Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China.
Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Sci Transl Med. 2024 Nov 6;16(772):eadh9940. doi: 10.1126/scitranslmed.adh9940.
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.
非酒精性脂肪性肝病（NAFLD）已成为全球常见的健康负担。NAFLD 的高度异质性仍然难以捉摸，并影响临床诊断和药物治疗的结果。已经基于临床、遗传、酒精或血清代谢分析提出了几种 NAFLD 分类。然而，准确预测 NAFLD 向肝硬化或肝细胞癌（HCC）的进展仍然是一个挑战。在这里，基于中国患者队列，我们使用整合的多组学（包括全基因组测序（WGS）、蛋白质组学、磷酸蛋白质组学、脂质组学和代谢组学）将 NAFLD 分为三个不同的分子亚型（NAFLD-mSI、NAFLD-mSII 和 NAFLD-mSIII），涵盖了广泛的肝脏、血液和尿液样本。我们发现，NAFLD-mSI 具有更高的 CYP1A2 和 CYP3A4 表达，通过调节游离脂肪酸/胆汁酸-mTOR-FXR/PPARα 信号缓解肝脂肪变性。NAFLD-mSII 由于脂质触发的 CCL2 和 CRP 产生导致肝脏 CCL2 和 CRP 产生，导致肝脏肝硬化风险增加，同时伴有 M1 和 M2 巨噬细胞的肝浸润增加。NAFLD-mSIII 由于 EGF-EGFR/CHKA/PI3K-PDK1-AKT 级联的激活导致 CEBPB 和 ERCC3 调节的癌基因转录增加，显示出 HCC 发展的潜在风险。接下来，我们在由三家不同中国医院的 92 名 NAFLD 患者组成的外部队列中验证了这三种 NAFLD 分子亚型的存在。这些发现可能有助于了解 NAFLD 异质性的分子特征，从而有助于临床诊断和治疗策略的制定，以预防肝硬化和 HCC 的发展。
