Although mitophagy is known to restrict NLRP3 inflammasome activation, the underlying regulatory mechanism remains poorly characterized. Here we describe a type of early endosome-dependent mitophagy that limits NLRP3 inflammasome activation. Deletion of the endosomal adaptor protein APPL1 impairs mitophagy, leading to accumulation of damaged mitochondria producing reactive oxygen species (ROS) and oxidized cytosolic mitochondrial DNA, which in turn trigger NLRP3 inflammasome overactivation in macrophages. NLRP3 agonist causes APPL1 to translocate from early endosomes to mitochondria, where it interacts with Rab5 to facilitate endosomal-mediated mitophagy. Mice deficient for APPL1 specifically in hematopoietic cell are more sensitive to endotoxin-induced sepsis, obesity-induced inflammation and glucose dysregulation. These are associated with increased expression of systemic interleukin-1β, a major product of NLRP3 inflammasome activation. Our findings indicate that the early endosomal machinery is essential to repress NLRP3 inflammasome hyperactivation by promoting mitophagy in macrophages.

Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG-VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte-specific deletion of MDM2 protects against high-fat high-cholesterol diet-induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG-VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein-protein interaction, which leads to reduced TG-VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2-ApoB interaction alleviates dietary-induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG-VLDL secretion. The effect of MDM2 on VLDL metabolism is p53-independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG-VLDL secretion in MAFLD. Inhibition of the MDM2-ApoB interaction may represent a potential therapeutic approach for MAFLD treatment.

No abstract

Introduction: Adipokines regulate whole-body energy homeostasis, insulin sensitivity and immunity by mediating the crosstalk between adipose tissues and multiple tissues, including liver, skeletal muscle, brain, pancreas and intestines. Recent studies revealed that intestines also exhibit insulin resistance and dysregulated immune homeostasis in obese condition. On the other hand, several adipokines including adiponectin and adipocyte fatty acid binding protein have been shown to regulate intestinal function. Here, we aim to investigate the relationship between the adipose tissue and gut homeostasis using lipodystrophy animal models. Methods: We employed our recently developed lipodystrophic mouse model, in which adipocyte MDM2 is genetically deleted (so-called Adipo-MDM2-KO mice). In fat transplantation experiment, subcutaneous fat form their wild type (WT) littermates was transplanted to the Adipo-MDM2-KO mice for 8 weeks. To assess gut permeability, Adipo-MDM2-KO mice and their wild type (WT) littermates were orally gavaged with DX-4000-FITC for 1 hour. Circulating LPS level were measured using the endotoxin assays, which reflects gut permeability and endotoxemia. For assessment of gut morphology, ileum isolated from Adipo-MDM2-KO mice and their WT littermates were subjected to Haemotoxylin and Eosin (H and E) staining. Results and Conclusion: Adipo-MDM2-KO mice exhibited impaired gut barrier function and altered gut microbiota composition when compared with the WT littermates. A higher level of DX-4000-FITC in the serum of Adipo-MDM2-KO mice were detected. In addition, circulating level of LPS was significantly increased in Adipo-MDM2-KO mice. H and E staining showed a change in gut morphology and an increased number of inflammatory cells in the ileum of Adipo-MDM2-KO mice. These results demonstrated that fat loss leads to intestinal dysfunction, therefore, the adipose tissue is required for gut homeostasis. Disclosure K. Long: None. Funding National Natural Science Foundation of China (91857119)