Cholesterol Sulfate as a Negative Regulator of Cellular Cholesterol Homeostasis.

Abstract

Cholesterol sulfate (CS), one of the most abundant cholesterol derivatives, recently emerged as a key regulatory molecule in several physiological processes. Here, we demonstrate multiple mechanisms by which CS reduces intracellular cholesterol levels. CS promotes the proteasomal degradation of HMG-CoA reductase (HMGCR) by enhancing INSIG-mediated ubiquitination, thereby inhibiting cholesterol synthesis. In addition, CS blocks low-density lipoprotein (LDL) receptor endocytosis, reducing LDL cholesterol (LDL-C) uptake. CS further suppresses the proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2), a master transcription factor governing cholesterol synthesis and uptake. Using in vitro and in vivo models, we show that CS lowers cholesterol by targeting both the cholesterol synthesis and uptake pathways, while also modulating an important feedback loop via SREBP2. These findings highlight the potential of CS as a modulator of cholesterol metabolism, offering new therapeutic insights into cholesterol-related disorders.