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The occurrence of LDs in >5% of hepatocytes is the main diagnostic criterion for NAFLD.

These are either derived directly from the diet or result from inflammation induced lipolysis in adipose tissues. Hepatocytes store triacylglycerides (TAGs) in LDs as a reaction to an overload with free fatty acids. Up to 27% of these further develop hepatocellular carcinoma. Approximately, 29% of patients with NASH develop cirrhosis. A “second hit”, frequently due to an increase of reactive oxygen species-mediated stress, induces the progression toward nonalcoholic steatohepatitis (NASH), which is accompanied by liver inflammation and fibrosis. This is often seen as a “first hit” manifesting in the rather benign accumulation of LDs, called steatosis. Insulin resistance and obesity-associated chronic inflammation of adipose tissue are critical factors for the development and progression of NAFLD. This is often associated with type 2 diabetes and considered part of the metabolic syndrome. Due to a high-fat diet and a lack of exercise, hepatocytes of NAFLD patients accumulate fat in the form of lipid droplets (LDs). N onalcoholic fatty liver disease (NAFLD) is a widespread disease in the western hemisphere. It permits the dissection of disease-promoting molecular pathways and allows us to investigate the influences of distinct genetic backgrounds on disease progression. Our model recapitulates many metabolic changes that are characteristic for NAFLD. Interference with PLIN2 and PPARα resulted in major alterations in gene expression, especially affecting lipid, glucose, and purine metabolism. We observed an upregulation of the lipid droplet coating protein Perilipin 2 (PLIN2), as well as of numerous genes of the peroxisome proliferator-activated receptor (PPAR) pathway, which constitutes a regulatory hub for metabolic processes. We induced fat storage in these HLCs and detected major expression changes of metabolism-associated genes, as well as an overall reduction of liver-related microRNAs.

In this study, we developed an in vitro model for NAFLD based on hepatocyte-like cells (HLCs) differentiated from human pluripotent stem cells. Nonalcoholic fatty liver disease (NAFLD/steatosis) is a metabolic disease characterized by the incorporation of fat into hepatocytes.