| Title : Macrophage CGI-58 deficiency promotes IL-1beta transcription by activating the SOCS3-FOXO1 pathway - Miao_2015_Clin.Sci.(Lond)_128_493 |
| Author(s) : Miao H , Ou J , Zhang X , Chen Y , Xue B , Shi H , Gan L , Yu L , Liang H |
| Ref : Clinical Science (Lond) , 128 :493 , 2015 |
| Abstract : Over-nutrition induces low-grade inflammation that dampens insulin sensitivity, but the underlying molecular mediators are not fully understood. Comparative gene identification-58 (CGI-58) is an intracellular lipolytic activator. In the present study, we show that in mouse visceral fat-derived macrophages or human peripheral blood monocytes, CGI-58 negatively and interleukin (IL)-1beta positively correlate with obesity. Saturated non-esterified fatty acid (NEFA) suppresses CGI-58 expression in macrophages and this suppression activates FOXO1 (forkhead box-containing protein O subfamily-1) through inhibition of FOXO1 phosphorylation. Activated FOXO1 binds to an insulin-responsive element in IL-1beta promoter region to potentiate IL-1beta transcription. Gain- and loss-of-function studies demonstrate that NEFA-induced CGI-58 suppression activates FOXO1 to augment IL-1beta transcription by dampening insulin signalling through induction of SOCS3 (suppressor of cytokine signalling 3) expression. CGI-58 deficiency-induced SOCS3 expression is NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome-dependent. Our data thus identified a vicious cycle (IL-1beta-SOCS3-FOXO1-IL-1beta) that amplifies IL-1beta secretion and is initiated by CGI-58 deficiency-induced activation of the NLRP3 inflammasome in macrophages. We further show that blocking this cycle with a FOXO1 inhibitor, an antioxidant that inhibits FOXO1 or IL-1 receptor antagonist alleviates chronic inflammation and insulin resistance in high-fat diet (HFD)-fed mice. Collectively, our data suggest that obesity-associated factors such as NEFA and lipopolysaccharide (LPS) probably adopt this vicious cycle to promote inflammation and insulin resistance. |
| ESTHER : Miao_2015_Clin.Sci.(Lond)_128_493 |
| PubMedSearch : Miao_2015_Clin.Sci.(Lond)_128_493 |
| PubMedID: 25431838 |
Miao H, Ou J, Zhang X, Chen Y, Xue B, Shi H, Gan L, Yu L, Liang H (2015)
Macrophage CGI-58 deficiency promotes IL-1beta transcription by activating the SOCS3-FOXO1 pathway
Clinical Science (Lond)
128 :493
Miao H, Ou J, Zhang X, Chen Y, Xue B, Shi H, Gan L, Yu L, Liang H (2015)
Clinical Science (Lond)
128 :493