Hepatic steatosis, also known as fatty liver disease, occurs due to abnormal lipid accumulation in the liver. It has been known that gut absorption also plays an important role in the mechanism underlying hepatic steatosis. Conventional in vitro cell culture models have limitations in recapitulating the mechanisms of hepatic steatosis because it does not include the gut absorption process. Previously, we reported development of a microfluidic gut-liver chip that can recapitulate the gut absorption of fatty acids and subsequent lipid accumulation in liver cells. In this study, we performed a series of experiments to verify that our gut-liver chip reproduces various aspects of hepatic steatosis. The absorption of fatty acids was evaluated under various culture conditions. The anti-steatotic effect of turofexorate isopropyl (XL-335) and metformin was tested, and both drugs showed different action mechanisms. In addition, the oxidative stress induced by lipid absorption was evaluated. Our results demonstrate the potential of the gut-liver chip for use as a novel, physiologically realistic in vitro model to study fatty liver disease.
K E Y W O R D Sfatty liver disease, gut-liver-on-a-chip, hepatic steatosis, multi-organ-on-a-chip, organ-ona-chip
| INTRODUCTIONHepatic steatosis involves excessive accumulation of lipids in the liver due to alcohol abuse or obesity and is also called fatty liver disease. 1 Chronic hepatic steatosis can develop into steatohepatitis, which is characterized by hepatic necrosis and inflammation, and eventually progress into hepatic fibrosis and liver cancer. 2 As the incidence of hepatic steatosis has increased, the importance of treatment has likewise increased. 3 In terms of the pathogenesis of fatty liver disease, oxidative stress and metabolic diseases, such as insulin resistance, type 2 diabetes, and obesity, were found to be major factors. 2,4 However, more in-depth studies are required to fully understand the mechanism of hepatic steatosis and to develop therapeutic drugs, as various factors affect the progression of hepatic steatosis. 5 In previous studies, tissue biopsies and animal models have been used for studying hepatic steatosis. 6,7 However, tissue biopsies require surgical procedures to obtain samples from patients, and partial biopsies cause significant errors. 7 In addition, animal models are not suitable for the study of hepatic steatosis, as their histological changes differ from those observed in humans. 6 in vitro models of hepatic steatosis is also available, where human primary hepatocytes or cell lines exposed to fatty acids to induce lipid accumulation. [8][9][10] Although conventional in vitro models are easily accessible, they possess limitations in reproducing the in vivo environments, such as dynamic supplement of nutrients and oxygen, three-dimensional (3D) microenvironment, and multi-organ interactions, and thereby render it challenging to understand the underlying mechanisms of the disease. 11,12 Recently, organ-on-a-chip technology has gained attention as n...