuclear receptors, namely HNF-4α and ERRα only, while the PGC-1α-L2L3 mutant cannot bind or activate any nuclear receptor ( Gaillard et al., 2006). Overexpression of PGC-1α-2X9 significantly repressed Cyp2r1, similar to the wildtype PGC-1α (I, Fig. 2B). On the other hand, PGC-1α-L2L3 did not affect Cyp2r1 and even caused a modest induction (I, Fig. ...

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... in the regulation of Cyp2r1, we used several approaches. We either knocked down the Errα mRNA by shRNA-Ad or inhibited the ERRα protein using the ERRα inverse agonist XCT790 combined with PGC-1α induction. In either case, abolishing the ERRα effect could abolish the repressive effect of PGC-1α induction on Cyp2r1 in mouse hepatocytes (I, Fig. 2C, ...

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... verify the role of PGC-1α in vivo, we utilized Pgc-1α knockout (KO) mice and wild-type littermates fed, or 12 h fasted. As expected, in the wildtype mice, 72 fasting significantly repressed Cyp2r1 in the liver, but surprisingly, the Pgc-1α KO did not abolish the suppressive effect of fasting on Cyp2r1 (I, Fig. 2F). ...

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... next considered that the chronic loss of Pgc-1α might be compensated by Pgc-1β, the close homolog to Pgc-1α, and the second member in the PGC-1 coactivators family ( Lai et al., 2008). Supporting this idea, Pgc-1β is induced by fasting, and it was more induced in the livers of Pgc-1α KO mice (Lai et al., 2008) (I, Fig. 2G). In general, PGC-1α and PGC-1β are thought to regulate different pathways, but recent reports demonstrated some functional overlap (Lai et al., 2008). Thus, we hypothesize that PGC-1β could compensate for the chronic loss of Pgc-1α, or it could even play an independent role in the repression of Cyp2r1. To test this hypothesis, we ...

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... Pgc-1α, or it could even play an independent role in the repression of Cyp2r1. To test this hypothesis, we utilized mice with liver-specific Pgc-1β knockout and wildtype littermates fed or 24 h fasted. Fasting again suppressed the Cyp2r1 in the livers of wild-type mice; however, the Pgc-1β KO in the liver did not abolish the effect of fasting (I, Fig. ...