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Integrated multi-omics analysis of liver metabolic dysregulation in ACE2 knockout mice

ABSTRACT: 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.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12389 | MetaboLights | 2025-06-23

REPOSITORIES: MetaboLights

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Project description:In order to characterize gene expression networks linked to AT1 angiotensin receptors in the kidney, we carried out genome-wide transcriptional analysis of RNA from kidneys of wild-type (WT) and AT1A receptor-deficient mice (KOs) at baseline and after 2 days of angiotensin II infusion (1 ug/kg/min), using Affymetrix GeneChip Mouse Genome 430 2.0 Arrays. At baseline, 405 genes were differentially expressed (>1.5X) between WT and KO kidneys. Of these, more than 80% were up-regulated in the KO group including genes involved in inflammation, oxidative stress, and cell proliferation. After 2 days of angiotensin II infusion in WT mice, expression of ~805 genes was altered (18% up-regulated, 82% repressed). Genes in metabolism and ion transport pathways were up-regulated while there was attenuated expression of protective genes against oxidative stress including glutathione synthetase and mitochondrial SOD2. Angiotensin II infusion has little effect on blood pressure in KOs. Nonetheless, expression of more than 250 genes was altered in kidneys from KO mice during angiotensin II infusion; 14% were up-regulated, while 86% were repressed including genes involved in immune responses, angiogenesis, and glutathione metabolism. Between WT and KO kidneys during angiotensin II infusion, 728 genes were differentially expressed; 10% were increased and 90% were decreased in the WT group. Differentially regulated pathways included those involved in ion transport, immune responses, metabolism, apoptosis, cell proliferation, and oxidative stress. This genome-wide assessment should facilitate identification of critical distal pathways linked to blood pressure regulation. To define gene expression patterns in kidney triggered by of activation AT1 receptors, we used genome-wide transcriptional analysis of RNA from kidneys of wild-type and AT1A receptor-deficient mice at baseline and after 2 days of angiotensin II infusion (1 ug/kg/min), using Affymetrix GeneChip Mouse Genome 430 2.0 Arrays. All of the experiments were conducted with male mice 2.5 months old and included 3 mice per experimental group. Synthesis of cRNA, hybridization and scanning of chips were conducted by Duke University microarray core facility (Duke University, Durham, NC).

Project description:The liver is a major site for synthesis, storage and redistribution of carbohydrates, proteins and lipids. In addition, it is well-known that maternal obesity (MO) increases risk of offspring cardiovascular disease (CVD), diabetes and obesity. However, the mechanisms by which the MO intrauterine environment predisposes offspring to CVD and metabolic dysregulation are unknown. The goal of this study was to assess the impact of MO on primate fetal liver and identify underlying molecular mechanisms by which MO increases disease risk. The goal of this study was to identify candidate molecular mechanisms underlying MO in the near-term NHP fetal liver. This is the first study of NHP fetal MO livers using unbiased transcriptome analysis to quantify hepatic gene expression, identify dysregulated signaling pathways and potential miRNAs regulating the disrupted metabolic processes. Unbiased gene (arrays) and microRNA (miRNA; small RNA-Seq) abundances were quantified in near-term (0.9 Gestation (0.9G)) baboon fetal livers (control (CON) = 6; MO = 5) and subjected to pathway and network analyses (GeneSifter, Ingenuity® Pathway Analysis (IPA)) to identify a coordinated molecular response to MO. Lipid and glycogen content (CON = 16; MO = 16) were quantified by Computer Assisted Stereology Toolbox (CAST) in 0.9G livers.Pairwise comparisons showed 933 differentially expressed genes between CON and MO livers: 350 genes were upregulated and 583 were downregulated. Pathway analysis revealed upregulation of Wnt/β-catenin signaling and downregulation of tricarboxylic acid (TCA) cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO fetal livers compared with CON. Inversely expressed miRNAs that target genes in these pathways provide additional support for the importance of these pathways in fetal liver metabolic regulation. Consistent with the observed pathway changes in MO, we found hepatic lipid content was threefold greater in MO than CON fetal livers (p=0.02). Molecular genetic analyses of CON and MO fetal baboon livers revealed dysregulation of Wnt/β-catenin signaling, TCA cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO livers, all of which are central to fatty acid metabolism and lipid storage. The marked lipid accumulation in MO fetal livers supports our hypothesis that dysregulation of these pathways detrimentally impacts lipid management. Furthermore, our findings demonstrate the detrimental impact of MO on fetal liver development and suggest impaired hepatic function prior to birth.

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Integrated multi-omics analysis of liver metabolic dysregulation in ACE2 knockout mice

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