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Serum proteomics and metabolomics reveal the characteristics of the A1762T/G1764A mutations in conjunction with the G1896A mutation.

ABSTRACT: Background and Objective: CHB is a complex heterogeneous disease with a high incidence and mortality rate. Especially, the mutant strains with A1762T/G1764A and G1896A mutations gradually gained survival advantages during the population evolution process. However, our current understanding of the potential pathogenic mechanism of the mutant strains is limited. Our goal is to use multi-omics analysis to elucidate the potential molecular mechanisms, develop biomarkers for assessing the severity of the disease, and explore potential therapeutic targets. Methods: Based on the sequencing results of serum HBV DNA in the samples, we finally included 108 patients with chronic hepatitis B. According to the sequencing results, they were divided into groups A (wild strain, WT = 27), B (G1896A = 27), C (A1762T/G1764A = 27), and D (A1762T/G1764A + G1896A = 27). We conducted non-target metabolomics and proteomics analyses to investigate the changes in the metabolism of infected liver cells caused by different site mutations. We selected the A1762T/G1764A group and the A1762T/G1764A + G1896A group for comparative analysis with the WT group, aiming to gain a deeper understanding of the pathogenic mechanism of the dominant mutant strains. Results: Compared with WT, the A1762T/G1764A group and the A1762T/G1764A + G1896A group identified 242 and 64 as well as 226 and 79 differentially expressed metabolites and proteins, respectively. Through ipath pathway analysis and KEGG pathway mapping analysis, we found that A1762T/G1764A and A1762T/G1764A + G1896A might aggravate liver injury by affecting base repair and increase lipid accumulation in liver cells by down-regulating cholesterol metabolism. In the A1762T/G1764A + G1896A group, four proteins, APOC2, APOA2, CETP, and ANGPTL4, coordinated their functions to inhibit lipid metabolism and aggravate lipid accumulation in liver cells. Conclusion: A1762T/G1764A and G1896A mutations may affect base repair and aggravate liver cell damage, and at the same time, by down-regulating the cholesterol metabolism pathway, aggravate lipid accumulation in liver cells and accelerate disease progression.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

SUBMITTER: Chen Yimin

LAB HEAD: Yimin Chen

PROVIDER: PXD066939 | Pride | 2026-04-14

REPOSITORIES: Pride

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Project description:Background & Aims Obesity is a major risk factor for metabolic associated steatotic liver disease (MASLD) which can progress from metabolic associated steatotic liver (MASL) to metabolic associated steatohepatitis (MASH). There are currently no effective and validated screening tools to stratify obese patients with a greater risk for MASH, independent of liver fibrosis, at a population level. We aimed to characterise the highly abundant and small protein plasma proteomes of worsening MASLD and overlay the liver-secreted proteome to generate a predictive model to stratify patients with and without MASH. Methods Venous blood and liver wedge biopsies were taken from 160 patients undergoing bariatric surgery. MASLD severity was assessed histologically. Liver biopsies from a subset of 96 patients were precision-cut and cultured to assess liver-secreted proteins. Proteomic analysis was performed using liquid chromatography-tandem mass spectrometry on the plasma and the incubation medium cutoff the liver slices. Results Current non-invasive scores failed to stratify MASH in our cohort. The top200 plasma proteome exhibited mild changes in patients with MASH compared to those with No pathology, while the SPEA approach identified substantial differences in plasma proteins of patients with MASH compared to those without MASH. Liver-secreted proteins were remodelled in MASH compared to MASL and individuals with No pathology. There were no significant changes in the liver-secreted proteins and plasma proteome when comparing MASL to those with No pathology. The APASHA model, comprised of APOF, PCSK9, AFM, and S100A6, HbA1c % and AZGP1 stratified MASH in the discovery (AUROC: 0.887, p<0.0001) and validation cohorts (AUROC:0.7673, p=0.0002) and outcompeted other non-invasive scores. Conclusions These proteomic investigations provide a detailed description of liver-secreted and plasma proteome with worsening MASLD. MASH remodels plasma and liver-secreted proteins. Plasma proteomics generated the APASHA model validated in two Australian bariatric cohorts. Further investigation is warranted to interrogate the utility of the APASHA model as a non-invasive risk prediction model in additional cohorts. Lay Summary: Metabolic-associated steatohepatitis (MASH), a more advanced form of metabolic-associated steatotic liver disease (MASLD), alters the levels of many proteins secreted by the liver and in the blood and those. The APASHA model, which is based on proteins that change in the blood or are secreted by the liver in cases of MASH, could potentially be developed into a simple blood test to predict MASH in high-risk groups.

