A Novel Hypothesis for the Protective Rise in Cholesterol Sulfate Against Lipid Metabolic Disorders

As a cholesterol metabolite, cholesterol sulfate (CS) is widely distributed in the human body, and its role as a regulatory factor has been continuously explored from the 1980s to the present day. However, changes in CS in metabolic disorders have not been systematically investigated. Here, rodent models of insulin resistance, fatty liver, and atherosclerosis were established. The CS content, CS to cholesterol ratio, and CS to total bile acids (TBA) ratio in the serum and liver of these model mice were compared with those of normal mice. Results showed the CS content was increased in fatty liver and atherosclerosis models of mice; meanwhile, it might be influenced by genotype, such as CD36 deficiency. The changes in the CS to cholesterol ratio were related to the amount and distribution of cholesterol. Besides, there was competition between the catabolism of cholesterol to bile acids or CS, as evidenced by the opposite trend between the TBA to cholesterol ratio and the CS to TBA ratio. Moreover, for the first time, it has been discovered that CS is enriched in lipid droplets, which further substantiates the close association between CS and lipid metabolism. Building on studies that demonstrated the beneficial effects of CS supplementation in alleviating lipid metabolic disorders, we first proposed the hypothesis that an increase in CS content may be protective against lipid metabolic disorders. This study provided a new perspective on the role of CS as a regulatory factor in metabolic disorders.