Destabilization of β cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes

• Main Authors: Zheng, Xiaofeng, Ho, Calvin Qing Wei, Chua, Minni, Stelmashenko, Olga, Yeo, Xin Yi, Muralidharan, Sneha, Torta, Federico, Chew, Elaine Guo Yan, Lian, Michelle Mulan, Foo, Jia Nee, Jung, Sangyong, Wong, Sunny Hei, Tan, Nguan Soon, Tong, Nanwei, Rutter, Guy A., Wenk, Markus R., Silver, David L., Berggren, Per-Olof, Ali, Yusuf
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Medicine; Diabetes; FIT2; Saturated Fatty Acids; ER Stress
• Online Access: https://hdl.handle.net/10356/160233
• Institution: Nanyang Technological University

SignificanceWith obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage-inducing transmembrane protein 2 (FIT2)-facilitated, pancreatic β cell LD biogenesis, which in turn induces β cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)-associated degradation. Loss of β cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.