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Published on: September 15, 2018
Single-nucleus RNA sequencing reveals HBV-driven metabolic reprogramming and TIMP1-mediated fibrosis in
Xiaonan Ren1, Cong Wang2, Boyin Qin1
1Department of Laboratory Animal Science, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Introduction:
Hepatitis B virus (HBV) infection remains a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. Despite advances in antiviral therapies, the mechanisms underlying HBV-induced metabolic reprogramming and liver fibrosis remain poorly understood.
Methods:
We employed single-nucleus RNA sequencing (snRNA-seq) which is particularly suitable for hepatocytic sequencing to dissect the transcriptional landscape of HBV-infected and uninfected hepatocytes in humanized URG mice (Hu-URG).
Results And Discussion:
Chronic HBV infection was successfully established in Hu-URG mice, with progressive increases in serum HBV DNA, HBsAg, and HBeAg levels. snRNA-seq revealed distinct human hepatocyte clusters (clusters 9, 16, 23) characterizing elevated expression of metabolic genes (ALB, UGT2B17, CYP2A6) in HBV-infected cells, while HBV-uninfected cells exhibited upregulation of TIMP1 and pro-fibrotic pathways. Immunofluorescence and histological analyses confirmed that HBV-uninfected hepatocytes (HBsAg-) displayed higher TIMP1 expression and reduced albumin (hALB) levels, correlating with increased collagen deposition in HBV-hu-URG mice. Notably, this TIMP1+HBsAg-hALBlow phenotype was also observed in liver biopsies from chronic HBV patients, underscoring its clinical relevance. Our findings highlight HBV-driven metabolic adaptation and identify TIMP1 as a potential mediator of fibrosis in uninfected hepatocytes, offering novel insights into HBV pathogenesis and therapeutic targeting.
