A German research group has used pluripotent stem cells to design a new in vitro model system for investigating nonalcoholic fatty liver disease (NAFLD). NAFLD, or steatosis, is a liver disease whose prevalence is probably much higher than estimated, and the new cases of it are increasing every year throughout the world. NAFLD is typically associated with obesity and type-2 diabetes. An estimated one-third of the general population of Western countries is thought to be affected with NAFLD, with or without symptoms. It usually results from a high caloric diet in combination with a lack of exercise. The liver begins to accumulate fat as lipid droplets. Initially, this is a benign state, but it can develop into nonalcoholic steatohepatitis (also known as NASH), an inflammatory disease of the liver. Then many patients develop fibrosis, cirrhosis or even liver cancer. However, in many cases patients die of heart failure before they develop severe liver damage.
A major obstacle that dogged NAFLD research was that biopsies of patients and healthy individuals were required. Researchers from the Institute for Stem Cell Research and Regenerative Medicine at the University Clinic of Düsseldorf, Germany solved this problem by reprogramming skin cells into induced pluripotent stem cells (iPSCs) that they differentiated into hepatocyte-like cells.
“Although our hepatocyte-like cells are not fully mature, they are already an excellent model system for the analysis of such a complex disease”, said Nina Graffmann, first author of the paper that appeared in the journal Stem Cells and Development.
The researchers recapitulated important steps of the disease in cultured cells. They demonstrated up-regulation of PLIN2, a protein called perilipin that surrounds lipid droplets. Mice without PLIN2 do not become obese, even when overfed with a high fat diet. Also the key role of PPARα, a transcription factor involved in controlling glucose and lipid metabolism, was reproduced in the tissue culture system. “In our system, we can efficiently induce lipid storage in hepatocyte-like cells and manipulate associated proteins or microRNAs by adding various factors into the culture. Thus, our in vitro model offers the opportunity to analyse drugs which might reduce the stored fat in hepatocytes,” Graffmann said.
Senior author James Adjaye and his colleagues hope to expand their model by deriving iPSCs from NAFLD patients. They hope to discover differences that might explain the course of NAFLD.
“Using as reference the data and biomarkers obtained from our initial analyses on patient liver biopsies and matching serum samples, we hope to better understand the etiology of NAFLD and the development of NASH at the level of the individual, with the ultimate aim of developing targeted therapy options,” said Adjayer.
This paper can be found at Nina Graffmann et al., “Modeling NAFLD with human pluripotent stem cell derived immature hepatocyte like cells reveals activation of PLIN2 and confirms regulatory functions of PPARα,”Stem Cells and Development, 2016; DOI: 10.1089/scd.2015.0383.