We show that in vitro stimulation with HSP70 and GRP78, as well as serum from obese IR subjects with NAFLD, impairs insulin-mediated glucose uptake and insulin signaling and stimulates fat accumulation in HepG2, circulating peripheral blood mononuclear cells (PBMCs) and monocyte subpopulations. Here, HSPA5 is linked to metabolic dysfunction-associated steatotic liver disease.