Integrated multi-omics analysis of liver metabolic dysregulation in ACE2 knockout mice
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ABSTRACT:
PROVIDER: PRJNA1251660 | ENA |
REPOSITORIES: ENA
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Project description:This study reveals the molecular mechanisms of liver metabolic dysregulation in ACE2 knockout (ACE2KO) mice through multi-omics analysis. ACE2 deficiency exacerbates lipid accumulation, disrupts RAS balance, and induces hepatocyte injury and inflammation. Integrated multi-omics analysis identified numerous differentially expressed genes, proteins, and metabolites, highlighting the PPAR signaling pathway as a central regulatory hub. ACE2 deletion also impairs detoxification and antioxidant balance, creating a self-reinforcing oxidative injury cycle. These findings provide new insights into the mechanisms and therapeutic targets of ACE2-related liver diseases.
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Project description:This study systematically investigated the impact of ACE2 knockout (ACE2KO) on hepatic metabolic homeostasis and its molecular mechanisms, using integrated transcriptomic, proteomic, and metabolomic profiling. ACE2 deficiency exacerbates hepatic lipid accumulation, as evidenced by elevated total cholesterol and triglyceride levels, while disrupting the renin-angiotensin system equilibrium via increased angiotensin II (Ang II) and reduced Ang-(1-7). Histopathological analysis revealed hepatocyte edema, vacuolar degeneration, and inflammatory infiltration in the ACE2KO mice. Multi-omics integration uncovered systemic metabolic dysregulation: transcriptomics identified 1,004 differentially expressed genes (DEGs), including lipid metabolism regulators (Scd1, Fabp1) and circadian rhythm modulators (Arntl, Cry1), 191 differentially expressed proteins (DEPs) associated with interferon signaling activation (Oas1a, Rsad2) and lipid synthesis suppression (Scd1, Fasn), and metabolomics highlighted 193 differential metabolites (DEMs) indicative of bile acid dysregulation, glutathione redox imbalance, and amino acid metabolism anomalies. Cross-omics analysis indicated that the PPAR signaling pathway is a central regulatory hub driving lipid metabolic reprogramming and oxidative stress amplification. Furthermore, ACE2 deletion disrupted cytochrome P450-mediated detoxification and glutathione metabolism, thereby establishing a self-reinforcing oxidative injury cycle. These findings comprehensively delineate ACE2’s multifaceted role in hepatic metabolic homeostasis and provide mechanistic insights into and therapeutic targets for ACE2-associated liver diseases.
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