Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes
Xiaofeng Zheng, Qing Wei Calvin Ho, Minni Chua, Olga Stelmashenko, Xin Yi Yeo, Sneha Muralidharan, Federico Torta, Elaine Guo Yan Chew, Michelle Mulan Lian, Jia Nee Foo, Sangyong Jung, Sunny H. Wong, Nguan Soon Tan, Nanwei Tong, Guy A. Rutter, Markus R. Wenk, David L. Silver, Per‐Olof Berggren, Yusuf Ali
Abstract
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.