期刊
CELL DEATH & DISEASE
卷 13, 期 4, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-022-04812-x
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资金
- National Natural Science Foundation of China [81730015, 82170504, 81974048, 82071803, 82000050, 82170239]
- China Postdoctoral Science Foundation [2021M691155]
- Fundamental Research Funds for the Central Universities (HUST) [2021GCRC037]
- Natural Science Foundation of Hubei Province [2019AAA032]
Nonalcoholic fatty liver disease (NAFLD) is a common disease without approved medications. The study identified BCL6 as a critical modulator of NAFLD and found that overexpression of BCL6 improves hepatic steatosis and insulin resistance.
Nonalcoholic fatty liver disease (NAFLD) is an ubiquitous disease that exists across a wide spectrum ranging from steatosis, steatohepatitis, advanced fibrosis, and liver cirrhosis. Hallmarks of NAFLD are lipid accumulation, insulin resistance, and chronic low-grade inflammation. However, there currently are no medications approved for NAFLD. B-cell lymphoma 6 (BCL6) is a transcriptional inhibitor that is vital for germinal center B-cell formation. Our study identified BCL6 as a critical modulator of hepatic lipid metabolism and appears to contribute to the initiation and progression of NAFLD. In our research, we induced hepatic BCL6 overexpression using adeno-associated virus (AAV), as well as conditional liver-specific BCL6 knockout mice (BCL6-CKO). With these models, we noted that BCL6 overexpression improved insulin resistance and hepatic steatosis in mice models maintained on a HFD diet. Conversely, these parameters worsened in the livers of mice with downregulated BCL6 levels. Mechanistically, the translocase fatty acid CD36 was determined to be a transcriptional target of BCL6 that influences its role in hepatic steatosis. BCL6 bound directly to the CD36 promoter region, restraining CD36 transcription under physiological conditions. We conclude that the hepatocyte BCL6 inhibits the NAFLD progression in mice, including deranged lipid accumulation and glucose metabolism, through a CD36-dependent manner. These results indicate that BCL6 may potentially be targeted in NAFLD treatment.
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