Hepatic activating transcription factor 3 protects against systemic inflammation by attenuating lipotoxicity

Area of Science:

• Molecular Biology
• Metabolic Disease Research
• Immunology

Background:

• Activating transcription factor 3 (ATF3) is implicated in lipid metabolism.
• The role of hepatic ATF3 in systemic inflammation and its mechanisms are not fully understood.

Purpose of the Study:

• To investigate the impact of hepatic ATF3 on systemic inflammation.
• To elucidate the underlying mechanisms of ATF3's anti-inflammatory effects.

Main Methods:

• Developed mouse models with liver-specific ATF3 overexpression or knockdown using adeno-associated virus vectors.
• Utilized high-fat diet-induced and genetic models of obesity and inflammation (db/db mice).
• Conducted co-culture studies with hepatocytes and adipose tissue.

Main Results:

• Hepatocyte ATF3 overexpression reduced high-fat diet-induced systemic inflammation and reversed inflammation in db/db mice.
• Loss of hepatic ATF3 exacerbated diet-induced systemic inflammation.
• ATF3's anti-inflammatory effects were linked to reduced hepatic lipid accumulation and lipotoxicity, potentially via AMPKα activation.

Conclusions:

• Hepatic ATF3 alleviates systemic inflammation by mitigating hepatic lipotoxicity.
• AMPKα activation may mediate the anti-inflammatory effects of ATF3.
• Targeting hepatic ATF3 offers a potential therapeutic strategy for inflammation associated with hepatic lipotoxicity.