Rdh10 and retinoic acid effects on differentiation

Rdh10 和视黄酸对分化的影响

• 批准号: 10217113
• 负责人: JOSEPH L NAPOLI
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217113
• 关键词: 11 cis Retinal; Ablation; Address; Adipocytes; Adult; All-Trans-Retinol; Anabolism; Animals; Astrocytes; Attenuated; BMP2 gene; Biogenesis; Body mass index; Bone Marrow; Cell Line; Cell Nucleus; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Conflict (Psychology); Dendritic Cells; Diet; Embryo; Embryonic Development; Enzymes; Equilibrium; Event; FOXO1A gene; Fat-Restricted Diet; Female; Fibroblasts; Gene Abnormality; Gene Expression; Genes; Health; Heterozygote; High Fat Diet; Homeostasis; Homozygote; Hormones; Human; Insulin; Knock-out; Life; Literature; Maps; Mesenchymal; Mesenchymal Stem Cells; Messenger RNA; Metabolic; Modeling; Mus; Nuclear; Obesity; Osteoblasts; Osteoporosis; Outcome; Pathology; Pharmacologic Actions; Phenotype; Physiological; Reaction; Reaction Time; Regulation; Reporting; Research; Retina; Retinal dehydrogenase; Retinoids; Retinol dehydrogenase; Role; Skin; Stimulus; Testing; Testis; Time; Tretinoin; Vitamin A; Weight Gain; Work; adipocyte differentiation; age related; aged; bone; bone health; calcification; energy balance; established cell line; expectation; health application; in vivo; in vivo Model; innovation; insight; lipid biosynthesis; lipid metabolism; male; osteoblast differentiation; postnatal; programs; stem cell differentiation; stem cell fate; stem cells; trait; visual cycle

Retinol dehydrogenase 10 (Rdh10) catalyzes the first and rate-limiting step in all-trans-retinoic acid (atRA) biosynthesis from retinol by generating retinal, which retinal dehydrogenases convert into atRA. Most Rdh10 research has focused on the visual cycle or embryonic development. Limited work has been done on postnatal Rdh10 function. Yet, atRA controls the fate of mesenchymal stem cell (MSC) differentiation into adipocytes vs osteoblasts in the adult to regulate adiposity and bone health. Mechanisms of atRA action in directing MSC differentiation remain unclear as does regulation of atRA biosynthesis. The literature contains conflicting reports as to the primary target genes regulated by atRA and other differentiation stimuli. Most studies of atRA regulation of the balance between adipocytes vs osteoblasts has been done in cell lines, and has focused on single genes controlling in one stem cell fate, often later during differentiation. The use of cell lines (e.g. 3T3- L1, F442A, C2C12, MC3T3-E1) most likely has contributed to the conflicting conclusions, because cell lines do not faithfully model primary cells, differ from each other, and even cell lines with the same nominal designation often differ as a result of long-term culture. This proposal addresses atRA function in directing MSC fate by proposing study of an in vivo model of atRA insufficiency, which will be accompanied by generating primary mouse embryonic fibroblasts to produce comprehensive mechanistic insight into determining adipocyte vs. osteoblast cell fates. The in vivo model relies on heterozygote ablated Rdh10 (Rdh10+/-) that has a phenotype of increased adiposity and adipocyte proliferation in bone marrow early in life, with decreased calcification of osteoblasts. The Rdh10+/- model (the homozygote is embryonic lethal) provides for consistently attenuated vitamin A function in vivo through reproducibly reduced atRA. This is an innovative model that will provide new insight into atRA function concerning regulating differentiation of adipocytes vs osteoblasts, and new insight into Rdh10 function and atRA biogenesis. Understanding the roles of Rdh10 and atRA in obesity and adipogenesis promises direct human health applications. This expectation is supported by the twenty-six intergenic traits related to body mass index and weight gain that map close to human Rdh10. Aim 1 will determine the phenotype and metabolic consequences of reducing Rdh10 expression and atRA concentrations in vivo (Rdh10+/- mice), focusing on adipocyte and osteoblast differentiation. This aim will test the hypothesis that Rdh10 is a major enzyme that controls atRA homeostasis to regulate retinoid function in adipocyte and osteoblast differentiation. Aim 2 will determine mechanism(s) that underlie the phenotype of Rdh10+/- mice with respect to cell fate determination. This aim will use two sets of MEF: 1) from Rdh10+/- mice; 2) immortalized MEF with a total knockout of Rdh10 to test the hypothesis that atRA generated by Rdh10 directs maturation of MSC by regulating gene expression very early in cell fate determination, and will identify the responsive genes.

视黄醇脱氢酶10 （Rdh10）催化全反式维甲酸（atRA）的第一步和限速步骤。

项目成果

Energy status regulates levels of the RAR/RXR ligand 9-cis-retinoic acid in mammalian tissues: Glucose reduces its synthesis in β-cells.

• DOI: 10.1016/j.jbc.2023.105255
• 发表时间: 2023-10
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Yoo, Hong Sik;Moss, Kristin Obrochta;Cockrum, Michael A.;Woo, Wonsik;Napoli, Joseph L.
• 通讯作者: Napoli, Joseph L.

Examination of Fluconazole-Induced Alopecia in an Animal Model and Human Cohort.

在动物模型和人类队列中检查氟康唑引起的脱发。

• DOI: 10.1128/aac.01384-18
• 发表时间: 2019
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Thompson3rd,GeorgeR;Krois,CharlesR;Affolter,VerenaK;Everett,AngelaD;Varjonen,EKatarina;Sharon,VictoriaR;Singapuri,Anil;Dennis,Michael;McHardy,Ian;Yoo,HongSik;Fedor,DawnM;Wiederhold,NathanP;Aaron,PhyliciaA;Gelli,Angie

Cyp26a1 supports postnatal retinoic acid homeostasis and glucoregulatory control.

• DOI: 10.1016/j.jbc.2023.104669
• 发表时间: 2023-05
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Yoo, Hong Sik;Cockrum, Michael A.;Napoli, Joseph L.
• 通讯作者: Napoli, Joseph L.

Post-natal all-trans-retinoic acid biosynthesis.

• DOI: 10.1016/bs.mie.2020.02.003
• 发表时间: 2020
• 期刊: Methods in enzymology
• 作者: J. L. Napoli

The glucocorticoid receptor represses, whereas C/EBPβ can enhance or repress CYP26A1 transcription.

• DOI: 10.1016/j.isci.2022.104564
• 发表时间: 2022-07-15
• 期刊: iScience
• 影响因子: 5.8
• 作者: Yoo HS;Rodriguez A;You D;Lee RA;Cockrum MA;Grimes JA;Wang JC;Kang S;Napoli JL
• 通讯作者: Napoli JL