Recent studies have suggested that vitamin D activities involve vitamin D receptor (VDR)-dependent and VDR-independent effects of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3) and 25-hydroxyvitamin D 3 (25(OH)D 3) and ligand-independent effects of the VDR. Here, we describe a novel in vivo system using genetically modified rats deficient in the Cyp27b1 or Vdr genes. Type II rickets model rats with a mutant Vdr (R270L), which recognizes 1,25(OH) 2 D 3 with an affinity equivalent to that for 25(OH)D 3 , were also generated. Although Cyp27b1-knockout (KO), Vdr-Ko, and Vdr (R270L) rats each showed rickets symptoms, including abnormal bone formation, they were significantly different from each other. Administration of 25(OH)D 3 reversed rickets symptoms in Cyp27b1-KO and Vdr (R270L) rats. Interestingly, 1,25(OH) 2 D 3 was synthesized in Cyp27b1-KO rats, probably by Cyp27a1. In contrast, the effects of 25(OH)D 3 on Vdr (R270L) rats strongly suggested a direct action of 25(OH)D 3 via VDR-genomic pathways. These results convincingly suggest the usefulness of our in vivo system. The active form of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3), plays important roles in osteogenesis, calcium homeostasis, cellular differentiation, and immune responses 1. 1,25(OH) 2 D 3 is generated by two hydroxylation steps from vitamin D 3 : C-25 hydroxylation by hepatic CYP2R1 and CYP27A1 and subsequent 1α-hydroxylation by renal 1α-hydroxylase (CYP27B1) 2. The vitamin D receptor (VDR) mediates the genomic action of active vitamin D 3. Binding of active vitamin D 3 to the VDR triggers its heterodimerization to the retinoid X receptor and subsequent translocation to the nucleus. This translocation results in regulating target gene expression by formation of the VDR complex on vitamin D-responsive elements in the promoter regions of target genes, such as osteocalcin and osteopontin in bones and the calcium channels and calbindins in intestines 3. CYP24A1, one of the well-known vitamin D target genes, is involved in inactivating 1,25(OH) 2 D 3 through sequential metabolism that starts with C-24 or C-23 hydroxylation of 1,25(OH) 2 D 3 4. A variety of vitamin D derivatives have been developed as drugs for rickets, osteoporosis, psoriasis, secondary hyperparathyroidism, and chronic kidney disease. Because all of these compounds show high affinity for the VDR, these pharmacological actions are considered to be VDR mediated. However, as with 1,25(OH) 2 D 3 , they might also have non-VDR-mediated actions. Thus, pharmacological action studies of vitamin D derivatives are essential for future drug discovery.

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Quercetin glycosides in the diet are absorbed and converted to glucuronides, sulfates, or mixed conjugates of glucuronide and sulfate in plasma. Physiological effects of quercetin conjugates (Q-conjugates) differ depending on the type and position of conjugation. We developed a comprehensive analysis of Q-conjugates, including mixed conjugates, by LC/MS/MS. The whole species of Q-conjugates in tail blood plasma was measured on days 1, 3, and 12 in rats fed a 0.24% quercetin glucoside-containing diet. Twenty-three Q-conjugate molecules were detected, and 16 Q-conjugates among these were quantified using standard compounds. The most abundant metabolite in the plasma was mixed conjugates, comprising isorhamnetin-7-O-glucuronide-4′-O-sulfate, followed by quercetin-7-O-glucuronide-4′-O-sulfate; together, they accounted for 86% of total Q-conjugates on day 12. The profile of quercetin conjugate species did not significantly change during 12 days. The total Q-conjugate molecules quantified by our method was comparable with the total Q-conjugates quantified using an enzymatic deconjugation method.

Scope: Isoliquiritigenin (ILG) has been reported to attenuate adipose tissue inflammation and metabolic disorder; however, the underlying mechanisms remain to be elucidated. The aim of this study is to elucidate whether ILG shows the anti-inflammatory and antimetabolic syndrome effects through gut microbiota modification. Methods and results: Mice are fed a high-fat diet (HFD) with or without ILG for up to 12 weeks. The effect of ILG on body weight, blood glucose level, adipose tissue inflammation, gut barrier function, and gut microbiota composition are investigated. ILG supplementation alleviates HFD-induced obesity, glucose tolerance, and insulin resistance and suppresses inflammatory gene expression in epididymal white adipose tissue (eWAT). Moreover, ILG supplementation modifies gut bacterial composition by increasing the abundance of antimetabolic disease-associated species (e.g., Parabacteroides goldsteinii and Akkemansia muciniphila) and up-regulated genes associated with gut barrier function. Fecal microbiome transplantation (FMT) from ILG-fed donors counteract HFD-induced body and eWAT weight changes, inflammation-related gene expression, glucose tolerance, and insulin resistance, thereby suggesting that ILG-responsive gut bacteria exerts anti-inflammatory and antimetabolic syndrome effects. Conclusion: Alterations in gut bacteria underly the beneficial effects of ILG against adipose tissue inflammation and metabolic disorders. ILG may be a promising prebiotic for the prevention and treatment of metabolic syndrome.