Project description:Anthocyanins and flavonols are natural compounds that accumulate preferentially in grapevine flowers and fruits. They are among the most abundant flavonoids and play a very important role in grape and wine quality. In particular, they confer and stabilize colour and contribute to other organoleptic characteristics of the final product. Their complex profile in terms of concentration and relative abundance varies among cultivars and makes wine typicity. The synthesis of these compounds is mainly regulated at transcriptional level. Flavonoids accumulate at specific stages and in specific tissues during flower and berry development, as a consequence of the timely expression of the genes necessary for their synthesis. Although the general flavonoid pathway has been genetically and biochemically elucidated and the main determinants of colour have been identified, the molecular reasons of the fine variation among grape cultivars are still not completely understood. To shed light on this issue, extreme genotypes of a segregating population derived from the cross Syrah x Pinot Noir were characterized at transcriptional level. The transcriptome analysis along three berry developmental stages of these genotypes has allowed the identification of a large set of transcripts differentially modulated between the two groups. A population derived from M-bM-^@M-^XSyrahM-bM-^@M-^Y x M-bM-^@M-^XPinot NoirM-bM-^@M-^Y consisting of 170 F1 individuals plus the parental lines was characterized for the content of flavonols and anthocyanins in the skins of mature berries (38E-L; 18M-BM-0Brix). Based on the biochemical data, 4 high- and 4 low-flavonol producers (HFPs and LFPs: F1 16, F1 56, F1 63, F1 223 and F1 64, F1 256, F1 260, PN), two of which having also either very high or very low anthocyanin content (HAPs and LAPs: F1 63, F1 223 and F1 256, F1 260), were selected for gene expression analysis. A representative sample for each individual (one biological replicate) was collected at three berry developmental stages (hard green berry (33E-L, PV), veraison (35E-L, 50% coloured berries, VER) and maturity (38E-L, 18M-BM-0Brix, MAT)) during the 2007 season.

Project description:The human liver plays a vital role in meeting the body's metabolic needs and maintaining homeostasis. To address the molecular mechanisms of liver function, we integrated multiple gene expression datasets from microarray, MPSS, SAGE and EST platforms to generate a transcriptome atlas of the normal human liver. The integrated liver transcriptome data should provide a valuable resource for the in-depth understanding of human liver biology and liver disease. Microarray is one of these platforms. In this part, adult human liver tissues from 10 adult human were surgically resected due to hemangioma in the liver. The gene expression of normal human liver was detected by Microarray platform. The samples were obtained from the portion unaffected by the hemangioma and were immediately frozen in liquid nitrogen. All procedures and risks were explained verbally, and patients provided written consent. The samples were sectioned and confirmed to be histologically normal. All laboratory data assessing hepatic function were within normal ranges, including serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, total bilirubin, albumin, prothrombin activity, glucose, cholesterol, and triglycerides (data not shown). Serological tests for hepatitis B surface antigen, hepatitis C virus antibodies, and human immunodeficiency virus antibodies also proved negative. Neither heavy alcohol consumption nor the intake of prescription or other drugs was observed before surgical resection. Total RNA was extracted according to the manufacturer’s instructions, and RNase-free DNase I was used to remove DNA contamination. Nucleic acid concentration and purity were assessed at 260 nm using a spectrophotometer (DU 530, Beckman-Coulter Inc., Fullerton, CA), and the quality was assessed using an Agilent 2100 Bioanalyzer. In order to address gene expression polymorphism, the total RNA from 10 livers was pooled. ***This submission represents the Affymetrix component of the study only***

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	Results.zip	Other
	XC02740DA_A1.raw	Raw
	XC02740DA_A2.raw	Raw
	XC02740DA_A3.raw	Raw
	XC02740DA_B1.raw	Raw

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Serum proteomics and metabolomics reveal the characteristics of the A1762T/G1764A mutations in conjunction with the G1896A mutation.

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