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Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and strongly correlates with the growing incidence of obesity and type II diabetes. We have developed a human-on-a-chip model composed of human hepatocytes and adipose tissue chambers capable of modeling the metabolic factors that contribute to liver disease development and progression, and evaluation of the therapeutic metformin. This model uses a serum-free, recirculating medium tailored to represent different human metabolic conditions over a 14-day period. The system validated the indirect influence of adipocyte physiology on hepatocytes that modeled important aspects of NAFLD progression, including insulin resistant biomarkers, differential adipokine signaling in different media and increased TNF-α-induced steatosis observed only in the two-tissue model. This model provides a simple but unique platform to evaluate aspects of an individual factor’s contribution to NAFLD development and mechanisms as well as evaluate preclinical drug efficacy and reassess human dosing regimens.
Highlights
Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic lipid storage in hepatocytes not driven by alcohol abuse, is the most common form of liver disease, affecting around 24% of individuals globally[1,2]
We developed and characterized a microfluidic HoaC model composed of adipocytes representing white adipose tissue (WAT) and functional liver cell chambers in recirculating, serum-free medium to study aspects of NAFLD and nonalcoholic steatohepatitis (NASH)
We have developed the first human-based multi-chamber HoaC model comprised of both hepatocytes and white adipocytes that enabled the modeling of NAFLD phenotypes in both liver and adipose modules as well as organ cross-talk
Summary
Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic lipid storage in hepatocytes not driven by alcohol abuse, is the most common form of liver disease, affecting around 24% of individuals globally[1,2]. NAFLD studies in humans are largely correlative, and because of high overlap between NAFLD and other metabolic syndrome diseases, it is difficult to study lipid dysfunction or inflammation in isolation. We developed and characterized a microfluidic HoaC model composed of adipocytes representing white adipose tissue (WAT) and functional liver cell chambers in recirculating, serum-free medium to study aspects of NAFLD and NASH. This system utilizes serum-free media formulations tailored to represent different human metabolic states—healthy, corresponding to normal human postprandial glucose and insulin concentrations, diabetic, with representative glucose and insulin, obese, with representative recirculating free fatty acids (FFA)[20], and proinflammatory, with tumor necrosis factor-alpha (TNF-α). Most important, we have shown that the anti-steatotic effects of the insulin-sensitizing drugs are only observed at doses well above those clinically administered in humans, demonstrating that this platform can be used to bridge the gap between assays performed in cell lines or rodents and long-term human efficacy, and can be a resource to give insight into why compounds that are successful under some conditions fail in human trials
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