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조회39

김현수Hyunsoo Kim

광주과학기술원

Exp. Mol. Med., 03 February 2025 | https://doi.org/10.1038/s12276-025-01396-2 Golgi condensation causes intestinal lipid accumulation through HIF-1α-mediated GM130 ubiquitination by NEDD4

Hyunsoo Kim ¹, Channy Park ¹, Xiaofan Wei ¹, Arun Chhetri ¹, Laxman Manandhar ¹, Gyuho Jang¹, Jaetaek Hwang ¹, Batchingis Chinbold ¹, Chagtsalmaa Chuluunbaatar ¹, Hyug Moo Kwon ² and Raekil Park ^1,*

¹Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
²School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.

^*Corresponding author: correspondence to Raekil Park

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.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-25)
연구진국내 연구진
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