C C chemokine ligand 3 deficiency ameliorates diet-induced steatohepatitis by regulating liver macrophage recruitment and M1/M2 status in mice

Xu, Liang; Chen, Yongping; Nagashimada, Mayumi; Zhuge, Fen; Chen, Guanliang; Li, Haoran; Pan, Tongtong; Yamashita, Tatsuya; Mukaida, Naofumi; Kaneko, Shuichi; Ota, Tsuguhito; Nagata, Naoto

doi:10.1016/j.metabol.2021.154914

Cited by 44 publications

(41 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unlike in a previous report [31,32], however, patients with simple fatty liver also showed a trend of increased serum CCL3 levels and a significant increase in hepatic CCL3 protein expression compared with those of healthy controls [33]. Additionally, the circulating levels of CCL3 were high according to the histological severity of ballooning, steatosis, and lobular inflammation [33]. These results suggest that CCL3 might be a causative factor, not just a result of advanced fibrosis, in NAFLD development.…”

Section: An Update On the Chemokine System In The Development Of Nafl...contrasting

confidence: 73%

“…Circulating CCL3 levels were significantly higher in NASH patients compared with healthy controls [31,32]. Recently, we also reported that the serum and hepatic protein levels of CCL3 were significantly higher in patients with NASH compared with those of healthy controls [33]. Unlike in a previous report [31,32], however, patients with simple fatty liver also showed a trend of increased serum CCL3 levels and a significant increase in hepatic CCL3 protein expression compared with those of healthy controls [33].…”

Section: An Update On the Chemokine System In The Development Of Nafl...contrasting

confidence: 60%

“…Recently, we also reported that the serum and hepatic protein levels of CCL3 were significantly higher in patients with NASH compared with those of healthy controls [33]. Unlike in a previous report [31,32], however, patients with simple fatty liver also showed a trend of increased serum CCL3 levels and a significant increase in hepatic CCL3 protein expression compared with those of healthy controls [33]. Additionally, the circulating levels of CCL3 were high according to the histological severity of ballooning, steatosis, and lobular inflammation [33].…”

Section: An Update On the Chemokine System In The Development Of Nafl...mentioning

confidence: 82%

See 2 more Smart Citations

An Update on the Chemokine System in the Development of NAFLD

Nagata

Chen

et al. 2022

Medicina

Self Cite

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Sustained hepatic inflammation is a key driver of the transition from simple fatty liver to nonalcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. Hepatic inflammation is orchestrated by chemokines, a family of chemoattractant cytokines that are produced by hepatocytes, Kupffer cells (liver resident macrophages), hepatic stellate cells, endothelial cells, and vascular smooth muscle cells. Over the last three decades, accumulating evidence from both clinical and experimental investigations demonstrated that chemokines and their receptors are increased in the livers of NAFLD patients and that CC chemokine ligand (CCL) 2 and CCL5 in particular play a pivotal role in inducing insulin resistance, steatosis, inflammation, and fibrosis in liver disease. Cenicriviroc (CVC), a dual antagonist of these chemokines’ receptors, CCR2 and CCR5, has been tested in clinical trials in patients with NASH-associated liver fibrosis. Additionally, recent studies revealed that other chemokines, such as CCL3, CCL25, CX3C chemokine ligand 1 (CX3CL1), CXC chemokine ligand 1 (CXCL1), and CXCL16, can also contribute to the pathogenesis of NAFLD. Here, we review recent updates on the roles of chemokines in the development of NAFLD and their blockade as a potential therapeutic approach.

