Revisiting hypocholesterolemia during prolonged sepsis: From targeted cholesterol repletion to unresolved adrenal and muscle dysfunction

Background Sepsis HDL- and LDL-hypocholesterolemia associate with adverse outcomes, but whether this necessitates supplementation or merely reflects disease severity remains unclear. We hypothesize that sustained hypocholesterolemia can contribute to ICU-acquired weakness and adrenal dysfunction, and that cholesterol supplementation can improve tissue cholesterol availability, muscle and adrenal integrity. Methods In a catheterized mouse model of cecal-ligation-and-puncture-induced sepsis (5-days), septic mice received continuous infusion with an LDL- (mouse study 1; n=51) (3.5 mg/d) or HDL-cholesterol (mouse study 2; n=47) (5 mg/d) enriched cholesterol mixture, compared to placebo, and healthy reference mice. Plasma HDL-, LDL-cholesterol, CORT, TNF-α and total bile acids were measured, in addition to muscle force, myofiber cholesterol, ex-vivo adrenal ACTH response, adrenal cholesterol and structure. Gene expression markers of cholesterol synthesis were measured in liver, adrenal and muscle tissue. Results LDL-cholesterol infusion in septic mice increased plasma LDL-, but not HDL-cholesterol, whereas HDL-cholesterol infusion increased plasma HDL- and LDL-cholesterol (P<0.0001 versus placebo). Cholesterol supplementation attenuated sepsis-induced adrenal cholesterol depletion (P<0.05), without improving adrenocortical structure or the adrenal ACTH response. Cholesterol supplementation did not affect muscle mass loss, force or myofiber cholesterol, but increased plasma bile acids and reduced markers of cholesterol synthesis in liver, adrenal and muscle versus placebo (P≤0.05). No additional effect on elevated plasma CORT and TNF-α was observed. Conclusion Cholesterol supplementation reversed sepsis-induced hypocholesterolemia, without reversing the sepsis-induced adrenal or muscle phenotype. Together with suppressed markers of cholesterol uptake, synthesis and increased bile acid formation, these findings argue against the need to treat hypocholesterolemia during prolonged sepsis.