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Role of visfatin in pathogenesis and progression of non-alcoholic fatty liver disease
- Author(s)
- 허유정
- Alternative Author(s)
- Yu Jung Heo
- Advisor
- 김혜진
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2021-02
- Language
- eng
- Keyword
- NAFLD; fibrosis; inflammation; insulin resistance; visfatin
- Alternative Abstract
- Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease affecting people worldwide. It includes a complex array of diseases ranging from simple steatosis to non-alcoholic steatohepatitis and cirrhosis. Insulin resistance and inflammation are primarily associated with the pathogenesis of NAFLD. Visfatin, an adipocytokine, was reported to induce pro-inflammatory cytokines and can be associated with liver fibrosis. This study aimed to investigate the role and related mechanism of action of visfatin in the progression of NAFLD. The objectives of the present study included the determination of the effect of visfatin on: i) insulin resistance and inflammation in hepatocytes; ii) chemokine secretion in macrophages and the activation of hepatic stellate cells (HSCs); and iii) hepatic inflammation and fibrosis in a methionine-choline-deficient (MCD)-diet-induced mouse model of NAFLD. Visfatin significantly decreased the level of phosphorylation in proteins involved in insulin signaling (IR, IRS-1, GSK, and AKT), increased IRS-1 S307 phosphorylation, and enhanced the level of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in HepG2 cells compared to that of the untreated cells. Interestingly, visfatin led to the activation of the JAK2/STAT3 and IKK/NF-κB but not the JNK, p38, and ERK signaling pathways. NF-κB and STAT3 inhibitor-mediated blockage of signaling pathways significantly decreased the level of pro-inflammatory cytokines leading to the rescue of insulin signaling. Thus, visfatin induced the secretion of pro-inflammatory cytokines and inhibited insulin signaling via the STAT3 and NF-κB pathways in HepG2 cells. Further, in THP-1 cells, a pro-monocytic cell line, visfatin enhanced the expression of both, the mRNA and protein levels of chemokine (C-C motif) ligand 20 (CCL20), an important inflammatory mediator, through the activation of the NF-κB, p38, and MKK3/6 signaling pathway. Co-treatment of cells with visfatin and inhibitors of NF-κB, p38, or MLK3, significantly inhibited the expression of visfatin-induced CCL20. Subsequently, co-culturing of LX-2 cells (human HSCs) with THP-1 cell culture supernatant in the presence or absence of anti-CCL20 neutralizing antibodies resulted in reduced expression of fibrosis markers in LX-2 cells in the presence of anti-CCL20 neutralizing antibodies. Thus, visfatin increased the expression of CCL20 through the NF-κB, p38, and MKK3/6 signaling pathway in macrophages. In addition, visfatin-induced CCL20 expression promoted the expression of fibrosis markers in HSCs. The role of visfatin in hepatic inflammation and fibrosis was investigated in a MCD-diet-induced NAFLD mouse model. Eight-week-old male C57BL/6J mice were randomly assigned to one of the following three groups: (i) saline-injected control diet group (CD/Sal; n = 8); (ii) saline-injected MCD diet group (MCD/Sal; n = 8); and (iii) visfatin-injected MCD diet group (MCD/visfatin; n = 8). At the end of the experiment, their livers were isolated and subjected to histological, biochemical, and molecular analyses. Hepatic steatosis was aggravated and the expression of pro-inflammatory cytokines was enhanced in the MCD/visfatin group, compared to that of the CD/Sal or MCD/Sal groups. Enhanced inflammatory cell infiltration indicated by F4/80, CD68, ly6G, and CD3, and expression of fibrosis markers including cTGF-β, TIMP1, collagen 1α2, collagen 3α2, αSMA, fibronectin, and vimentin were evident in the liver of the MCD/visfatin group. In addition, visfatin upregulated ER stress and ROS, and activated JNK signaling in the liver of MCD/visfatin group, compared to that of the CD/Sal or MCD/Sal groups. Thus, visfatin aggravated hepatic inflammation and fibrosis in the MCD-diet-fed mouse model. In conclusion, visfatin can exacerbate hepatic insulin resistance and aggravate hepatic inflammation and fibrosis. Thus, visfatin can play an important role in the pathogenesis and progression of NAFLD.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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