Atypical sphingolipids in alcoholic liver disease

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Alcoholic liver disease (ALD) is one of the leading causes of liver failure in the U.S., and accounts for 4% of mortality worldwide. Sphingolipids, a lipid class bearing signaling properties, have been implicated in numerous liver pathologies. Sphingolipids are formed by serine palmitoyltransferase, a heterodimeric enzyme composed of the subunits Sptlc1 and Spltc2. This heterodimer combines serine and palmitoyl-CoA to generate dihydrosphingosine, which serves as a scaffold for generation of all downstream sphingolipids (e.g., ceramides, sphingomyelins, glycosphingolipids, sphingosine-1-phosphate, etc.). Despite their implication in pathology, sphingolipids are required by all eukaryotic cells. However, a previously identified novel pool of sphingolipids were identified. These lipids arise from a dimerization of Sptlc1 with a novel SPT subunit, Sptlc3. Here we show that Sptlc3 is induced in a mouse model of ALD leading to an increase in atypical sphingolipids, which we show to regulate several pathways in a potentially protective manner. Therefore, we propose that the canonical sphingolipids derived from Sptlc1/2 heterodimer are homeostatic and/or play a role in liver pathology, but in some hepatic insults Sptlc3 is induced, changing the intracellular sphingolipidome in a protective manner. This would present the opportunity for therapeutic intervention directed toward atypical, Sptlc3-derived sphingolipids, leaving the homeostatic sphingolipid pool intact. The scientific premise behind our hypothesis is that sphingolipid metabolism could be targeted to prevent or reverse alcoholic liver injury. Our hypothesis is that injury induces these atypical sphingolipids, or a subset thereof, which activate pathways regulating autophagy/mitophagy, in a manner that expedites recovery from mitochondrial damage caused by metabolism of ethanol, and that inducing their production will attenuate injury. This will be tested in 3 aims: 1- determine the mechanism of SPTLC3 upregulation in hepatocytes, and how this alters sphingolipid profiles, 2-establish the role(s) of SPTLC3 and d16-sphingolipids in mitophagy, mitochondrial function, and regulation of nuclear receptor transcription factors 3- assess the impact of alcohol feeding on the hepatocyte-specific Sptlc3 knockout mouse. The far-reaching goal of this project is to pursue future treatments for ALD based on manipulating metabolism of atypical sphingolipids in hepatocytes.