PLRC member and Co-director of the Human Synthetic Liver Biology Core at the PLRC, Dr. Lansing Taylor, co-authored a review article in Experimental Biology and Medicine, entitled “Qualifying the progression of non-alcoholic fatty liver disease in human biomimetic liver microphysiology systems with fluorescent protein biosensors.” Other PLRC members who contributed to this study are Dr. Alex Soto-Gutierrez, co-director HSLBC, Dr. Jaideep Behari, Dr. Larry Vernetti, Dr. Manush Saydmohammed, and Dr. Anupma Jha.
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Saydmohammed M, Jha A, Mahajan V, Gavlock D, Shun TY, DeBiasio R, Lefever D, Li X, Reese C, Kershaw EE, Yechoor V, Behari J, Soto-Gutierrez A, Vernetti L, Stern A, Gough A, Miedel MT, Lansing Taylor D. Quantifying the progression of non-alcoholic fatty liver disease in human biomimetic liver microphysiology systems with fluorescent protein biosensors. Exp Biol Med (Maywood). 2021 May 6:15353702211009228. doi: 10.1177/15353702211009228. Epub ahead of print. PMID: 33957803.
Metabolic syndrome is a complex disease that involves multiple organ systems including a critical role for the liver. Non-alcoholic fatty liver disease (NAFLD) is a key component of the metabolic syndrome and fatty liver is linked to a range of metabolic dysfunctions that occur in approximately 25% of the population. A panel of experts recently agreed that the acronym, NAFLD, did not properly characterize this heterogeneous disease given the associated metabolic abnormalities such as type 2 diabetes mellitus (T2D), obesity, and hypertension. Therefore, metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as the new term to cover the heterogeneity identified in the NAFLD patient population. Although many rodent models of NAFLD/NASH have been developed, they do not recapitulate the full disease spectrum in patients. Therefore, a platform has evolved initially focused on human biomimetic liver microphysiology systems that integrates fluorescent protein biosensors along with other key metrics, the microphysiology systems database, and quantitative systems pharmacology. Quantitative systems pharmacology is being applied to investigate the mechanisms of NAFLD/MAFLD progression to select molecular targets for fluorescent protein biosensors, to integrate computational and experimental methods to predict drugs for repurposing, and to facilitate novel drug development. Fluorescent protein biosensors are critical components of the platform since they enable monitoring of the pathophysiology of disease progression by defining and quantifying the temporal and spatial dynamics of protein functions in the biosensor cells, and serve as minimally invasive biomarkers of the physiological state of the microphysiology system experimental disease models. Here, we summarize the progress in developing human microphysiology system disease models of NAFLD/MAFLD from several laboratories, developing fluorescent protein biosensors to monitor and to measure NAFLD/MAFLD disease progression and implementation of quantitative systems pharmacology with the goal of repurposing drugs and guiding the creation of novel therapeutics.