Impact of infusing the cholesterol precursor mevalonate on the hypocholesterolemia of sepsis and its potential consequences: a paradoxical response

Hypocholesterolemia hallmarks sepsis, though its pathophysiology and tissue-specific consequences are unclear. As low circulating cholesterol may reflect impaired endogenous cholesterol synthesis, we hypothesized that infusion of the cholesterol precursor mevalonate can reverse sepsis-induced hypocholesterolemia, whereby beneficially affecting adrenal and muscle integrity. In a catheterized mouse model of cecal-ligation and puncture-induced sepsis (male 24-week-old C57BL/6J mice), septic mice received either 5-day mevalonate infusion (78 mg/d) or placebo, versus healthy controls (n=50). Plasma HDL-, LDL-cholesterol, corticosterone, total bile acids, and adrenocortical lipids, myofiber cholesterol and muscle force were quantified. Expression markers of cholesterol homeostasis and structural integrity were investigated in adrenal, muscle and liver tissue. Liver mevalonate metabolites were quantified with LC-MS. Next, a secondary analysis on a prospective observational human study on the time course of adrenal function in the ICU was performed to assess the association between plasma cholesterol and cortisol (n=47). Also, plasma mevalonate was quantified with LC-MS. In septic mice, 5-day mevalonate infusion worsened HDL- and LDL-hypocholesterolemia versus placebo (P<0.05). Decreased hepatic cholesterol synthesis expression markers, apolipoproteins and hepatic cholesterol concentrations were observed in mevalonate-infused septic mice versus placebo (P<0.05). No additional effect on plasma corticosterone, bile acids, myofiber cholesterol, and loss of muscle force and adrenocortical lipid depletion was observed. In prolonged sepsis patients, plasma mevalonate was increased, whereas plasma HDL- and LDL-cholesterol were low (P<0.05), but did not correlate with plasma cortisol. To conclude, mevalonate infusion worsened sepsis-induced hypocholesterolemia, possibly due to increased feedback on hepatic cholesterol synthesis, without aggravating the adrenal or muscle sepsis phenotype.