Endocrine Abstracts

JOINT1651

Background: Hypocholesterolemia is a hallmark of sepsis, associated with adverse outcomes. Both serum HDL- and LDL-cholesterol rapidly drop from the onset of critical illness onwards. Whether hypocholesterolemia necessitates intervention or merely reflects a marker of disease severity is unclear. We hypothesize that low cholesterol levels are potential contributors to ICU-acquired muscle weakness and adrenal failure and that supplementation with cholesterol can improve tissue cholesterol availability, thereby improving muscle and adrenal integrity. Our hypothesis was tested in a clinically relevant mouse model of prolonged sepsis.

Methods: In a catheterized mouse model of cecal-ligation and puncture-induced, fluid resuscitated and antibiotics-treated prolonged (5 days) sepsis, septic mice received continuous IV-infusion of a bovine serum cholesterol mixture containing predominantly LDL-cholesterol (animal study 1; n=51), or human plasma purified HDL-cholesterol (animal study 2; n=47), as compared to placebo. Healthy mice served as controls. Plasma HDL-, LDL-cholesterol, CORT, TNF-α and total bile acids were measured, in addition to ex vivo specific muscle force, and adrenal cholesterol content (Oil Red O staining) and structure (H&E staining). Gene expression markers of inflammation (Tnf-α) and cholesterol synthesis (Hmgcs1, Hmgcr, Fdft1) were measured in the liver.

Results: In both studies, mortality was not affected by the cholesterol supplementation. In animal study 1, five-day LDL-supplementation in septic mice increased plasma LDL-cholesterol but not HDL-cholesterol as compared to placebo (P<0.0001) and attenuated the sepsis-induced reduction of adrenal cholesterol content (P=0.0004) but without improving the distortion of adrenal structure. LDL-supplementation had no additional effect on sepsis-induced loss of muscle mass and force. In contrast, plasma total bile acids were elevated and hepatic gene expression markers of cholesterol synthesis were overall decreased with LDL-supplementation as compared to placebo, whereas Tnf-α expression was further increased (P<0.05). Elevated plasma CORT and TNF-α were not affected by LDL-supplementation. In animal study 2, five-day HDL-supplementation of septic mice substantially increased plasma HDL-cholesterol and even more so LDL-cholesterol as compared to placebo (P<0.0001). HDL-supplementation attenuated the sepsis-induced reduction of adrenal cholesterol content (P=0.006) but without improving adrenal structure. Also, HDL-supplementation did not attenuate the sepsis-induced loss of muscle mass and force. Additional analyses are currently ongoing to further assess the impact on cholesterol homeostasis and functional markers in muscle, adrenal and liver tissue.

Conclusion: Cholesterol supplementation reversed hypocholesterolemia in prolonged septic mice, but without reversing adrenal structural changes or muscle function. Tissue-specific effects on inflammation and cholesterol homeostasis require further investigation.