{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE346nnn/GSE346814/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE346814"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Hepatocyte-Specific Nrf2 Deficiency Alters Cholesterol Metabolism, Leading to Mitigated Atherosclerosis in ApoE-Knockout Mice","description":"Hypercholesterolemia and hyperlipidemia are major contributors to the pathogenesis and progression of atherosclerosis and cardiovascular diseases (CVDs). Nuclear factor erythroid-derived 2-like 2 (NRF2) exerts antioxidant and anti-inflammatory effects while regulating glucose and lipid metabolism. However, the precise role and molecular mechanisms of NRF2 in hepatic cholesterol metabolism remain incompletely understood. Approach and Results: ApoE-knockout (ApoE-KO) mice were crossed with hepatocyte-specific Nrf2-knockout (Nrf2(H)-KO) mice to explore how NRF2 modulated cholesterol metabolism and the progression of atherosclerosis in vivo. Atherosclerotic lesion areas in Nrf2(H)-KO;ApoE-KO mice were significantly reduced compared with control counterparts (Nrf2-LoxP;ApoE-KO). Total cholesterol and LDL-cholesterol levels in plasma of Nrf2(H)-KO;ApoE-KO mice were significantly decreased, consistent with atherosclerotic phenotypes. 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.","dates":{"publication":"2026/09/15"},"accession":"GSE346814","cross_references":{"GSM":["GSM10040826","GSM10040819","GSM10040821","GSM10040820","GSM10040825","GSM10040824","GSM10040823","GSM10040822"],"GPL":["28330"],"GSE":["346814"],"taxon":["Mus musculus"]}}