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.

Keywords: Ceramide; Lipid; Lipidomics; Metabolic syndrome; NAFLD; NASH; Non-alcoholic fatty liver disease; Sphingolipids; Sphingosine-1-phosphate.

Figure 1. Partial sphingolipid metabolic pathway with structures of selected species and numerically designated enzymatic reactions

Enzymes correspond to serine palmitoyltransferase – 1, 3-ketosphinganine reductase – 2, dihydroceramide synthases – 3, dihydroceramide desaturases – 4, sphingomyelin synthases – 5, glucosylceramide synthase - 6, ceramide kinase – 7, lactosylceramide synthase – 8, sialyltransferase 1 – 9, sialidase – 10, galactosidase – 11, sphingomyelinases (C-type) – 12, ceramidases – 13, β-glucoceramidase – 14, ceramide-1-phosphate phosphatase (putative) – 15, sphingosine / sphinganine kinases – 16, sphingosine-1-phosphate phosphatase – 17, and sphingosine-1-phosphate lyase – 18.

Figure 2. Ceramide synthase isoenzymes generate distinct ceramide species

(A) general ceramide synthase (CerS) reaction. (B) Different CerS isoforms show dinstinct Acyl-CoA selectivity and therefore generate distinct ceramide speciess. For example CerS6 utilizes palmitoyl-CoA, whereas CerS2 uses very long chain Acyl-CoAs, such as C24:0-CoA, shown here.

Figure 3. Product ion scans by ABSciex 5500 Qtrap

(A) d17:1 sphingosine, an odd-chain synthetic sphingoid base, which is a commonly used sphingolipid standard. (B) d18:1 dihydrosphingosine/sphinganine, and (C) d18:1/12:0 ceramide.