Non-alcoholic fatty liver disease: Insights from sphingolipidomics

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major clinical concern and its treatment consumes abundant resources. While accumulation of lipids in hepatocytes initiates the disease, this in itself is not necessarily harmful; rather, initiation of inflammation and subsequent fibrosis and cirrhosis are critical steps in NAFLD pathology. Mechanisms linking lipid overload to downstream disease progression are not fully understood; however, bioactive lipid metabolism may underlie instigation of proinflammatory signaling. With the advent of high-throughput, sensitive, and quantitative mass spectrometry-based methods for assessing lipid profiles in NAFLD, several trends have emerged, including that increases in specific sphingolipids correlate with the transition from the relatively benign condition of simple fatty liver to the much more concerning inflamed state. Continued studies that implement sphingolipid profiling will enable the extrapolations of candidate enzymes and pathways involved in NAFLD, either in biopsies or plasma from human samples, and also in animal models, from which data are much more abundant. While most data thus far are derived from targeted lipidomics approaches, unbiased, semi-quantitative approaches hold additional promise for furthering our understanding of sphingolipids as markers of and players in NAFLD.

The plasma lipidome of the Quaker parrot (Myiopsitta monachus)

“…Ceramides are clinically important metabolites and lipid precursors and can also act as bioactive lipids. They have frequently been identified as potential biomarkers for a variety of diseases in humans and mammalian models [ 20 , 49 , 50 ]. Therefore, these similarities in parrots may translate into similar ceramide profiles for lipid-related diseases.…”

“…Comprehensive lipid analysis by mass spectrometry is known as lipidomics. This approach is revolutionizing the way lipid metabolic disorders are investigated as a results of the vast amount of data generated when blood lipids are analyzed using lipidomics [16][17][18][19][20]. Further, in the context of dyslipidemia, specific lipid species of complex lipids may be better targets or biomarkers than crude measurements of a single lipid molecule such as cholesterol (the cholesterol test measures both free cholesterol and the cholesterol moiety of a variety of cholesteryl esters) and triglycerides (the triglyceride test only measures the glycerol backbone of the molecule).…”

“…Therefore, thousands of species of fatty acyls, triglycerides, phospholipids, sphingolipids, and cholesteryl esters with a variety of saturated and unsaturated fatty acid chains can be measured in plasma. In humans, lipidomics has been used to study the lipidome [ 8 , 21 ], dyslipidemia [ 22 , 23 ], various clinical lipid-accumulation disorders [ 17 , 19 , 20 ], and statin pharmacology [ 24 , 25 ]. However, this powerful analytical technique has not been applied to psittacine birds or used in avian health research as far as the authors know.…”

GC-TOF-MS-Based Metabolomics Analyses of Liver and Intestinal Contents in the Overfed vs. Normally-Fed Geese

“…Ceramide can activate the NF-κB signaling pathway and promote the occurrence and development of inflammation in NAFLD [ 24 , 25 ]. Furthermore, ceramide and sphingosine can induce cell apoptosis, and excessive apoptosis can lead to extensive inflammatory response and necrosis in liver cells [ 26 , 27 ]. In the current study, the sphingosine levels were decreased in the liver and cecal content of the overfed geese.…”

Editorial for BBRC lipidomics special issue

“…In part 2, these authors [8] discussed the potential impact of sphingolipidomics from large cohorts of patients on patient care and diagnosis. The review by Cowart and colleagues [9] discusses the use of targeted sphingolipidomics in non-alcoholic fatty liver disease in animal models and human patient samples. While most data thus far are derived from targeted lipidomics approaches, unbiased, semi-quantitative approaches hold additional promise for furthering our understanding of sphingolipids as biomarkers of and players in non-alcoholic fatty liver disease, that is now emerging as a major clinical concern.…”