A multi-omic landscape of steatosis-to-NASH progression

  • Life Metab. 2022 Dec 1;1(3):242-257. doi: 10.1093/lifemeta/loac034.
Liping Xiang  1  2 ,  Xiaoyan Li  3 ,  Yunchen Luo  4 ,  Bing Zhou  1 ,  Yuejun Liu  2 ,  Yao Li  5 ,  Duojiao Wu  6 ,  Lijing Jia  7 ,  Pei-Wu Zhu  8 ,  Ming-Hua Zheng  9 ,  Hua Wang  3 ,  Yan Lu  10
Affiliations
  • 1. Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3. Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 4. Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5. Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Shanghai, China.
  • 7. Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China.
  • 8. Department of Laboratory Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 9. MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 10. Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PMID: 39872077 DOI: 10.1093/lifemeta/loac034
Abstract

Nonalcoholic steatohepatitis (NASH) has emerged as a major cause of liver failure and hepatocellular carcinoma. Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology. Here, we present comprehensive multi-omic profiles of preclinical animal models to identify genes, non-coding RNAs, proteins, and plasma metabolites involved in this progression. In particular, by transcriptomics analysis, we identified Growth Differentiation Factor 3 (GDF3) as a candidate noninvasive biomarker in NASH. Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH, and differences in these levels provide a high diagnostic accuracy of NASH diagnosis (AUROC = 0.90; 95% confidence interval: 0.85-0.95) with a good sensitivity (90.7%) and specificity (86.4%). In addition, by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH, we show that Ferroptosis may be a potential target to treat NASH. Moreover, by using competing endogenous RNAs network analysis, we found that several miRNAs, including miR-582-5p and miR-292a-3p, and lncRNAs, including XLOC-085738 and XLOC-041531, are associated with steatosis-to-NASH progression. Collectively, our data provide a valuable resource into the molecular characterization of NASH progression, leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that Ferroptosis is a therapeutic target for the disease.

Keywords
GDF3; ferroptosis; multi-omics; nonalcoholic steatohepatitis; simple steatosis.
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