Holistic characterization of single-hepatocyte transcriptome responses to high-fat diet
Autor: | Jun Hee Lee, Hyun Min Kang, Chun-Seok Cho, Sung Rye Park, Jingyue Xi |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Male medicine.medical_specialty Physiology Endocrinology Diabetes and Metabolism Population Biology Diet High-Fat Transcriptome 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Thinness Physiology (medical) Internal medicine Lipid droplet Nonalcoholic fatty liver disease medicine Animals Obesity education Cells Cultured education.field_of_study Gene Expression Profiling nutritional and metabolic diseases Lipid metabolism medicine.disease Dietary Fats Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Gene Expression Regulation 030220 oncology & carcinogenesis Hepatocyte Hepatic stellate cell Hepatocytes Single-Cell Analysis Research Article |
Zdroj: | Am J Physiol Endocrinol Metab |
ISSN: | 1522-1555 |
Popis: | During nutritional overload and obesity, hepatocyte function is grossly altered, and a subset of hepatocytes begins to accumulate fat droplets, leading to nonalcoholic fatty liver disease (NAFLD). Recent single-cell studies revealed how nonparenchymal cells, such as macrophages, hepatic stellate cells, and endothelial cells, heterogeneously respond to NAFLD. However, it remains to be characterized how hepatocytes, the major constituents of the liver, respond to nutritional overload in NAFLD. Here, using droplet-based, single-cell RNA sequencing (Drop-seq), we characterized how the transcriptomic landscape of individual hepatocytes is altered in response to high-fat diet (HFD) and NAFLD. We showed that the entire hepatocyte population undergoes substantial transcriptome changes upon HFD, although the patterns of alteration were highly heterogeneous, with zonation-dependent and -independent effects. Periportal (zone 1) hepatocytes downregulated many zone 1-specific marker genes, whereas a small number of genes mediating gluconeogenesis were upregulated. Pericentral (zone 3) hepatocytes also downregulated many zone 3-specific genes; however, they upregulated several genes that promote HFD-induced fat droplet formation, consistent with findings that zone 3 hepatocytes accumulate more lipid droplets. Zone 3 hepatocytes also upregulated ketogenic pathways as an adaptive mechanism to HFD. Interestingly, many of the top HFD-induced genes, which encode proteins regulating lipid metabolism, were strongly co-expressed with each other in a subset of hepatocytes, producing a variegated pattern of spatial co-localization that is independent of metabolic zonation. In conclusion, our data set provides a useful resource for understanding hepatocellular alteration during NAFLD at single cell level. |
Databáze: | OpenAIRE |
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