C–C motif chemokine CCL11 is a novel regulator and a potential therapeutic target in non-alcoholic fatty liver disease
Zhiwen Fan,
Xinyue Sun,
Xuelian Chen,
Huimin Liu,
Xiulian Miao,
Yan Guo,
Yong Xu,
Jie Li,
Xiaoping Zou,
Zilong Li
Affiliations
Zhiwen Fan
Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
Xinyue Sun
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
Xuelian Chen
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
Huimin Liu
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
Xiulian Miao
College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
Yan Guo
College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
Yong Xu
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China; College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
Jie Li
Department of Infectious Diseases, Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical School, Nanjing, China; Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China; Corresponding authors. Addresses: Nanjing Drum Tower Hospital, Nanjing 210008, China (J. Li and X. Zou); China Pharmaceutical University, Nanjing 211198, China (Z. Li).
Xiaoping Zou
Department of Gastroenterology, Taikang Xianlin Drum Tower Hospital Affiliated with Nanjing University Medical School, Nanjing, China; Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China; Corresponding authors. Addresses: Nanjing Drum Tower Hospital, Nanjing 210008, China (J. Li and X. Zou); China Pharmaceutical University, Nanjing 211198, China (Z. Li).
Zilong Li
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China; College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China; Corresponding authors. Addresses: Nanjing Drum Tower Hospital, Nanjing 210008, China (J. Li and X. Zou); China Pharmaceutical University, Nanjing 211198, China (Z. Li).
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by accelerated lipid deposition, aberrant inflammation, and excessive extracellular matrix production in the liver. Short of effective intervention, NAFLD can progress to cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of the C–C motif ligand 11 (CCL11) in NAFLD pathogenesis. Methods: NAFLD was induced by feeding mice with a high-fat high-carbohydrate diet. CCL11 targeting was achieved by genetic deletion or pharmaceutical inhibition. The transcriptome was analysed using RNA-seq. Results: We report that CCL11 expression was activated at the transcription level by free fatty acids (palmitate) in hepatocytes. CCL11 knockdown attenuated whereas CCL11 treatment directly promoted production of pro-inflammatory/pro-lipogenic mediators in hepatocytes. Compared with wild-type littermates, CCL11 knockout mice displayed an ameliorated phenotype of NAFLD when fed a high-fat high-carbohydrate diet as evidenced by decelerated body weight gain, improved insulin sensitivity, dampened lipid accumulation, reduced immune cell infiltration, and weakened liver fibrosis. RNA-seq revealed that interferon regulatory factor 1 as a mediator of CCL11 induced changes in hepatocytes. Importantly, CCL11 neutralisation or antagonism mitigated NAFLD pathogenesis in mice. Finally, a positive correlation between CCL11 expression and NAFLD parameters was identified in human patients. Conclusions: Our data suggest that CCL11 is a novel regulator of NAFLD and can be effectively targeted for NAFLD intervention. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper we describe the regulatory role of CCL11, a C–C motif ligand chemokine, in NAFLD pathogenesis. Our data provide novel insights and translational potential for NAFLD intervention.
