These pathways induce inflammatory reactions and hepatocyte apoptosis and promote NASH progression.304 Activated hepatic IRE1ɑ can increase the release of ceramide-rich EVs via XBP1-induced transcription of serine palmitoyl transferase, leading to the recruitment of monocyte-derived macrophages to the liver and to NASH in mice.305 In addition, cysteine-rich with EGF-like domains 2 (Creld2), which is a target of the UPR sensor ATF6, promotes tolerance to ER stress by augmenting protein folding. Here, CRELD2 is linked to metabolic dysfunction-associated steatohepatitis.