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Updated: Jul 15, 2025
An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
CARD9 deficiency aggravated nonalcoholic steatohepatitis in mice through increasing inflammatory response
Xin Liu1, Yi Fang2, Chenchen Qian2
1Joint Research Centre on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang 315700, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Insights
Caspase recruitment domain family member 9 (CARD9) deficiency worsens nonalcoholic steatohepatitis (NASH) and liver fibrosis. CARD9 plays a protective role in NASH development by regulating inflammatory and lipid metabolism genes.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Nonalcoholic steatohepatitis (NASH) is a major cause of liver disease globally.
- The role of Caspase recruitment domain family member 9 (CARD9) in NASH pathogenesis is currently unknown.
Purpose of the Study:
- To investigate the role of CARD9 in the development of NASH and liver fibrosis.
Main Methods:
- NASH and liver fibrosis models were established in CARD9-knockout and wild-type mice using methionine/choline-deficient (MCD) or high-fat high-cholesterol (HFHC) diets, and carbon tetrachloride (CCl4) administration.
- In vitro studies utilized Kupffer cells treated with palmitate to assess CARD9's effect on inflammatory and metabolic gene expression.
Main Results:
- CARD9 deficiency accelerated NASH progression in diet-induced models, with increased fibrosis, adipogenesis, and inflammation.
- CARD9 deficiency exacerbated CCl4-induced liver fibrosis.
- In vitro, CARD9 deficiency upregulated S100a8/a9 expression in Kupffer cells, promoting pro-inflammatory, fibrotic, and lipid metabolism gene expression.
Conclusions:
- CARD9 deficiency exacerbates NASH and liver fibrosis development.
- CARD9 plays a protective role in NASH by modulating inflammatory responses and lipid metabolism.
- Targeting CARD9 may offer novel therapeutic strategies for NASH.
Abstract:
Nonalcoholic steatohepatitis (NASH), a subtype of nonalcoholic fatty liver disease (NAFLD), is the leading cause of liver-related morbidity worldwide. Caspase recruitment domain family member 9 (CARD9), a myeloid cell-specific signaling protein, belongs to the CARD protein family. However, its role in NASH is unknown. Therefore, this study aimed to investigate the role of CARD9 in the development of NASH. NASH models were established using CARD9-knockout and wild-type mice. They were either fed a methionine/choline deficient (MCD) diet for 6 weeks or a high-fat high-cholesterol (HFHC) diet for 16 weeks. Liver fibrosis model was also developed using CCl4. CARD9 deficiency accelerated steatohepatitis development in MCD or HFHC diet-fed mice, accompanied by an upregulation of fibrosis, adipogenesis, and proinflammatory genes. CARD9 deficiency was found to exacerbate CCl4-induced liver fibrosis. In vitro studies demonstrated that CARD9 deficiency induced the expression of S100a8/a9 through Toll-like receptor in Kupffer cells treated with palmitate. This led to an increased expression of proinflammatory, fibrosis, and lipid metabolism-related genes in NASH progression. These results highlight the role of CARD9 in the development of NASH and provide new insights into the therapeutic strategies for NASH.
