Grasp55 −/− mice display impaired fat absorption and resistance to high-fat diet-induced obesity

Jiyoon Kim, Hyeyon Kim, Shin Hye Noh, Dong Geon Jang, Shi Young Park, Dongkook Min, Hyunki Kim, Hee Seok Kweon, Hoguen Kim, Sowon Aum, Sookyung Seo, Cheol Soo Choi, Hail Kim, Jae Woo Kim, Seok Jun Moon, Heon Yung Gee, Min Goo Lee

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Abstract

The Golgi apparatus plays a central role in the intracellular transport of macromolecules. However, molecular mechanisms of Golgi-mediated lipid transport remain poorly understood. Here, we show that genetic inactivation of the Golgi-resident protein GRASP55 in mice reduces whole-body fat mass via impaired intestinal fat absorption and evokes resistance to high-fat diet induced body weight gain. Mechanistic analyses reveal that GRASP55 participates in the Golgi-mediated lipid droplet (LD) targeting of some LD-associated lipases, such as ATGL and MGL, which is required for sustained lipid supply for chylomicron assembly and secretion. Consequently, GRASP55 deficiency leads to reduced chylomicron secretion and abnormally large LD formation in intestinal epithelial cells upon exogenous lipid challenge. Notably, deletion of dGrasp in Drosophila causes similar defects of lipid accumulation in the midgut. These results highlight the importance of the Golgi complex in cellular lipid regulation, which is evolutionary conserved, and uncover potential therapeutic targets for obesity-associated diseases.

Original languageEnglish
Article number1418
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Kim, J., Kim, H., Noh, S. H., Jang, D. G., Park, S. Y., Min, D., Kim, H., Kweon, H. S., Kim, H., Aum, S., Seo, S., Choi, C. S., Kim, H., Kim, J. W., Moon, S. J., Gee, H. Y., & Lee, M. G. (2020). Grasp55 −/− mice display impaired fat absorption and resistance to high-fat diet-induced obesity. Nature communications, 11(1), [1418]. https://doi.org/10.1038/s41467-020-14912-x