show abstract

Section: An Update On the Chemokine System In The Development Of Nafl...contrasting

confidence: 73%

Section: An Update On the Chemokine System In The Development Of Nafl...contrasting

confidence: 60%

Section: An Update On the Chemokine System In The Development Of Nafl...mentioning

confidence: 82%

See 1 more Smart Citation

An Update on the Chemokine System in the Development of NAFLD

Nagata

Chen

et al. 2022

Medicina

Self Cite

View full text Add to dashboard Cite

show abstract

“…Among the 154 genes modulated by compound 2 treatment compared to the group of mice subjected to HFD-F alone, the most downregulated gene is the chemokine Ccl3 with a fold change of–45.68 ( Figure 7O and Supplementary Table S2 ). This finding is very interesting because elevated levels of Ccl3 have been documented in the serum and liver of patients with NASH and moreover the deletion of this gene protects mice from diet-induced steatohepatitis, hepatic fibrosis, and insulin resistance ( Xu et al, 2021 ). Furthermore, among the genes most downregulated by compound 2 we also find the chemokines Cxcl2 and Ccl2 with a fold of–12.23 and–9.45, respectively ( Figures 7P,Q ) and Serpine 1 ( Figure 7R ).…”

Section: Resultsmentioning

confidence: 97%

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease

et al. 2022

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are two highly prevalent human diseases caused by excessive fat deposition in the liver. Although multiple approaches have been suggested, NAFLD/NASH remains an unmet clinical need. Here, we report the discovery of a novel class of hybrid molecules designed to function as cysteinyl leukotriene receptor 1 (CysLT1R) antagonists and G protein bile acid receptor 1 (GPBAR1/TGR5) agonists for the treatment of NAFLD/NASH. The most potent of these compounds generated by harnessing the scaffold of the previously described CystLT1R antagonists showed efficacy in reversing liver histopathology features in a preclinical model of NASH, reshaping the liver transcriptome and the lipid and energy metabolism in the liver and adipose tissues. In summary, the present study described a novel orally active dual CysLT1R antagonist/GPBAR1 agonist that effectively protects against the development of NAFLD/NASH, showing promise for further development.

show abstract

“…Chemokines and their receptors, such as CCL25 and CCR9, play important roles in the hepatic infiltration of macrophages and other immune cells in NAFLD/NASH [ 97 , 98 ]. Therefore, inhibiting this axis may prevent liver inflammation and liver fibrosis.…”

Section: Treatment Options For Nafld and Nash Based On Modulation Of Gut Microbiota Intrahepatic Immunity And Metabolic Signaling Pathwaymentioning

confidence: 99%

Diet and Gut Microbiota Interaction-Derived Metabolites and Intrahepatic Immune Response in NAFLD Development and Treatment

Yang

Khoukaz

et al. 2021

Biomedicines

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) with pathogenesis ranging from nonalcoholic fatty liver (NAFL) to the advanced form of nonalcoholic steatohepatitis (NASH) affects about 25% of the global population. NAFLD is a chronic liver disease associated with obesity, type 2 diabetes, and metabolic syndrome, which is the most increasing factor that causes hepatocellular carcinoma (HCC). Although advanced progress has been made in exploring the pathogenesis of NAFLD and penitential therapeutic targets, no therapeutic agent has been approved by Food and Drug Administration (FDA) in the United States. Gut microbiota-derived components and metabolites play pivotal roles in shaping intrahepatic immunity during the progression of NAFLD or NASH. With the advance of techniques, such as single-cell RNA sequencing (scRNA-seq), each subtype of immune cells in the liver has been studied to explore their roles in the pathogenesis of NAFLD. In addition, new molecules involved in gut microbiota-mediated effects on NAFLD are found. Based on these findings, we first summarized the interaction of diet-gut microbiota-derived metabolites and activation of intrahepatic immunity during NAFLD development and progression. Treatment options by targeting gut microbiota and important molecular signaling pathways are then discussed. Finally, undergoing clinical trials are selected to present the potential application of treatments against NAFLD or NASH.

show abstract

C C chemokine ligand 3 deficiency ameliorates diet-induced steatohepatitis by regulating liver macrophage recruitment and M1/M2 status in mice

Cited by 44 publications

References 43 publications

An Update on the Chemokine System in the Development of NAFLD

An Update on the Chemokine System in the Development of NAFLD

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease

Diet and Gut Microbiota Interaction-Derived Metabolites and Intrahepatic Immune Response in NAFLD Development and Treatment

Contact Info

Product

Resources

About