Steatosis induced CCL5 contributes to early-stage liver fibrosis in nonalcoholic fatty liver disease progress

详细信息    查看全文

• 作者：Bing-Hang Li^a ; ¹ ; Fang-Ping He^b ; ¹ ; Xin Yang^c ; Yuan-Wen Chen^a ; ^{drchenyuanwen@163.com} ; Jian-Gao Fan^a ; ^{fattyliver2004@126.com}
• 关键词：CCL5 ; chemokine (C-C motif) ligand 5 ; RANTES ; regulated upon activation normal T-cell expressed and secreted ; CCR5 ; C-C chemokine receptor type 5 ; NAFLD ; nonalcoholic fatty liver disease ; NASH ; non-alcoholic steatohepatitis ; HFD ; high-fat-diet ; α-SMA ; alpha smooth muscle actin ; TGF-β ; transforming growth factor-β ; FFA ; free fatty acid ; MMP-2 ; matrix metalloproteinase-2 ; C/EBP-β ; CCAAT/enhancer-binding protein-β ; NF-κB ; nuclear factor kappa-light-chain-enhancer of activated B cells ; XBP-1 ; X box
• 刊名：Translational Research
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：180
• 期：Complete
• 页码：103-117.e4
• 全文大小：3587 K
• 卷排序：180

文摘

The rapidly increasing prevalence of nonalcoholic fatty liver disease (NAFLD) has become one of the major public health threats in China and worldwide. However, during the development of NAFLD, the key mechanism underlying the progression of related fibrosis remains unclear, which greatly impedes the development of optimal NAFLD therapy. In the current study, we were endeavored to characterize a proinflammatory cytokine, CCL5, as a major contributor for fibrosis in NAFLD. The results showed that CCL5 was highly expressed in fatty liver and NASH patients. In NAFLD rats induced by 8-week-HFD, CCL5 and its receptor, CCR5, were significantly up-regulated and liver fibrosis exclusively occurred in this group. In addition, we showed that hepatocytes are the major source contributing to this CCL5 elevation. Interestingly, a CCL5 inhibitor Met-CCL5, significantly decreased liver fibrosis but not hepatic steatosis. Using a cell model of hepatic steatosis, we found that the conditioned medium of lipid-overloaded hepatocytes (Fa2N-4 cells) which produced excessive CCL5 stimulated the profibrotic activities of hepatic stellate cells (LX-2) as manifested by increased migration rate, proliferation and collagen production of LX-2 cells. CCL5 knockdown in Fa2N-4 cells, Met-CCL5 or CCR5 antibody treatment on LX-2 cells all significantly inhibited the conditioned medium of FFA-treated Fa2N-4 cells to exert stimulatory effects on LX-2 cells. Consistently, the conditioned medium of Fa2N-4 cells with CCL5 over-expression significantly enhanced migration rate, cell proliferation and collagen production of LX-2 cells. All these results support that CCL5 produced by steatotic hepatocytes plays an essential role in fibrotic signaling machinery of NAFLD. In addition, we were able to identify C/EBP-β as the up-stream regulator of CCL5 gene transcription in hepatocytes treated with free fatty acid (FFA). Our data strongly supported that CCL5 plays a pivotal regulatory role in hepatic fibrosis during NAFLD, which constitutes a novel and exciting observation that may call for potential future development of specific CCL5-targeted NAFLD therapy.