Endocrine Abstracts

Background: Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diseases starting with pathological accumulation of intrahepatocellular triglyceride (TG) (i.e. steatosis), which can progress to steatohepatitis (NASH) and cirrhosis. Insulin resistance is often associated with the development of steatosis and disease progression however, the underlying mechanisms for this are poorly defined. A major challenge in modelling human NAFLD disease progression is the lack of physiologically-relevant preclinical models to investigate mechanisms.

Objective: The aim of the study was to use a physiologically-relevant and human-centric cellular model to determine the impact of fatty acid (FA) composition on the development of hepatic steatosis and insulin resistance.

Methods: Human Huh7 hepatocytes were maintained in human serum and exposed to repeated doses of a mixture of sugars (glucose, fructose), two compositions of FAs, one enriched in unsaturated FAs (OPLA) and the other saturated FAs (POLA), and insulin for 7 days. Cell and media were collected and TG synthesis and secretion, along with glycogen and glucose production were measured.

Results: Both OPLA and POLA-treated cells had similar intracellular TG content and were considered steatotic. Despite this, POLA-treated cells expressed greater markers of ER stress and had attenuated secretion of TG compared to OPLA-treated cells. In contrast to OPLA treatment, POLA-treated cells were unable to suppress glucose production, synthesize glycogen, or activate key proteins in insulin signaling with acute insulin treatment, suggesting insulin resistance. Further, POLA-treated cells, compared to OPLA, displayed more microvesicular (small droplet) steatosis.

Conclusions: POLA treated cells were steatotic, insulin resistant, and displayed lipid droplet morphology suggestive of disease progression toward NASH. This cellular model can be used to dissect the key proteins and pathways that differentiate NAFLD prognosis.