Golgi condensation causes intestinal lipid accumulation through HIF-1α-mediated GM130 ubiquitination by NEDD4

Abstract

The breakdown of Golgi proteins disrupts lipid trafficking, leading to lipid accumulation in the small intestine. However, the causal mechanism of the effects of Golgi protein degradation on the Golgi structure related to lipid trafficking in the small intestine remains unknown. Here we find that Golgi protein degradation occurs under hypoxic conditions in high-fat-diet-fed mice. Hypoxia-induced degradation promotes structural changes in the Golgi apparatus, termed ‘Golgi condensation’. In addition, hypoxia-inducible factor 1α (HIF-1α) activation enhances Golgi condensation through the ubiquitination and degradation of Golgi matrix protein 130 (GM130), which is facilitated by neural precursor cell expressed developmentally downregulated protein 4 (NEDD4). Golgi condensation upon exposure to hypoxia promotes lipid accumulation, apolipoprotein A1 retention and decreased chylomicron secretion in the intestinal epithelium. Golgi condensation and lipid accumulation induced by GM130 depletion are reversed by exogenous GM130 induction in the intestinal epithelium. Inhibition of either HIF-1α or NEDD4 protects against GM130 degradation and, thereby, rescues cells from Golgi condensation, which further increases apolipoprotein A1 secretion and lipid accumulation both in vivo and in vitro. Furthermore, the HIF-1α inhibitor PX-478 prevents Golgi condensation, which decreases lipid accumulation and promotes high-density lipoprotein secretion in high-fat-diet-fed mice. Overall, our results suggest that Golgi condensation plays a key role in lipid trafficking in the small intestine through the HIF-1α- and NEDD4-mediated degradation of GM130, and these findings highlight the possibility that the prevention of structural modifications in the Golgi apparatus can ameliorate intestinal lipid accumulation in obese individuals. This study explores how low oxygen levels affect the Golgi apparatus, a cell structure involved in processing and packaging proteins and lipids. The study used mice and cell models to investigate these effects. They found that HIF-1α causes the Golgi apparatus to condense or shrink, which disrupts its function. This change is linked to increased lipid accumulation in the small intestine. The researchers discovered that HIF-1α plays a crucial role in this process by promoting the degradation of another protein, GM130, which is essential for maintaining Golgi structure, and NEDD4, a E3 ligase, which contributes on GM130 degradation. The findings suggest that preventing Golgi condensation by inhibiting HIF-1α could reduce lipid buildup in the obese intestine. This research provides new insights into how hypoxia affects lipid metabolism and could lead to potential treatments for obesity-related conditions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.