Quantitative modelling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease

Abstract

<p><a href="https://www.sciencedirect.com/topics/engineering/nonalcoholics" title="Learn more about Nonalcoholic from ScienceDirect's AI-generated Topic Pages">Nonalcoholic</a> fatty liver disease (NAFLD) is an increasingly prevalent disease that is associated with multiple metabolic disturbances, yet the metabolic pathways underlying its progression are poorly understood. Here, we studied metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed whole liver tissue <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/transcriptomics" title="Learn more about transcriptomics from ScienceDirect's AI-generated Topic Pages">transcriptomics</a> and serum <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/metabolomics" title="Learn more about metabolomics from ScienceDirect's AI-generated Topic Pages">metabolomics</a> data obtained from a large, prospectively enrolled cohort of 206 histologically characterized patients derived from the European NAFLD Registry and developed genome-scale metabolic models (GEMs) of <a href="https://www.sciencedirect.com/topics/engineering/human-hepatocytes" title="Learn more about human hepatocytes from ScienceDirect's AI-generated Topic Pages">human hepatocytes</a> at different stages of NAFLD. We identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/glycosphingolipid" title="Learn more about glycosphingolipids from ScienceDirect's AI-generated Topic Pages">glycosphingolipids</a>, and their link with complex <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/glycosaminoglycan" title="Learn more about glycosaminoglycans from ScienceDirect's AI-generated Topic Pages">glycosaminoglycans</a> in advanced fibrosis. Furthermore, we derived GEMs and identified metabolic signatures of three common NAFLD-associated gene variants <em>(PNPLA3</em>, <em>TM6SF2</em>, and <em>HSD17B13)</em>. The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD.<br></p>