Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERR⍺-dependent manner

Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of autophagy repressor mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions.

Notably, this phenotype was found exacerbated in mice with genetic or pharmacological inhibition of the master transcriptional regulator of energy metabolism, nuclear receptor ERR⍺. In this study, we show that combining autophagy inhibitor chloroquine with the autophagy inducer rapamycin attenuates the severity of hepatic lipid deposition observed with rapamycin monotherapy. Bulk mRNA-seq profiling showed that chloroquine co-injection reverses the upregulation of a large proportion of genes linked to lipid metabolism homeostasis found induced by rapamycin alone.