Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis
Lise Van Wyngene1,2, Tineke Vanderhaeghen1,2, Steven Timmermans1,2
1Center for Inflammation Research, VIB, Ghent, Belgium.
EMBO Molecular Medicine
|January 10, 2020
Summary
Sepsis disrupts the liver's fatty acid breakdown, causing harm. A drug targeting PPAR-alpha (peroxisome proliferator-activated receptor alpha) shows promise in protecting liver function and reducing damage during sepsis.
Area of Science:
- Metabolic pathways and liver function in critical illness.
Background:
- Sepsis is a life-threatening condition with significant unmet medical needs.
- While inflammation is well-studied, metabolic dysfunction in sepsis is increasingly recognized.
- The liver's role as a metabolic hub, particularly involving PPARα (peroxisome proliferator-activated receptor alpha), is critical during energy demands.
Purpose of the Study:
- To investigate the role of hepatic PPARα in liver dysfunction during sepsis.
- To explore whether targeting PPARα can mitigate sepsis-induced metabolic derangements and tissue damage.
Main Methods:
- Induction of bacterial sepsis in mice.
- Assessment of hepatic PPARα levels and downstream metabolic consequences.
- Administration of a PPARα agonist (pemafibrate) to evaluate protective effects.
Main Results:
- Sepsis induced a starvation response characterized by decreased hepatic PPARα levels.
- Reduced PPARα function led to excess free fatty acids and glycerol, causing lipotoxicity.
- Treatment with pemafibrate protected mice against bacterial sepsis, reduced lipotoxicity, and minimized tissue damage.
Conclusions:
- Hepatic PPARα decline contributes to liver dysfunction and lipotoxicity in sepsis.
- Pharmacological activation of PPARα with pemafibrate offers a potential therapeutic strategy for sepsis.
- Findings suggest new therapeutic avenues for sepsis, considering increased lipolysis in patients.
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