Increased Diacylglycerols Characterize Hepatic Lipid Changes in Progression of Human Nonalcoholic Fatty Liver Disease; Comparison to a Murine Model

Abstract

Background and AimsThe spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The goal of this study was to characterize changes in lipid species through progression of human NAFLD using advanced lipidomic technology and compare this with a murine model of early and advanced NAFLD.MethodsUtilizing mass spectrometry lipidomics, over 250 phospholipid and diacylglycerol species (DAGs) were identified in normal and diseased human and murine liver extracts.ResultsSignificant differences between phospholipid composition of normal and diseased livers were demonstrated, notably among DAG species, consistent with previous reports that DAG transferases are involved in the progression of NAFLD and liver fibrosis. In addition, a novel phospholipid species (ether linked phosphatidylinositol) was identified in human cirrhotic liver extracts.ConclusionsUsing parallel lipidomics analysis of murine and human liver tissues it was determined that mice maintained on a high-fat diet provide a reproducible model of NAFLD in regards to specificity of lipid species in the liver. These studies demonstrated that novel lipid species may serve as markers of advanced liver disease and importantly, marked increases in DAG species are a hallmark of NAFLD. Elevated DAGs may contribute to altered triglyceride, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) levels characteristic of the disease and specific DAG species might be important lipid signaling molecules in the progression of NAFLD.

Biomarkers of NAFLD progression: a lipidomics approach to an epidemic

“…1B ). Such a pattern is in accordance with a previous study fi nding differences between the livers of normal, steatotic, and cirrhotic patients in PUFAcontaining GPLs ( 47 ). Most of the sphingolipid species that differed in both the liver and plasma across histological 6-phosphogluconate ( P = 0.048) shown in supplementary Fig.…”

Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

“…The enzymes PS synthases PTDSS1 and PTDSS2 that catalyse the production of PS by condensation of phosphatidylcholine and phosphatidylethanolamine, respectively, were significantly downregulated in NASH patients. The significant changes in the level of PS in cirrhotic (severe stage of NASH) livers was previously reported in a study on changes in lipid species in subjects with cirrhotic livers compared with healthy controls 47 . Given that PS is essential for hepatocytes, we hypothesize that decreased activity of these enzymes may be associated with a decrease in the endogenous level of serine, which is the second most connected node in our identified Reporter Subnetworks (Fig.…”

“…Taken together, the results suggest that the changes in the level of PS in the liver 47 as well as the relative increase in the homocysteine blood level 49 is caused by decreased level of endogenous serine. To test this hypothesis, we checked the expression level of enzymes that catalyse the biosynthesis of serine in the liver of NASH patients, and it was observed that the expression levels of PHGDH, PSAT1, PSPH in serine synthesis pathway (SSP), and SHMT1 and SHMT2 enzymes were significantly downregulated (Supplementary Table 6).…”

The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes

“…An almost 4-fold increase relative to total lipid content was measured upon short-time fasting, an 0.5-fold increase upon KO-effect, whereas super stress returned the fasting DG level to levels measured in ATGL-KO mice. We conclude that substantial enhancement of DG amounts in the liver ( 6,26 ), particularly in hepatocyte LDs ( 11 ), can be considered a further indicator of insulin resistance; this does not apply to the smaller DG increases caused by ATGL defi ciency, however. In line with this, a long-term study with liver-specifi c ATGL-KO mice revealed progressive hepatosteatosis, but unchanged insulin tolerance; a compensatory mechanism was suggested by reduced DG acyltransferase 2 mRNA (responsible for TG synthesis) and increased lipolysomal activity for TG degradation ( 17 ).…”