Elevated plasma cholesterol improves sepsis outcome by promoting hepatic metabolic reprogramming

Area of Science:

• Biochemistry
• Immunology
• Metabolomics

Background:

• Sepsis presents a critical global health challenge with high mortality rates.
• Current therapeutic interventions for sepsis remain limited.
• The potential protective role of plasma cholesterol in sepsis is not well understood.

Purpose of the Study:

• To investigate the association between plasma cholesterol levels and sepsis survival.
• To explore the underlying mechanisms by which elevated cholesterol may confer protection against sepsis.

Main Methods:

• Analysis of 2,787 sepsis patients from the MIMIC-IV database.
• Comparison of cholesterol levels between survivors and non-survivors.
• Multivariable Cox regression to assess mortality risk.
• Causality testing in C57BL/6J mice using high-cholesterol diets and cecal ligation and puncture (CLP) model.

Main Results:

• Sepsis survivors exhibited significantly higher plasma cholesterol levels compared to non-survivors.
• Elevated cholesterol (≥133 mg/dL) was independently associated with a reduced 28-day mortality risk.
• In mice, a high-cholesterol diet improved survival post-CLP, linked to hepatic metabolic reprogramming, enhanced oxidative phosphorylation, and antioxidant pathways, not broad immune activation.
• Inhibition of mitochondrial respiration negated the survival advantage in mice.

Conclusions:

• Elevated plasma cholesterol is associated with improved sepsis outcomes.
• Hepatic metabolic reprogramming, particularly involving bioenergetic pathways, appears to mediate cholesterol's protective effects.
• Targeting hepatic bioenergetics represents a promising therapeutic strategy for sepsis.