Hepatocyte-Specific Nrf2 Deficiency Alters Cholesterol Metabolism, Leading to Mitigated Atherosclerosis in ApoE-Knockout Mice

Furthermore, hepatic triglyceride levels and cholesterol contents were increased in Nrf2(H)-KO;ApoE-KO mice. The hepatic transcriptomic analysis highlighted lipid metabolism pathway alterations in Nrf2(H)-KO;ApoE-KO mice, and carboxylesterase 1 (Ces1s) and lipocalin gene family member major urinary proteins (Mups) clusters markedly reduced expression in Nrf2(H)-KO;ApoE-KO livers. Liver proteomics analysis corroborated the transcriptomic findings.

The current findings suggest that NRF2-modulated CES1s and MUPs may regulate cholesterol metabolism in the ApoE-KO model. Conclusions: Hepatocyte-specific Nrf2 deficiency significantly reduced plasma cholesterol levels, thereby attenuating atherosclerotic plaque formation and progression in the ApoE-KO background. This study established NRF2 in hepatocytes as a potential therapeutic target for controlling hypercholesterolemia and preventing atherosclerosis development.