Mus musculus Transcriptome or Gene expression. Mus musculus

We show intricate crosstalk between two pathways that are critical for maintenance of hepatic ER homeostasis and adjustement to nutrient stress. Hepatic ER-stress induced by fructose feeding triggers IRE1 activation and induction of the PIDDosome consisting of caspase-2, RAIDD and PIDD, along with the SCAP inhibitor INSIG-2. While inhibiting caspase-2 mediated SREBP activation, PIDDosome ablation also attenuated IRE1 activation and INSIG-2 induction. SCAP ablation, however, potentiated fructose-induced ER-stress and activation of IRE1, whose inhibition prevented fructose-induced damage to the SCAP-deficient liver. Thus, IRE1-PIDDosome and SCAP are opposing regulators of nutrient-induced hepatic ER stress that can be relieved by IRE1 inhibition and aggravated by SCAP ablation.