HSD17B13 Deficiency Modulates Interferon Signaling to Ameliorate Metabolic Dysfunction-Associated Steatohepatitis Fibrosis

The discovery that loss-of-function variants in HSD17B13 are associated with protection from Metabolic dysfunction-associated steatohepatitis (MASH, previously known as NASH) and fibrosis led to the use of HSD17B13-targeting agents in clinical trials but the underlying mechanism remains unknown. We were able to phenocopy the human findings in Hsd17b13-knockout (KO) mice fed choline-deficient amino acid-defined high fat diet (CDAA-HFD). Metabolomic and lipidomic analysis identified a beneficial shift in Hsd17b13-KO from lipotoxic cholesterol and ceramides to neutral lipids and sphingomyelins. Hepatic interferon signaling was upregulated in Hsd17b13-KO in parallel with the decrease in fibrosis. We confirmed in vitro that medium from Hsd17b13-depleted hepatocytes decreases hepatic stellate cell (HSC) activation. Hsd17b13 depletion was sufficient to induce hepatocyte interferon signaling, and induction of this pathway was sufficient to inhibit medium-exposed HSCs. We show that DiHOMEs, lipokines derived from linoleic acid, are likely the mediator by which HSD17B13 affects interferon signaling. Finally, we find a similar upregulation of hepatic interferon signaling in human subjects who carry the HSD17B13 rs72613567 loss-of-function variant. Collectively, our data suggest that loss of HSD17B13 attenuates MASH fibrosis through augmentation of protective hepatocyte interferon signaling to mitigate HSC activation. These findings shed new light on potential strategies to treat MASH-associated fibrosis.