HNF4α contributes to hepatic CAR dysfunction in polymicrobial sepsis

Area of Science:

• Hepatology and Molecular Endocrinology
• Sepsis Pathophysiology and Metabolism

Background:

• Constitutive androstane receptor (CAR) regulates hepatic metabolism and is a potential therapeutic target for liver diseases.
• CAR's role in sepsis, a life-threatening condition with altered drug metabolism and liver function, remains largely unexplored.
• Hypothesis: CAR function is impaired during sepsis, impacting liver processes.

Purpose of the Study:

• To investigate the functional status of CAR in the liver during sepsis.
• To elucidate the molecular mechanisms underlying CAR dysfunction in sepsis.
• To assess the therapeutic potential of targeting CAR in sepsis.

Main Methods:

• Sepsis model induction and administration of CAR agonist (TCPOBOP) and inhibitor (CINPA1).
• Analysis of *Nr1i3* mRNA expression, HNF4α binding to the *Nr1i3* promoter, and Ppara expression.
• Assessment of CAR DNA binding, chromatin accessibility, and gene expression related to metabolism and acute phase response.

Main Results:

• CAR function is significantly diminished in the liver during sepsis, evidenced by reduced response to TCPOBOP.
• Sepsis downregulates *Nr1i3* transcription via decreased HNF4α binding and reduced Ppara expression, impairing CAR DNA binding.
• CAR loss-of-function in sepsis leads to altered metabolic gene expression and an acute phase response, but inhibiting CAR worsens sepsis lethality.

Conclusions:

• CAR plays a crucial role in maintaining hepatic metabolism, regeneration, and survival during sepsis.
• CAR is rapidly downregulated in sepsis, making it an unlikely therapeutic target; upstream regulators like HNF4α warrant further investigation.
• Targeting HNF4α may offer a more promising therapeutic strategy for sepsis management.