Regulation of lipid absorption by enterocytes can influence metabolic status in humans and contribute to obesity and related complications. The intracellular steps of chylomicron biogenesis and transport from the Endoplasmic Reticulum (ER) to the Golgi complex have been described, but the mechanisms for post-Golgi transport and secretion of chylomicrons have not been identified. Using a newly generated Dennd5b−/− mouse, we demonstrate an essential role for this gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. In mice, loss of Dennd5b results in resistance to western diet induced obesity, changes in plasma lipids, and reduced aortic atherosclerosis. In humans, two independent exome sequencing studies reveal that a common DENND5B variant, p.(R52K), is correlated with body mass index. These studies establish an important role for DENND5B in post-Golgi chylomicron secretion and a subsequent influence on body composition and peripheral lipoprotein metabolism.
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I.J.K. was supported by grants U01HG006379, HL135879, and HL137010. The Mayo Vascular Disease Biorepository was funded by NIH grant HL-75794 and a Marriot Award for Individualized Medicine.
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-40296-0.
Gordon, Scott M.; Neufeld, Edward B.; Yang, Zhihong; Pryor, Milton; Freeman, Lita A.; Fan, Xiao; Kullo, Iftikhar J.; Biesecker, Leslie G.; and Remaley, Alan T., "DENND5B Regulates Intestinal Triglyceride Absorption and Body Mass" (2019). Saha Cardiovascular Research Center Faculty Publications. 41.