Antagonizing effect of CLPABP on the function of HuR as a regulator of ARE-containing leptin mRNA stability and the effect of its depletion on obesity in old male mouse
| Autor: | Ryota Matsunaga, Hiroaki Konishi, Hiroshi Kiyonari, Fumio Shimamoto, Hiroshi Jikihara, Tasuku Nishino, Satoshi Tashiro, Guangying Qi, Takaya Abe, Moe Uchida, Kyoko Inagaki-Ohara, Akane Maeda |
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| Rok vydání: | 2016 |
| Předmět: |
Leptin
Male 0301 basic medicine Aging medicine.medical_specialty Transcription Genetic RNA Stability Adipose tissue Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Stress granule Downregulation and upregulation Internal medicine Chlorocebus aethiops Gene expression medicine Cardiolipin Animals Obesity RNA Messenger RNA Processing Post-Transcriptional 3' Untranslated Regions Molecular Biology Lipid-Linked Proteins AU Rich Elements Mice Knockout Messenger RNA Base Sequence Cell Biology Sex-Determining Region Y Protein 030104 developmental biology Endocrinology ELAV Proteins Gene Expression Regulation chemistry COS Cells Knockout mouse Metabolome Gene Deletion 030217 neurology & neurosurgery Subcellular Fractions |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1861:1816-1827 |
| ISSN: | 1388-1981 |
| Popis: | Cardiolipin and phosphatidic acid-binding protein (CLPABP) is a pleckstrin homology domain-containing protein and is localized on the surface of mitochondria of cultured cells as a large protein–RNA complex. To analyze the physiological functions of CLPABP, we established and characterized a CLPABP knockout (KO) mouse. Although expression levels of CLPABP transcripts in the developmental organs were high, CLPABP KO mice were normal at birth and grew normally when young. However, old male mice presented a fatty phenotype, similar to that seen in metabolic syndrome, in parallel with elevated male- and age-dependent CLPABP gene expression. One of the reasons for this obesity in CLPABP KO mice is dependence on increases in leptin concentration in plasma. The leptin transcripts were also upregulated in the adipose tissue of KO mice compared with wild-type (WT) mice. To understand the difference in levels of the transcriptional product, we focused on the effect of CLPABP on the stability of mRNA involving an AU-rich element (ARE) in its 3′UTR dependence on the RNA stabilizer, human antigen R (HuR), which is one of the CLPABP-binding proteins. Increase in stability of ARE-containing mRNAs of leptin by HuR was antagonized by the expression of CLPABP in cultured cells. Depletion of CLPABP disturbed the normal subcellular localization of HuR to stress granules, and overexpression of CLPABP induced instability of leptin mRNA by inhibiting HuR function. Consequently, leptin levels in old male mice might be regulated by CLPABP expression, which might lead to body weight control. |
| Databáze: | OpenAIRE |
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