Spatial multi-omics characterizes GPR35-relevant lipid metabolism signatures across liver zonation in MASLD

作者：Wuxiyar Otkur, Yiran Zhang, Yirong Li, Wenjun Bao, Tingze Feng, Bo Wu, Yaolu Ma, Jing Shi, Li Wang, Shaojun Pei, Wen Wang, Jixia Wang, Yaopeng Zhao, Yanfang Liu, Xiuling Li, Tian Xia, Fangjun Wang, Di Chen, Xinmiao Liang, Hai-long Piao · 发表于：Life Metabolism · 年份：2024 · DOI：10.1093/lifemeta/loae021 · 被引用次数：12 · 研究领域：Liver Disease Diagnosis and Treatment、Pancreatic function and diabetes、Endoplasmic Reticulum Stress and Disease

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and cancer. The zonal distribution of biomolecules in the liver is implicated in mediating the disease progression. Recently, G-protein-coupled receptor 35 (GPR35) has been highlighted to play a role in MASLD, but the precise mechanism is not fully understood, particularly, in a liver-zonal manner. Here, we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD, by combining lipid metabolomics, spatial transcriptomics (ST), and spatial metabolomics (SM). We found that GPR35 influenced lipid accumulation, inflammatory and metabolism-related factors in specific regions, notably affecting the anti-inflammation factor ELF4 (E74 like E-twenty six (ETS) transcription factor 4), lipid homeostasis key factor CIDEA (cell death-inducing DNA fragmentation factor alpha (DFFA)-like effector A), and the injury response-related genes SAA1/2/3 (serum amyloid A1/2/3), thereby impacting MASLD progression. Furthermore, SM elucidated specific metabolite distributions across different liver regions, such as C10H11N4O7P (3ʹ,5ʹ-cyclic inosine monophosphate (3ʹ,5ʹ-IMP)) for the central vein, and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression. Taken together, GPR35 regulates hep...