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Quantitative genome-scale analysis of human liver reveals dysregulation of glycosphingolipid pathways in progressive nonalcoholic fatty liver disease

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a well-defined chronic liver diseases closely related with metabolic disorders. The prevalence of NAFLD is rapidly increasing worldwide, while the pathology and the underlying mechanisms driving NAFLD are not fully understood. In NAFLD, a series of metabolic changes takes place in the liver. However, the alteration of the metabolic pathways in the human liver along the progression of NAFLD, i.e., the transition from nonalcoholic steatosis (NAFL) to steatohepatitis (NASH) through cirrhosis remains to be discovered. Here, we sought to examine the metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed the whole liver tissue transcriptomic (RNA-Seq) and serum metabolomics data obtained from a large, prospectively enrolled cohort of histologically characterized patients derived from the European NAFLD Registry (n=206), and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. The integrative approach employed in this study has enabled us to understand the regulation of the metabolic pathways of human liver in NAFL, and with progressive NASH-associated fibrosis (F0–F4). Our study identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids (GSLs), and their link with complex glycosaminoglycans (GAGs) in advanced fibrosis. The study provides insights into the underlying pathways of the progressive fibrosing steatohepatitis. Furthermore, by applying genome-scale metabolic modeling (GSMM), we were able to identify the metabolic differences among carriers of widely validated genetic variants associated with NAFLD / NASH disease severity in three genes (PNPLA3, TM6SF2 and HSD17B13).

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Blood

DISEASE(S): Fatty Liver Disease

SUBMITTER: Partho Sen

PROVIDER: ST001964 | MetabolomicsWorkbench | Thu Feb 18 00:00:00 GMT 2021

REPOSITORIES: MetabolomicsWorkbench

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Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

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Quantitative genome-scale analysis of human liver reveals dysregulation of glycosphingolipid pathways in progressive nonalcoholic fatty liver disease

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