The adaptive unfolded protein responses (UPR) initiated by ER stress have been implicated in metabolic dysfunctions and liver diseases. Growth differentiation factor 15 (GDF15) shows a broad range of effects on lipid homeostasis. The functional interconnections between ER stress and GDF15 are still unclear, however. Here we present that hepatic excess lipid accumulation along with ER stress could exacerbate GDF15 expression in mouse liver. Administration of chemical ER stressor tunicamycin to activate the UPR pathway resulted in robust increase of hepatic and circulating GDF15 levels. Further studies revealed that C/EBP-homologous protein (CHOP) of the UPR pathway could directly bind to the promoter of GDF15 and activate its transcription under ER stress conditions both ex vivo and in vivo. Ectopic expression of hepatic GDF15 reduced lipid accumulation in liver and alleviated non-alcoholic fatty liver disease (NAFLD) progression via enhancing hepatic fatty acid beta-oxidation in HFD-feeding mice. Together, our results demonstrate that hepatic GDF15 acts as a downstream component of the UPR program and exerts beneficial functions in regulating lipid metabolism of liver. (C) 2017 Elsevier Inc. All rights reserved.