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Updated: Jun 26, 2025
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting
Qi Wang1,2, Qingfa Bu2,3, Zibo Xu2
1Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China.
Background/Aims:
Metabolic dysfunction-associated steatohepatitis (MASH) is an unmet clinical challenge due to the rapid increased occurrence but lacking approved drugs. Autophagy-related protein 16-like 1 (ATG16L1) plays an important role in the process of autophagy, which is indispensable for proper biogenesis of the autophagosome, but its role in modulating macrophage-related inflammation and metabolism during MASH has not been documented. Here, we aimed to elucidate the role of ATG16L1 in the progression of MASH.
Methods:
Expression analysis was performed with liver samples from human and mice. MASH models were induced in myeloid-specific Atg16l1-deficient and myeloid-specific Atg16l1-overexpressed mice by high-fat and high-cholesterol diet or methionine- and choline-deficient diet to explore the function and mechanism of macrophage ATG16L1 in MASH.
Results:
Macrophage-specific Atg16l1 knockout exacerbated MASH and inhibited energy expenditure, whereas macrophage-specific Atg16l1 transgenic overexpression attenuated MASH and promotes energy expenditure. Mechanistically, Atg16l1 knockout inhibited macrophage lipophagy, thereby suppressing macrophage β-oxidation and decreasing the production of 4-hydroxynonenal, which further inhibited stimulator of interferon genes(STING) carbonylation. STING palmitoylation was enhanced, STING trafficking from the endoplasmic reticulum to the Golgi was promoted, and downstream STING signaling was activated, promoting proinflammatory and profibrotic cytokines secretion, resulting in hepatic steatosis and hepatic stellate cells activation. Moreover, Atg16l1-deficiency enhanced macrophage phagosome ability but inhibited lysosome formation, engulfing mtDNA released by pyroptotic hepatocytes. Increased mtDNA promoted cGAS/STING signaling activation. Moreover, pharmacological promotion of ATG16L1 substantially blocked MASH progression.
Conclusion:
ATG16L1 suppresses MASH progression by maintaining macrophage lipophagy, restraining liver inflammation, and may be a promising therapeutic target for MASH management.
Insights
Autophagy-related protein 16-like 1 (ATG16L1) suppresses metabolic dysfunction-associated steatohepatitis (MASH) by enhancing macrophage function. Promoting ATG16L1 may offer a new therapeutic strategy for MASH.
Area of Science:
- Hepatology and Immunology
- Cellular Metabolism
- Autophagy Research
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is a growing health concern with limited treatment options.
- The role of autophagy-related protein 16-like 1 (ATG16L1) in macrophage-mediated inflammation and metabolism during MASH remains largely unexplored.
Purpose of the Study:
- To investigate the function and mechanism of ATG16L1 in macrophages during MASH progression.
- To determine if ATG16L1 can be a therapeutic target for MASH.
Main Methods:
- Analysis of liver samples from human and MASH model mice (myeloid-specific Atg16l1-deficient and overexpressed).
- Induction of MASH using high-fat/high-cholesterol or methionine- and choline-deficient diets.
- Assessment of macrophage autophagy, lipophagy, inflammation, and metabolic pathways.
Main Results:
- Macrophage-specific ATG16L1 deficiency worsened MASH and reduced energy expenditure.
- ATG16L1 deficiency impaired macrophage lipophagy, suppressed beta-oxidation, and promoted STING pathway activation via increased mtDNA uptake.
- Overexpression of ATG16L1 attenuated MASH and enhanced energy expenditure; pharmacological ATG16L1 promotion blocked MASH progression.
Conclusions:
- ATG16L1 plays a protective role in MASH by maintaining macrophage lipophagy and reducing liver inflammation.
- Targeting ATG16L1 represents a potential therapeutic strategy for managing MASH.
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