Pharmacologic targeting of the UPR in obesity-linked liver dysfunction

SUMMARY Unhealthy diets and increasingly sedentary lifestyles have led to an epidemic rise in obesity and obesity-related disorders such as Type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD), the latter of which can progress to the more severe condition nonalcoholic steatohepatitis (NASH). Despite their prevalence, limited options exist to treat obesity-linked diseases, particularly NAFLD/NASH. This has led to significant interest in developing new therapeutic strategies to mitigate the tissue-specific metabolic dysfunction implicated in obesity and obesity-driven pathologies. Clinical, biological, and biochemical evidence demonstrates that dysregulated signaling through the unfolded protein response (UPR), the stress-responsive signaling pathway that remodels cellular physiology to counter endoplasmic reticulum (ER) stress, is a critical determinant in dictating the metabolic imbalances associated with obesity and obesity-linked conditions. The UPR comprises three signaling pathways activated downstream of the ER stress sensing proteins IRE1, PERK, and ATF6. Signaling through the PERK arm of the UPR is generally associated with pathologic outcomes in obesity. In contrast, signaling downstream of IRE1 and ATF6, primarily mediated by the adaptive stress-responsive transcription factors XBP1s and ATF6, respectively, has been shown to protect various organs from obesity-linked alterations. This suggests that activation of protective IRE1/XBP1s and ATF6 signaling may represent a new strategy to alleviate metabolic dysfunction in obesity-linked diseases. We hypothesize that pharmacologic activation of protective IRE1/XBP1s or ATF6 signaling will foster adaptive remodeling in multiple key metabolic tissues to broadly ameliorate tissue-specific pathologies associated with obesity. We recently developed first-in- class, highly-selective IRE1/XBP1s and ATF6 activating compounds that enable us, for the first time, to determine the impact of pharmacologic activation of these protective UPR pathways in mouse models of T2D and NAFLD/NASH. Using these compounds, we have shown that pharmacologic IRE1/XBP1s or ATF6 activation stimulates adaptive remodeling that mitigates damage in multiple organs central to obesity-related conditions, including liver and pancreas. Here, we expand these findings to define how increased protective IRE1/XBP1s or ATF6 signaling corrects tissue-specific metabolic defects to enhance overall metabolic health in mouse models of T2D and NAFLD/NASH. Through these efforts, we will reveal new mechanisms whereby protective IRE1/XBP1s and ATF6 signaling remodel tissue-specific and organismal metabolism in obesity-linked disorders and establish pharmacologic IRE1/XBP1s and ATF6 activation as broadly-applicable therapeutic strategies to mitigate the systemic metabolic dysfunction seen in obesity-driven conditions such as T2D and NAFLD/NASH.