Myeloid-specific IRE1alpha as a mediator of nonalcoholic fatty liver disease

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PROJECT SUMMARY/ABSTRACT Alongside the unabating global obesity crisis, there has been a rise in non-alcoholic fatty liver disease (NAFLD), now affecting as many as ~1-in-3 Americans. While fatty liver has its own impact on liver function, a greater risk to liver health is its potential to develop into nonalcoholic steatohepatitis (NASH), hepatic cirrhosis and/or hepatocellular carcinoma. There are currently no medications approved to treat NAFLD. Moreover, complications of NASH such as hepatic insulin resistance manifest long before liver failure, and NAFLD is present in ~70% of type 2 diabetics. The mechanisms by which NAFLD develops are not well defined, but chronic nutrient excess is implicated. Indeed, mice fed high fat/sugar diets replicates many NAFLD pathologies. In particular, so called “Western” diets high in saturated fatty acids (SFA) induce endoplasmic reticulum (ER) stress in the liver, as well as activation & accumulation of hepatic myeloid cells (MCs). These MCs are key drivers of NAFLD, as grossly depleting them reduces disease severity in mice. Our lab showed excess dietary SFAs activate the ER sensor IRE1alpha (IRE1a) in MCs, and that this is necessary for SFAs to activate the NLRP3- inflammasome. This is important given that the NLRP3 inflammasome, a key inflammatory apparatus that produces IL-1beta, is an ongoing target for amelioration of obesity-associated metabolic diseases. Moreover, we found SFAs activate IRE1a via their flux into cellular phospholipids, suggesting IRE1a not only senses unfolded proteins (canonical ER stress), but also ER membrane saturation. Thus, it is remarkable the potentially important role of MC-specific IRE1a in the pathogenesis of NAFLD & NASH remains largely unexplored. We hypothesize that, in the context of nutrient excess, MC-specific IRE1a mediates activation of the NLRP3 inflammasome within the liver in a manner essential for the progression of NAFLD. We propose to test this hypothesis, including the extent to which MC-specific IRE1a can be targeted to reverse established NASH, using highly innovative & specific new mouse models. We also aim to define the specific structural domain of IRE1a required for MCs to activate the NLRP3 inflammasome and stimulate consequent IL-1beta secretion in response to SFA excess. The proposal will be carried out at UCSF, a world leader in pioneering biomedical research to improve healthcare & expand basic scientific knowledge. UCSF conducts research of the highest caliber, evidenced by being the highest NIH-funded public academic institution. UCSF fosters a highly collaborative, cross-disciplinary research environment, features that are increasingly vital for modern biomedical research. This is leveraged in the current proposal by bringing together mentorship relevant to the liver, ER stress, & immune regulation, promoting an integrated research project with an ultimate focus on metabolic dysfunction. Finally, Dr. Bolus’ current goal is to become an independent investigator, and we have strategically designed his training plan to contain key elements tailored to achieve this. This plan includes development of presentation skills (verbal, visual, & written), local & broader scientific networking, expertise in publishing & dissemination of his research, and successful grant writing.