Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy

作者：Shuai Chen, Qinghe Zeng, Xiurong Cai, Jiaming Xue, Peng Song, Liming Tang, Christophe Klein, Frank Tacke, Adrien Guillot, Hanyang Liu · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.04.10.588826 · 被引用次数：1 · 研究领域：Liver Disease Diagnosis and Treatment、Diet and metabolism studies、Adipose Tissue and Metabolism

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive liver disease that encompasses a spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests that dietary restriction (DR) and sleeve gastrectomy (SG) can lead to remission of hepatic steatosis and inflammation through weight loss, but it is unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims to elucidate the intricate hepatic changes following DR, SG or sham surgery in rats fed a high-fat diet as a model of obesity-related MASLD, in comparison to a clinical cohort of patients undergoing SG. Single-cell and single-nuclei transcriptome analysis, spatial metabolomics, and immunohistochemistry revealed the liver landscape, while circulating biomarkers were measured in serum samples. Artificial intelligence (AI)-assisted image analysis characterized the spatial distribution of hepatocytes, myeloid cells and lymphocytes. In patients and experimental MASLD rats, SG improved BMI, circulating liver injury biomarkers and triglyceride levels. Both DR and SG attenuated liver steatosis and fibrosis in rats. Metabolism-related genes ( Ppara , Cyp2e1 and Cyp7a1 ) were upregulated in hepatocytes upon DR and SG, while SG broadly upregulated lipid metabolism on cholangiocytes, monocytes, macrophages, and neutrophils. Furthermore, SG promoted myeloid cell accumulation in the liver not only ameliorating inflamm...