Elevated plasma cholesterol causally improves sepsis outcome by promoting hepatic metabolic reprogramming

Area of Science:

• Biochemistry
• Pathophysiology
• Genomics

Background:

• Sepsis is a life-threatening condition with high mortality and limited treatment options.
• Low cholesterol levels (hypocholesterolemia) are linked to poor sepsis outcomes, but the causal role and mechanisms are unclear.

Purpose of the Study:

• To investigate if higher plasma cholesterol improves sepsis survival.
• To determine the mechanistic basis for cholesterol's effect on sepsis outcomes.

Main Methods:

• Analysis of septic patient data from the MIMIC-IV database, comparing cholesterol levels between survivors and non-survivors.
• Cox regression to assess the association between cholesterol and mortality, adjusting for covariates.
• Cecal ligation and puncture (CLP) in mice fed a high-cholesterol diet (HCD) or regular diet (RD) to induce sepsis and evaluate survival.

Main Results:

• Septic patients who survived had significantly higher cholesterol levels than non-survivors.
• High cholesterol (≥ 133 mg/dL) was independently associated with a 20% reduction in 28-day mortality.
• In mice, HCD significantly improved sepsis survival from 52.5% to 90% and induced hepatic metabolic reprogramming, including enhanced oxidative phosphorylation and antioxidant pathways.

Conclusions:

• Elevated plasma cholesterol causally improves sepsis outcomes through hepatic metabolic reprogramming.
• These findings provide mechanistic insight into clinical observations and highlight hepatic bioenergetics as a potential therapeutic target for sepsis.