ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression

Area of Science:

• Hepatology
• Molecular Biology
• Metabolic Disease

Background:

• Activating transcription factor 4 (ATF4) regulates oxidative stress in various cell types.
• Its specific role in hepatocytes, particularly under high-fat diet (HFD) conditions, remains uncharacterized.

Purpose of the Study:

• To investigate the role of ATF4 in hepatocytes during oxidative stress induced by a high-fat diet.
• To elucidate the molecular mechanisms by which ATF4 influences HFD-induced liver damage.

Main Methods:

• Primary hepatocyte culture and ATF4 knockdown models.
• High-fat diet (HFD) administration in mice with ATF4 knockdown.
• Measurement of reactive oxygen species (ROS), triglyceride (TG) accumulation, and CYP2E1 expression.
• Analysis of CYP2E1 promoter activity and in vivo inhibition studies.

Main Results:

• ATF4 deficiency blocked palmitate-stimulated ROS production and TG accumulation in primary hepatocytes.
• Knocking down ATF4 in mice reduced HFD-induced oxidative stress, TG accumulation, and CYP2E1 expression.
• CYP2E1 expression was indirectly regulated by ATF4 via a CREB-dependent pathway.
• Inhibition of CYP2E1 reduced ATF4-stimulated ROS production in vivo.

Conclusions:

• ATF4 is a novel regulator of oxidative stress and triglyceride accumulation in hepatocytes under HFD conditions.
• ATF4 plays a protective role against HFD-induced liver injury by modulating CYP2E1 expression.
• Targeting ATF4 or its downstream pathways may offer therapeutic strategies for managing diet-induced liver disease.