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

BACKGROUND: Activating transcription factor 3 (ATF3) is known to play a key role in regulating lipid and lipoprotein metabolism. However, the effects of hepatic ATF3 on systemic inflammation and the underlying mechanisms remain unclear. METHODS: An adeno-associated virus with hepatocyte-specific promoter was used to construct mouse models with hepatocyte-specific overexpression or knockdown of ATF3. RESULTS: Overexpression of human ATF3 in hepatocytes prevented high-fat (HF) diet-induced systemic inflammation in C57BL/6J mice and reversed systemic inflammation in db/db mice. Conversely, hepatocyte-specific loss of ATF3 aggravated diet-induced systemic inflammation. In co-culture studies, the anti-inflammatory effect of hepatocyte ATF3 on adipose tissue was found to be dependent on the presence of free fatty acids mixture. Mechanistically, ATF3 ameliorated HF diet-induced hepatic lipid accumulation and lipotoxicity likely mediated through AMPKα activation. CONCLUSION: Our findings collectively indicate that hepatocyte ATF3 alleviates systemic inflammation by reducing hepatic lipotoxicity, a mechanism that may involve the activation of AMPKα. Targeting hepatic ATF3 represents a promising therapeutic strategy for systemic inflammation induced by hepatic lipotoxicity.