Metabolic liver disease arises due to dysregulated signaling between hepatocytes and non-parenchymal cells (NPCs). Through parallel RNA sequencing screens in diet-induced and genetic mouse models, backdropped by human transcriptomic data, we identified latent TGFβ binding protein-3 (LTBP3) – a regulator of TGFβ secretion – as a novel contributor to metabolic liver disease pathogenesis. GalNAc-conjugated Ltbp3 ASO reduced hepatic triglyceride accumulation in diet-induced metabolic liver disease mouse models, which was phenocopied in mice lacking hepatocyte TGFβ activity, but surprisingly not in hepatocyte-specific Ltbp3 knockout mice. This discordance prompted evaluation as to whether GalNAc-based tools are hepatocyte-specific. In fact, we found that GalNAc-Ltbp3 ASO also targeted multiple NPC populations, reducing intrahepatic TGFβ activity, culminating to lowered lipid content by increased proteasomal degradation of the key lipogenic enzyme Acetyl-CoA-Carboxylase 1 (ACC1) in hepatocytes. These data reveal a previously unrecognized NPC-hepatocyte axis to regulate lipogenesis in metabolic liver disease.