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Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Specific knockout of notch-1 attenuates non-alcoholic fatty liver disease by promoting SHP2 phosphorylation
Qian Gao1, Yonggang Lu2, Weiling Zhou1
1Department of Endocrine and Metabolic Diseases, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Objective:
To investigate the effect of Notch-1 signaling on NAFLD and its molecular mechanism.
Methods:
The lipid deposition in liver tissues was detected by oil red O staining. Western blotting was performed to detect the expressions of SREBP1C, SREBP2, LXR, IL-1β, IL-18, NLRP3, Notch-1, NOX2, NOX4, p-PI3K and p-SHP2 in macrophages, and the expressions of ALIX, CD9, IL-1β and SREBP1C in exosomes. Macrophages in the Notch-1MAC-KO group and Notch-1WT group were treated with FFA, and those in the Notch-1WT+FFA group and Notch-1MAC-KO+FFA group were treated with SHP2 inhibitors PHPS1 and Relaxin.
Results:
It was observed by oil red O staining that lipid deposition in mice with NAFLD was reduced in the Notch-1MAC-KO group. The results of Western blotting showed that the expressions of ALIX, CD9, IL-1β and SREBP1C in macrophage exosomes were significantly lower in the Notch-1MAC-KO group than in the Notch-1WT group. In macrophages, the expressions of SREBP1C, SREBP2, LXR, IL-1β, IL-18, Notch-1, NOX2, NOX4 and p-PI3K significantly decreased, while the expression of p-SHP2 significantly increased in the Notch-1MAC-KO group compared with the Notch-1WT group. The Notch-1MAC-KO+FFA group had significantly decreased expressions of SREBP1C, NLRP3, IL-1β, IL-18, SREBP2, NOX2, NOX4 and p-PI3K and a significantly increased expression of p-SHP2 compared with the Notch-1WT+FFA group. However, the differences in the above proteins were all eliminated after PHPS1 and Relaxin were added.
Conclusion:
Specific knockout of Notch-1 attenuates NAFLD, and reduces inflammation and lipid deposition in the liver by promoting SHP2 phosphorylation.
Insights
Specific knockout of Notch-1 signaling in macrophages reduces non-alcoholic fatty liver disease (NAFLD) by decreasing liver inflammation and lipid deposition. This occurs through promoting SHP2 phosphorylation, offering a potential therapeutic target for NAFLD.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern.
- The role of Notch-1 signaling in the pathogenesis of NAFLD remains incompletely understood.
Purpose of the Study:
- To investigate the impact of Notch-1 signaling in macrophages on NAFLD.
- To elucidate the molecular mechanisms underlying Notch-1's effect on NAFLD.
Main Methods:
- Utilized a mouse model with specific knockout of Notch-1 in macrophages (Notch-1MAC-KO).
- Assessed liver lipid deposition using oil red O staining.
- Analyzed protein expression in macrophages and exosomes via Western blotting, including key markers for lipid metabolism, inflammation, and signaling pathways (e.g., SREBP1C, IL-1β, Notch-1, p-SHP2).
- Investigated the effects of SHP2 inhibitors (PHPS1 and Relaxin).
Main Results:
- Notch-1 knockout in macrophages significantly reduced lipid deposition and inflammation in NAFLD mice.
- Macrophage-derived exosomal expressions of ALIX, CD9, IL-1β, and SREBP1C were decreased in Notch-1MAC-KO mice.
- Knockout of Notch-1 in macrophages led to decreased expression of SREBP1C, SREBP2, LXR, IL-1β, IL-18, NOX2, NOX4, and p-PI3K, alongside increased p-SHP2 expression.
- Treatment with SHP2 inhibitors mimicked the protective effects of Notch-1 knockout, normalizing protein expression levels.
Conclusions:
- Specific knockout of Notch-1 in macrophages attenuates NAFLD.
- This attenuation is mediated by reduced liver inflammation and lipid deposition.
- The mechanism involves the promotion of SHP2 phosphorylation, highlighting a potential therapeutic strategy for NAFLD.
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