Heat Shock Protein 90 Modulates Lipid Homeostasis by Regulating the Stability and Function of Sterol Regulatory Element binding Protein (SREBP) and SREBP Cleavage activating Protein*
Sterol regulatory element binding proteins (SREBPs) are the key transcription factors that modulate lipid biosynthesis. SREBPs are synthesized as endoplasmic reticulum bound precursors that require proteolytic activation in the Golgi apparatus. The stability and maturation of precursor SREBPs depend on their binding to SREBP cleavage activating protein (SCAP) which escorts the SCAP SREBP complex to the Golgi apparatus. In this study, we identified heat shock protein (HSP) 90 as a novel SREBP regulator that binds to and stabilizes SCAP SREBP. In HepG2 cells, HSP90 inhibition led to proteasome dependent degradation of SCAP SREBP, which resulted in the down regulation of SREBP target genes and the reduction in intracellular triglyceride and cholesterol levels. We also demonstrated in vivo that HSP90 inhibition decreased SCAP SREBP protein, down regulated SREBP target genes, and reduced lipids levels in mouse livers. We propose that HSP90 plays an indispensable role in SREBP regulation by stabilizing the SCAP SREBP complex, facilitating the activation of SREBP to maintain lipids homeostasis.
The Journal of Biological Chemistry