CCN1 expression in hepatocytes contributes to macrophage infiltration in nonalcoholic fatty liver disease in mice.
Our objective was to investigate the potential roles of CCN1 in the inflammation and macrophage infiltration of nonalcoholic fatty liver disease (NAFLD). The regulation of hepatic CCN1 expression was investigated in vitro with murine primary hepatocytes treated with free fatty acids or lipopolysaccharide (LPS) and in vivo with high-fat (HF) diet-fed mice or ob/ob mice. CCN1 protein and a liver-specific CCN1 expression plasmid were administered to mice fed a normal diet (ND) or HF diet. Myeloid-derived macrophages and RAW264.7 cells were also treated with CCN1 in vitro to determine the chemotactic effects of CCN1 on macrophages. LPS treatment significantly increased hepatic CCN1 expression in HF diet-fed mice and ob/ob mice. LPS and FFAs induced CCN1 expression in primary murine hepatocytes in vitro through the TLR4/MyD88/AP-1 pathway. CCN1 protein and overexpression of CCN1 in the liver induced more severe hepatic inflammation and macrophage infiltrates in HF mice than in ND mice. CCN1 recruited macrophages through activation of the Mek/Erk signaling pathway in myeloid-derived macrophages and RAW264.7 cells in vitro. Endotoxin and FFA-induced CCN1 expression in hepatocytes is involved in the hepatic proinflammatory response and macrophage infiltration in murine NAFLD.
Division of Gastroenterology and Hepatology, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai,  China.
Zhaolian
Z
Bian
Yanshen
Y
Peng
Zhengrui
Z
You
Qixia
Q
Wang
Qi
Q
Miao
Yuan
Y
Liu
Xiaofeng
X
Han
Dekai
D
Qiu
Zhiping
Z
Li
Xiong
X
Ma
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005234:Fatty Liver / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D039481:CD11b Antigen; D055515:Cysteine-Rich Protein 61; D005230:Fatty Acids, Nonesterified; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1