4.7 Article

A Quantitative Systems Pharmacology Model of Liver Lipid Metabolism for Investigation of Non-Alcoholic Fatty Liver Disease

Journal

FRONTIERS IN PHARMACOLOGY
Volume 13, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.910789

Keywords

QSP; NAFLD; liver; mathematical modeling; steatosis; triglyceride; metabolism

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This study developed a Quantitative Systems Pharmacology model of human hepatocyte lipid metabolism, which can generate a virtual population of patients and determine the best points of intervention for reducing hepatic steatosis.
Non-alcoholic fatty liver disease is a metabolic and inflammatory disease that afflicts many people worldwide and presently has few treatment options. To enhance the preclinical to clinical translation and the design of early clinical trials for novel therapeutics, we developed a Quantitative Systems Pharmacology model of human hepatocyte lipid metabolism. The intended application of the model is for simulating anti-steatotic therapies for reversing fatty liver. We parameterized the model using literature data from humans with both normal and elevated liver fat. We assessed that the model construct was sufficient to generate a virtual population of NAFLD patients that matched relevant statistics of a published clinical cohort, and then validated the model response to treatment by simulating pioglitazone and diet intervention in the virtual population. Finally, a sensitivity analysis was performed to determine the best points of intervention for reducing hepatic steatosis. Analysis of the model suggests the most potent method for reducing hepatic steatosis is by limiting non-esterified fatty acid flux from the adipose to the liver.

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