Dietary exposure to polystyrene nanoplastics impairs fasting-induced lipolysis in adipose tissue from high-fat diet fed mice.

The health concerns of microplastics (MPs) and nanoplastics (NPs) surge, but the key indicators to evaluate the adverse risks of MPs/NPs are elusive. Recently, MPs/Ps were found to disturb glucose and lipid metabolism in rodents, suggesting that MPs/NPs may play a role in obesity progression. In this study, we firstly demonstrated that the distribution of fluorescent polystyrene nanoplastics (nPS, 60 nm) white adipose tissue (WAT) of mice. Furthermore, nPS could traffic across adipocytes in vitro and reduced lipolysis under ß-adrenergic stimulation in adipocytes in vitro and ex vivo. Consistently, chronic oral exposure to nPS at the dietary exposure relevant concentrations (3 and 223 µg/kg body weight) impaired fasting-induced lipid mobilization in obese mice and subsequently contributed to larger adipocyte size in the subcutaneous WAT. In addition, the chronic exposure of nPS induced macrophage infiltration in the small intestine and increased lipid accumulation in the liver, accelerating the disruption of systemic metabolism. Collectively, our findings highlight the potential obesogenic role of nPS via diminishing lipid mobilization in WAT of obese mice and suggest that lipolysis relevant parameters may be used for evaluating the adverse effect of MPs/NPs in clinics.

Hepatic MDM2 Causes Metabolic Associated Fatty Liver Disease by Blocking Triglyceride-VLDL Secretion via ApoB Degradation.

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.

The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages.

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-1ß, 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.