21st Century COE Program Human Nutritional Science on Stress Control
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Dr. Miyamoto's Labo
Prof. Ken-ichi Miyamoto
Department of Molecular Nutrition
Molecular Nutrition, Graduate School of Nutrtion and Bioscience, The University of Tokushima

Ken-ichi Miyamoto, Sawako Tatsumi

Dr. Miyamoto's Labo
Aging is a complex biological process driven by a selective class of molecules and pathways that affect overall deterioration of physiological functions to increase the risk-related diseases.
Klotho was first described as an aging gene and was later shown to be regulator of phosphate and vitamin D metabolism. Klotho can extend life span when overexpression in the mouse, and Klotho mutant mice (reduction of klotho protein) show short life span, osteoporosis and ectopic calcification. A major breakthrough in klotho biology has been achieved by the demonstration of strikingly similar physical and biochemical phenotypes of FGF23 knockout and klotho hypomorph mice which led to the identification of klotho as a cofactor in FGF23 and its receptor interactions. In addition, klotho significantly enhances the ability of FGF23 to induce phosphorylation of an FGF receptor substrate and ERK in various cell types, suggesting that klotho acts as a cofactor that is essential for activation FGF23-mediated signaling. We are especially interested in identification the mediators of klotho/FGF23 signaling and aging. We generated several knockout mice and analyzed their role in vivo.
Dietary stress and aging
An intervention that can delay ageing in many animal models is calorie or food restriction. Food restriction without malnutrition prolongs the lifespan of animal species from single-cell organisms to mammals. In addition to promoting longevity, food restriction delays or prevents age-related diseases such as diabetes, cardiovascular disease, cancer and renal failure, increases the stress resistance of organs such as the heart and brain, and prolongs the period of healthy functioning. Life-long CR protect age-related bone loss and microstructural deterioration on mouse and rat (1). Calorie Restriction (CR) is the first and most compelling example of life extension in mammals. Sirt2 (silent information regulator 2) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is required for longevity due to calorie restriction in the budding yeast and in the fruit fly. We demonstrated that the Sir2 homologue, SIRT1 regulates the gluconeogenic/glycolytic pathways in liver in response dietary Pi restriction. In addition, Pi restriction causes many changes in mineral metabolism and extends lifespan in the fly and rodents. We are studying how this metabolism is connected to the aging.
CR(moderate dietary stress)projects against age-related bone loss in F344 rats
Pi homeostasis and FGF23/klotho signal
The klotho gene encodes a cell-surface protein with a short cytoplasmic tail whose extracellular domain consists of tandem duplicated copies of a glucosidase-like sequence, which can be released as a soluble form of Klotho. It was subsequently found that klotho mutant mice had markedly increased levels of calcium, phosphate, and the active metabolite of vitamin D, 1,25-dihydroxyvitamin D. These animals die prematurely because their kidneys and other tissues become calcified. This, and the somatic features of the klotho phenotype, was reminiscent of mice lacking the FGF23 gene, which led to the observation that serum levels of FGF23 were markedly elevated in klotho mutant mice, thus establishing that klotho is genetically downstream of FGF23 (2). Further experiments showed that binding to Klotho converts FGF receptors from low-affinity to high-affinity FGF23 receptors now report that klotho is also a regulator of calcium homeostasis on its own. The pathway by which klotho regulates phosphate and vitamin D metabolism thus intersects with the newly discovered FGF23 pathway (3). FGF23 is a secreted phosphatonin, a factor that induces renal phosphate wasting and inhibits synthesis of 1,25-dihydroxyvitamin D. FGF23 causes renal phosphate wasting in both inherited and acquired forms of hypophosphatemic rickets. The predominant source of FGF23 is osteocytes and osteoblasts in bone, where its secretion is repressed by dentin matrix protein 1 (DMP1) (4). Our research focuses on the regulation of FGF23/klotho signaling and Pi homeostasis.
Pi transporter knockout mice
Abnormalities of the inorganic phosphate (Pi) reabsorption in the kidney result in various metabolic disorders. Na+-dependent Pi (Na/Pi) transporters in the brush border membrane of proximal tubular cells mediate the rate-limiting step in the overall Pi-reabsorptive process. Type IIa and type IIc Na/Pi cotransporters are expressed in the apical membrane of proximal tubular cells and mediate Na/Pi cotransport; the extent of Pi reabsorption in the proximal tubules is determined largely by the abundance of the type IIa Na/Pi cotransporter. However, several studies suggest that the type IIc cotransporter in Pi reabsorption may also play a role in this process. For example, mutation of the type IIc Na/Pi cotransporter gene results in hereditary hypophosphatemic rickets with hypercalciuria, suggesting that the type IIc transporter plays an important role in renal Pi reabsorption in humans and may be a key determinant of the plasma Pi concentration (5). The type IIc Na/Pi transporter is regulated by parathyroid hormone, dietary Pi, and fibroblast growth factor 23, and studies suggest a differential regulation of the IIa and IIc transporters (5). Indeed, differences in temporal and/or spatial expression of the type IIa and type IIc Na/Pi transporters may be required for normal phosphate homeostasis and bone development. Several human disorders are associated with renal Pi wasting. The best characterized include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We aim at addressing the molecular basis underlying HHRH.
References
  1. Tatsumi S et al. Life-long caloric restriction reveals biphasic and dimorphic effects on bone metabolism in rodents Endocrinology. (2007) In press
  2. Segawa H et al. Correlation between hyperphosphatemia and type II NaPi cotransporter activity in klotho mice. Am J Physiol Renal Physiol 292:F769-F779,2007
  3. Saito H et al. Circulating FGF-23 is regulated by 1 alfa 25-dihydroxyvitamin D3 and phosphours in vivo. J Biol Chem 280:2543-2549, 2005
  4. Tatsumi S et al. Targeted Ablation of Osteocytes Induces Osteoporosis with Defective Mechanotransduction Cell Metabolism. 5, 464475 (2007)
  5. Miyamoto K et al. New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphatetransporter.

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