Summary of project PR000796
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000796. The data can be accessed directly via it's Project DOI: 10.21228/M8SM3C This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR000796 |
| Project DOI: | doi: 10.21228/M8SM3C |
| Project Title: | Generation of human fatty liver using custom-engineered induced pluripotent stem cells with modifiable SIRT1 metabolism |
| Project Summary: | The mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis, and endstage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 indicate that this molecule plays a role in the development of fatty liver in inbred animals. The ability to perform similar studies using human tissue has been limited by the genetically variability in baseline SIRT1 expression in man. We now report generation of human induced pluripotent stem (iPS) cells with controlled expression of SIRT1. By differentiating edited iPS cells into hepatocytes and then knocking down (KD) SIRT1, we found that downregulated SIRT1 regulates lipid homeostasis by increasing Srebp1c (a transcription factor driving fatty acid biosynthesis), and by decreasing PPARa and its transcriptional co-activator PGC1a, to exacerbate fat accumulation. To model human fatty livers, we repopulated the parenchyma of decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1-knockdown iPS-derived hepatocytes. When SIRT1-metabolism was modified, the human iPS-derived liver tissue developed macrosteatosis and generated cells with a proinflammatory phenotype. Our data indicate that SIRT1 plays an important role in the regulation of hepatic lipid homeostasis and inflammation in the human liver. Given the ability to generate and characterize bioengineered and genetically-edited human liver tissue, we believe that use of genetically modifiable human tissue may become an important tool for investigating human liver biology and disease. |
| Institute: | University of Pittsburgh |
| Department: | Department of Pathology |
| Last Name: | Soto-Gutierrez |
| First Name: | Alejandro |
| Address: | 200 Lothrop Street, 423 Biomedical Science Tower, Pittsburgh, PA 15261, USA |
| Email: | als208@pitt.edu |
| Phone: | +14126480064 |
Summary of all studies in project PR000796
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST001185 | Genetic and metabolic characterization of bioengineered human fatty liver tissue with modified SIRT1 expression | Homo sapiens | University of Pittsburgh | MS* | 2020-01-06 | 1 | 13 | Uploaded data (4.2M)* |
