Abstract
Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern. With a propensity to progress towards non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, NAFLD is an important link amongst a multitude of comorbidities including obesity, diabetes, and cardiovascular and kidney disease. As several in vivo models of hyperglycemia and NAFLD are employed to investigate the pathophysiology of this disease process, we aimed to characterize an in vitro model of hyperglycemia that was amenable to address molecular mechanisms and therapeutic targets at the cellular level. Utilizing hyperglycemic cell culturing conditions, we induced steatosis within a human hepatocyte cell line (HepG2 cells), as confirmed by electron microscopy. The deposition and accumulation of lipids within hyperglycemic HepG2 cells is significantly greater than in normoglycemic cells, as visualized and quantified by Nile red staining. Alanine aminotransferase (ALT) and alkaline phosphatase (ALP), diagnostic biomarkers for liver damage and disease, were found to be upregulated in hyperglycemic HepG2 cells as compared with normoglycemic cells. Suppression of CEACAM1, GLUT2, and PON1, and elevation of CD36, PCK1, and G6PK were also found to be characteristic in hyperglycemic HepG2 cells compared with normoglycemic cells, suggesting insulin resistance and NAFLD. These in vitro findings mirror the characteristic genetic and phenotypic profile seen in Leprdb/J mice, a well-established in vivo model of NAFLD. In conclusion, we characterize an in vitro model displaying several key genetic and phenotypic characteristics in common with NAFLD that may assist future studies in addressing the molecular mechanisms and therapeutic targets to combat this disease.
Highlights
Liver disease has become a serious health burden globally and is becoming a leading health concern within the United States
Non-alcoholic fatty liver disease (NAFLD) is a globally prevalent health concern that is an important link amongst a multitude of comorbidities, having been referred to as a “multisystem disease” [7]
Because there is an urgent need to address key knowledge gaps regarding molecular mechanisms and therapeutic approaches surrounding NAFLD, this study aimed to provide a novel in vitro model which recapitulated several key features of NAFLD and could be used to advance research in this area
Summary
With several in vivo models of NAFLD being established and widely utilized, an in vitro model would be advantageous in order to allow for focused, high throughput investigation into molecular mechanisms and therapeutic discovery. Utilizing a diabetes-like induction method, which simulates one of several physiologically relevant pathways of NAFLD pathogenesis, we have characterized a novel, simple, and efficient in vitro model that shares many characteristics of NAFLD. We believe that this in vitro model will facilitate a wide range of mechanistic and therapeutic discoveries at the cellular level in order to rapidly drive progress in combatting NAFLD globally
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