Mitochondrial Oxysterol Signaling in Epigenetic Regulation and Therapeutic Development

Oxysterols are oxygenated cholesterol derivatives with receptor-dependent and epigenetic activities. This review examines how mitochondrial cholesterol metabolism and oxysterol sulfation may connect lipid metabolism to DNA methylation and communication between hepatocytes and macrophages. Biochemical studies show that 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC) activate DNA methyltransferase 1 (DNMT1), whereas their 3-sulfated derivatives inhibit the activities of DNMT1, DNMT3A, and DNMT3B. Cholestenoic acid (CA) has a concentration-dependent effect, activating DNMT1 at lower concentrations and inhibiting it at higher concentrations. In hepatocyte models, these activities are associated with altered promoter CpG methylation and expression of genes involved in lipid metabolism, inflammatory responses, and cell survival. The sulfated CA metabolite, 3β-sulfate-5-cholestenoic acid (3SCA), is secreted by hepatocytes and modifies inflammatory gene expression in macrophages. We propose an oxysterol epigenetic rheostat in which metabolite concentrations and sulfation influence DNMT activities. Published animal studies support protective effects of 25-hydroxycholesterol 3-sulfate in fatty liver disease, endotoxemia, and acetaminophen-induced liver injury. Its clinical formulation, larsucosterol, has shown favorable hepatic and metabolic signals in Phase 1b fatty liver studies and nominally significant mortality reductions in prespecified US Phase 2b alcohol-associated hepatitis (AH) analyses. These encouraging findings require confirmation because the overall Phase 2b primary endpoint was not met. Larsucosterol has received Fast Track and Breakthrough Therapy designations from the US Food and Drug Administration (FDA) for AH and is currently being evaluated in a registrational Phase 3 trial.