Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2
Bin Liu,Liping Xiang,Jing Ji,Wei Liu,Ying Chen,Mingfeng Xia,Yuejun Liu,Wen-Yue Liu,Peiwu Zhu,Yi Jin,Yu Han,Jieli Lu,Xiaoying Li,Ming-Hua Zheng,Yan Lu +14 more
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TLDR
In this article, the authors identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice, and showed that both chronic injection and overexpression of SPARcl1 exaggerated hepatic inflammation and liver injury in mice.Abstract:
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of chronic liver disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms of NASH progression remain incompletely understood. White adipose tissue (WAT) has emerged as an important endocrine organ and contributes not only to the initial stage of NAFLD, but also to its severity. In the current study, through transcriptomic analysis we identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice. Plasma Sparcl1 levels were similarly elevated and positively correlated with hepatic pathological features in NASH patients. Functional studies showed that both chronic injection of recombinant Sparcl1 protein and overexpression of Sparcl1 exaggerated hepatic inflammation and liver injury in mice. In contrast, genetic ablation of Sparcl1, knockdown of Sparcl1 in WAT, and treatment with a Sparcl1-neutralizing antibody dramatically alleviated diet-induced NASH pathogenesis. Mechanistically, Sparcl1 promoted the expression of C-C motif chemokine ligand 2 (CCL2) in hepatocytes through binding to Toll-like receptor 4 (TLR4) and activation of the NF-κB/p65 signaling pathway. Genetically or pharmacologically blocking the CCL2/CCR2 pathway attenuated the hepatic inflammatory response evoked by Sparcl1. Thus, our results demonstrated an important role for Sparcl1 in NASH progression, suggesting a potential target for therapeutic intervention.read more
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Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation
TL;DR: An updated understanding of organokines and their role in AT inflammation and related metabolic abnormalities is provided to highlight the molecular mechanisms underlying the effects of these organokine effects and their clinical significance.
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M2 macrophage-derived exosomal microRNA-411-5p impedes the activation of hepatic stellate cells by targeting CAMSAP1 in NASH model
TL;DR: Younossi et al. as discussed by the authors found that exosomal miR-411-5p from M2 macrophages significantly inhibit hepatic stellate cells (HSCs) activation.
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Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis
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Targeting adipose tissue to tackle NASH: SPARCL1 as an emerging player.
TL;DR: Liu et al. as discussed by the authors demonstrate that secreted protein acidic and rich in cysteine-like protein 1 (SPARCL1) was highly upregulated in adipose tissue and played a role in exacerbating NASH progression in a mouse model of NASH.
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Hepatocellular cystathionine γ lyase/hydrogen sulfide attenuates nonalcoholic fatty liver disease by activating farnesoid X receptor
Wenjing Xu,Changting Cui,Chunmei Cui,Zhenzhen Chen,Haizeng Zhang,Qinghua Cui,Guoheng Xu,Ji-Mim Fan,Yu Han,Liangjie Tang,Giovanni Targher,Christopher D. Byrne,Ming-Hua Zheng,Liming Yang,Jun Cai,Bin Geng +15 more
TL;DR: FXR-sulfhydration is a novel post-translational modification affected by hepatic endogenous CSE/H2 S that may promote FXR activity and attenuate NAFLD.
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