Sepsis: a failing starvation response.

Area of Science:

• Biochemistry
• Pathophysiology
• Metabolic Medicine

Background:

• Sepsis accounts for approximately 20% of global annual deaths, with current management remaining largely supportive.
• Decades of clinical trials targeting sepsis inflammation have yielded limited success.
• Emerging evidence highlights significant metabolic dysregulation in sepsis, suggesting metabolic pathways as potential therapeutic targets.

Purpose of the Study:

• To review the literature on metabolic dysregulation in sepsis.
• To elucidate mechanisms underlying sepsis-induced metabolic alterations.
• To identify potential therapeutic targets for preventing or reversing fatal metabolic derangements in sepsis.

Main Methods:

• Literature review of studies on sepsis pathophysiology and metabolism.
• Analysis of molecular mechanisms involving transcription factors in sepsis.
• Identification of key metabolic pathways affected during sepsis.

Main Results:

• Sepsis triggers a starvation response with increased release of metabolites like lactate and free fatty acids.
• Downregulation of glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes contributes to metabolite toxicity.
• Impaired conversion of metabolites into essential molecules like glucose and ketones is observed.

Conclusions:

• Metabolic dysregulation is a critical, yet often overlooked, aspect of sepsis.
• Targeting the activity of transcription factors GR and PPARα may offer novel therapeutic avenues.
• Interventions aimed at correcting metabolic derangements hold promise for improving sepsis outcomes.