DNAJB4 Protects Against Atherosclerosis by Stabilizing the HSP70-LXRα Axis in Hepatic Lipid Metabolism

DNAJB4, a member of the DNAJ/HSP40 family, functions as a co-chaperone of HSP70, regulating protein homeostasis and cellular functions. However, the molecular mechanism underlying the biological effect of DNAJB4 on lipid metabolism remains unclear. We investigated the role of DNAJB4 and its molecular mechanism in hyperlipidemia and atheroprone apolipoprotein E-null (apoe^-/- ) mice. Western blot analysis and immunohistochemistry were used to assess decreased DNAJB4 expression in apoe^-/- mice. Moreover, the genetic deletion of DNAJB4 led to an increase in hepatic lipid accumulation and hyperlipidemia in apoe^-/- mice, as evidenced by decreased expression of proteins related to cholesterol esterification and clearance, and an increased hepatic level of triglycerides, fatty acids, glycerol, free cholesterol, total cholesterol, and bile acid. Mechanistically, DNAJB4 deficiency impaired the protein stability of HSP70, reduced nuclear HSP70 association, and downregulated HSP70-induced LXRα transcription. The genetic deletion of DNAJB4 also promoted LXRα protein degradation and reduced LXRα autoregulation, thereby exacerbating the decrease in LXRα and LXRα-mediated gene expression. Furthermore, treatment with curcumin and andrographolide, the inducers of DNAJB4, did not reduce the atherosclerotic lesions at the aortic sinus in apoe^-/-dnajb4^-/- mice, suggesting that DNAJB4 is required for the atheroprotective effect of curcumin and andrographolide. Our findings indicate that DNAJB4 plays a crucial role in regulating the HSP70-LXRα axis in hyperlipidemia, hepatic lipid accumulation, and atherosclerosis. Here, we identify DNAJB4 as a critical HSP70 co-chaperone that stabilizes HSP70, promotes its nuclear association, and sustains LXRα autoregulation in hepatic lipid metabolism.