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The Many Roles of Cholesterol in Sepsis: A Review. RATIONALE: The biological functions of cholesterol are diverse, ranging from cell membrane integrity and signalling, immunity, to the synthesis of steroid and sex hormones, Vitamin D, bile acids and oxysterols. Multiple studies have demonstrated hypocholesterolemia in sepsis, the degree of which is an excellent prognosticator of poor outcomes. However, the clinical significance of hypocholesterolemia has been largely unrecognized. OBJECTIVES/METHODS: We undertook a detailed review of the biological roles of cholesterol, the impact of sepsis, its reliability as a prognosticator in sepsis, and the potential utility of cholesterol as a treatment. MEASUREMENTS AND MAIN RESULTS: Sepsis affects cholesterol synthesis, transport and metabolism. This likely impacts upon its biological functions including immunity, hormone and vitamin production, and cell membrane receptor sensitivity. Early preclinical studies show promise for cholesterol as a pleiotropic therapeutic agent. CONCLUSIONS: Hypocholesterolemia is a frequent condition in sepsis and an important early prognosticator. Low plasma levels are associated with wider changes in cholesterol metabolism and its functional roles, and these appear to play a significant role in sepsis pathophysiology. The therapeutic impact of cholesterol elevation warrants further investigation.