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.
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.
Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
Tasuku
T
Nishino
Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
Ryota
R
Matsunaga
Department of Health Science, Prefectural University of Hiroshima, Hiroshima 734-8558, Japan.
Hiroshi
H
Jikihara
Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
Moe
M
Uchida
Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
Akane
A
Maeda
Department of Health Science, Prefectural University of Hiroshima, Hiroshima 734-8558, Japan.
Guangying
G
Qi
Genetic Engineering Team, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima Minami-machi,Chuou-ku, Kobe 650-0047, Japan.
Takaya
T
Abe
Animal Resource Development Unit, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan; Genetic Engineering Team, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima Minami-machi,Chuou-ku, Kobe 650-0047, Japan.
Hiroshi
H
Kiyonari
Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Satoshi
S
Tashiro
Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
Kyoko
K
Inagaki-Ohara
Department of Health Science, Prefectural University of Hiroshima, Hiroshima 734-8558, Japan.
Fumio
F
Shimamoto
Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan. Electronic address: hkonishi@pu-hiroshima.ac.jp.
Hiroaki
H
Konishi
D020413:3' Untranslated Regions / Q000235:genetics; D063307:AU Rich Elements / Q000235:genetics*; D000375:Aging / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D051959:ELAV Proteins / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D058635:Lipid-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D055442:Metabolome; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D051959:ELAV Proteins; D020738:Leptin; D058635:Lipid-Linked Proteins; D012333:RNA, Messenger; D051876:Sex-Determining Region Y Protein; C497746:Sry protein, mouse
Cardiolipin; Knockout mouse; Mitochondria; Obesity; RNA granule; mRNA stability