ERN1 and Insulin resistance: The appearance of insulin resistance, de novo lipogenesis, inflammation, and oxidative stress during the development of NASH seems intertwined and each is linked to endoplasmic reticulum (ER) dysfunction.4, 8 Aberrant protein folding within the ER, which represents ER stress, stimulates the unfolded protein response (UPR) through activation of 3 pathways, controlled by inositol requiring kinase-1α (IRE1α), activating transcription factor-6 (ATF6), and PRK-like ER kinase (PERK), and together these initiate an adaptive program that serves to restore proteostasis.9