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Title 

ANGPTL6 expression is coupled with mitochondrial OXPHOS function to regulate adipose FGF21

Authors 

S G KangH S YiM J ChoiM J RyuS JungH K ChungJ Y ChangY K KimS E LeeH W KimH ChoiD S KimJ H LeeK S KimH J KimChul Ho LeeY OikeM Shong

Publisher 

BioScientifica

Issue Date 

2017

Citation 

Journal of Endocrinology

Keywords 

Angptl6Crif1MitochondriaOxidative phosphorylation

Abstract 

Recent studies revealed that the inhibition of mitochondrial oxidative phosphorylation (OXPHOS) is coupled with the mitochondrial unfolded protein response, thereby stimulating the secretion of non-cell autonomous factors, which may control systemic energy metabolism and longevity. However, the nature and roles of noncell autonomous factors induced in adipose tissue in response to reduced OXPHOS function remain to be clarified in mammals. CR6-interacting factor 1 (CRIF1) is an essential mitoribosomal protein for the intramitochondrial production of mtDNAencoded OXPHOS subunits. Deficiency of CRIF1 impairs the proper formation of the OXPHOS complex, resulting in reduced function. To determine which secretory factors are induced in response to reduced mitochondrial OXPHOS function, we analyzed gene expression datasets in Crif1-depleted mouse embryonic fibroblasts. Crif1 deficiency preferentially increased the expression of angiopoietin-like 6 (Angptl6) and did not affect other members of the ANGPTL family. Moreover, treatment with mitochondrial OXPHOS inhibitors increased the expression of Angptl6 in cultured adipocytes. To confirm Angptl6 induction in vivo, we generated a murine model of reduced mitochondrial OXPHOS function using adipose tissue-specific Crif1-deficient mice and verified the upregulation of Angptl6 and fibroblast growth factor 21 (Fgf21) in white adipose tissue. Treatment with recombinant ANGPTL6 protein increased oxygen consumption and Pparα expression through the extracellular signal-regulated kinase/ mitogen-activated protein kinase pathway in cultured adipocytes. Furthermore, the ANGPTL6-mediated increase in Pparα expression resulted in increased FGF21 expression, thereby promoting β-oxidation. In conclusion, mitochondrial OXPHOS function governs the expression of ANGPTL6, which is an essential factor for FGF21 production in adipose tissue and cultured adipocytes.

ISSN 

0022-0795

Link 

http://dx.doi.org/10.1530/JOE-16-0549

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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