Discovery of A Novel Regulator, 3β-Sulfate-5-Cholestenoic Acid, of Lipid Metabolism and Inflammation.

Abstract

Mitochondrial oxysterols, cholestenoic acid (CA), 25-hydroxycholesterol (25HC), and 27-hydroxycholesterol (27HC), are potent regulators involved in many important biological events. This study aimed to investigate the metabolic pathways of these oxysterols and their roles between hepatocytes and macrophages. LC-MS-MS analysis showed a novel regulatory molecule, 3β-sulfate-5-cholestenoic acid (3SCA), following addition of CA in media culturing hepatocytes. Further study showed that 3SCA could also derived from 27HC. As comparison, 25HC was converted to 25HC3S, of which mostly remained in the cells and nuclei. Functional study showed that 3SCA significantly downregulated the expression of genes involved in lipid metabolism in hepatocytes and suppressed gene expression of pro-inflammatory cytokines induced by LPS in human macrophages. Based on the results, we conclude that 3SCA acts as a secretory regulator for the regulation of lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings shed light on understanding the unique metabolic pathways of these oxysterols and their possible roles in liver tissues.