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Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic
Zheng Liu1, Hao Wang2, Yuan Liang3,4
1Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Abstract:
Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis(MASH). However, the roles of macrophage E2F2 in the progression of MASH have not been elucidated. This study reveals that the expression of macrophage E2F2 is dramatically downregulated in MASH livers from mice and humans, and that this expression is adversely correlated with the severity of the disease. Myeloid-specific E2F2 depletion aggravates intrahepatic inflammation, hepatic stellate cell activation, and hepatocyte lipid accumulation during MASH progression. Mechanistically, E2F2 can inhibit the SLC7A5 transcription directly. E2F2 deficiency upregulates the expression of SLC7A5 to mediate amino acids flux, resulting in enhanced glycolysis, impaired mitochondrial function, and increased macrophages proinflammatory response in a Leu-mTORC1-dependent manner. Moreover, bioinformatics analysis and CUT &Tag assay identify the direct binding of Nrf2 to E2F2 promoter to promote its transcription and nuclear translocation. Genetic or pharmacological activation of Nrf2 effectively activates E2F2 to attenuate the MASH progression. Finally, patients treated with CDK4/6 inhibitors demonstrate reduced E2F2 activity but increased SLC7A5 activity in PBMCs. These findings indicated macrophage E2F2 suppresses MASH progression by reprogramming amino acid metabolism via SLC7A5- Leu-mTORC1 signaling pathway. Activating E2F2 holds promise as a therapeutic strategy for MASH.
Insights
Macrophage E2F2 suppresses metabolic dysfunction-associated steatohepatitis (MASH) progression by regulating amino acid metabolism. Activating E2F2 shows potential for treating MASH.
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Macrophages play a key role in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH).
- The specific function of E2F2 in macrophages during MASH progression remains unclear.
Purpose of the Study:
- To investigate the role of macrophage E2F2 in MASH development and progression.
- To elucidate the underlying molecular mechanisms by which E2F2 influences MASH.
Main Methods:
- Analysis of E2F2 expression in MASH livers from mice and humans.
- Myeloid-specific E2F2 depletion models to assess its impact on MASH.
- Mechanistic studies involving SLC7A5 transcription, amino acid flux, and mTORC1 signaling.
- Bioinformatics analysis and CUT &Tag assays to identify Nrf2 regulation of E2F2.
- Evaluation of patient data from CDK4/6 inhibitor treatment.
Main Results:
- Macrophage E2F2 expression is downregulated in MASH and correlates with disease severity.
- E2F2 deficiency exacerbates MASH-related inflammation, fibrosis, and lipid accumulation.
- E2F2 directly inhibits SLC7A5 transcription, impacting amino acid metabolism, glycolysis, and mitochondrial function.
- Nrf2 directly binds to the E2F2 promoter, enhancing its transcription and nuclear translocation.
- Nrf2 activation of E2F2 attenuates MASH progression; CDK4/6 inhibitors reduce E2F2 activity in patients.
Conclusions:
- Macrophage E2F2 acts as a suppressor of MASH by reprogramming amino acid metabolism through the SLC7A5-Leu-mTORC1 pathway.
- Targeting E2F2 activation presents a promising therapeutic avenue for MASH treatment.
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