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Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population

Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population
Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population
Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid–mTOR–FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.
1946-6234
Ding, Jingjing
0be95fee-485c-4ac7-8d66-55c03ba1dbb2
Liu, Huaizheng
68916fd2-fb02-4cc9-ba20-704df697f572
Zhang, Xiaoxun
e2351cea-bc58-4d9c-abf7-38e69a133ef5
Byrne, Chrisopher D.
1370b997-cead-4229-83a7-53301ed2a43c
et al.
Ding, Jingjing
0be95fee-485c-4ac7-8d66-55c03ba1dbb2
Liu, Huaizheng
68916fd2-fb02-4cc9-ba20-704df697f572
Zhang, Xiaoxun
e2351cea-bc58-4d9c-abf7-38e69a133ef5
Byrne, Chrisopher D.
1370b997-cead-4229-83a7-53301ed2a43c

Ding, Jingjing, Liu, Huaizheng and Zhang, Xiaoxun , et al. (2024) Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population. Science Translational Medicine, 16 (772). (doi:10.1126/scitranslmed.adh9940).

Record type: Article

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid–mTOR–FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.

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More information

Accepted/In Press date: 4 October 2024
e-pub ahead of print date: 6 November 2024
Published date: 6 November 2024
Additional Information: Authors: Jingjing Ding, Huaizheng Liu, Xiaoxun Zhang, Nan Zhao, Ying Peng, Junping Shi , Jinjun Chen, Xiaoling Chi, Ling Li, Mengni Zhang, Wen-Yue Liu, Liangjun Zhang, Jiafeng Ouyang, Qian Yuan, Min Liao, Ya Tan, Mingqiao Li, Ziqian Xu, Wan Tang, Chuanming Xie, Yi Li, Qiong Pan, Ying Xu, Shi-Ying Cai, Christopher D Byrne, Giovanni Targher, Xinshou Ouyang, Liqun Zhang, Zhongyong Jiang, Ming-Hua Zheng, Fengjun Sun, Jin Chai.

Identifiers

Local EPrints ID: 496892
URI: http://eprints.soton.ac.uk/id/eprint/496892
ISSN: 1946-6234
PURE UUID: 1e4bb2e4-e995-48d9-896d-1a49a5d3cd35
ORCID for Chrisopher D. Byrne: ORCID iD orcid.org/0000-0001-6322-7753

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Date deposited: 08 Jan 2025 11:39
Last modified: 10 Jan 2025 02:38

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Contributors

Author: Jingjing Ding
Author: Huaizheng Liu
Author: Xiaoxun Zhang
Corporate Author: et al.

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