Vitamin D(3) Metabolic Enzymes in Plateau Zokor (Myospalax baileyi) and Plateau Pika (Ochotona curzoniae): Expression and Response to Hypoxia

SIMPLE SUMMARY: Vitamin D(3) is mainly synthesized in the skin after exposure to sunlight and plays a fundamental role in the absorption of calcium and phosphate. Lithocholic acid increases intestinal calcium absorption in vitamin D-deficient rats. The plateau zokor, which lives underground throughout its life, and plateau pika are unique animal species on the Qinghai-Tibet Plateau. To investigate how animals that are rarely exposed to sunlight deal with the expected deficit in vitamin D(3) levels and the effect of hypoxia on vitamin D(3) metabolism, the levels of key biomarkers related to vitamin D(3) metabolism, and the mRNA and protein levels of enzymes involved in key pathways were measured. Plateau zokor was deficient in vitamin D(3) and has a higher level of lithocholic acid, but its calcium levels were within the normal range. The levels of vitamin D(3) and the expression levels of vitamin D(3) metabolism-related genes CYP2R1 and CYP27B1 decreased with increasing altitude in plateau pika. Plateau zokor was deficient in vitamin D(3), and lithocholic acid appears to substitute it. In addition, hypoxia suppresses vitamin D(3) in plateau pika by down-regulating the expression of vitamin D(3) metabolism-related genes. ABSTRACT: Vitamin D(3) (D(3)) is produced endogenously from 7-dehydrocholesterol by irradiation and is an important secosteroid for the absorption of calcium and phosphate. Lithocholic acid (LCA) increases intestinal paracellular calcium absorption in a vitamin D receptor-dependent manner in vitamin D-deficient rats. The plateau zokor (Myospalax baileyi), a strictly subterranean species, and plateau pika are endemic to the Qinghai-Tibet Plateau. To verify whether the zokors were deficient in D(3) and reveal the effects of hypoxia on D(3) metabolism in the zokors and pikas, we measured the levels of 25(OH)D(3), calcium, and LCA, and quantified the expression levels of D(3) metabolism-related genes. The results showed an undetectable serum level of 25(OH)D(3) and a significantly higher concentration of LCA in the serum of plateau zokor, but its calcium concentration was within the normal range compared with that of plateau pika and Sprague-Dawley rats. With increasing altitude, the serum 25(OH)D(3) levels in plateau pika decreased significantly, and the mRNA and protein levels of CYP2R1 (in the liver) and CYP27B1 (in the kidney) in plateau pika decreased significantly. Our results indicate that plateau zokors were deficient in D(3) and abundant in LCA, which might be a substitution of D(3) in the zokor. Furthermore, hypoxia suppresses the metabolism of D(3) by down-regulating the expression of CYP2R1 and CYP27B1 in plateau pika.