Atypical sphingolipids in alcoholic liver disease

酒精性肝病（ALD）是美国肝衰竭的主要原因之一，占到了4%， 全世界的死亡率。鞘脂是一类具有信号传导特性的脂质，已经涉及到许多 肝脏病理学鞘脂由丝氨酸棕榈酰转移酶形成，丝氨酸棕榈酰转移酶是一种异二聚体酶， 亚基Sptlc 1和Spltc 2的基因。这种异二聚体结合丝氨酸和棕榈酰辅酶A， 二氢鞘氨醇，其用作产生所有下游鞘脂的支架（例如，神经酰胺， 鞘磷脂、鞘糖脂、鞘氨醇-1-磷酸等）。尽管它们在病理学上有牵连， 鞘脂是所有真核细胞所必需的。然而，以前发现的一种新的鞘脂库， 被确认了身份这些脂质来自Sptlc 1与新的SPT亚基Sptlc 3的二聚化。在此我们表明 Sptlc 3在ALD的小鼠模型中被诱导，导致非典型鞘脂的增加， 以一种潜在的保护性方式调节几种途径。因此，我们建议， 衍生自Sptlc 1/2异源二聚体鞘脂是稳态的和/或在肝脏病理学中起作用，但在某些情况下， 肝损伤Sptlc 3被诱导，以保护性方式改变细胞内鞘脂组。这将 提供了针对非典型Sptlc 3衍生鞘脂的治疗干预的机会， 保持体内平衡的鞘脂池完整。 我们的假设背后的科学前提是，鞘脂代谢可以有针对性地预防 或逆转酒精性肝损伤。我们的假设是，损伤诱导这些非典型鞘脂，或一个子集 其激活调节自噬/线粒体自噬的途径， 乙醇代谢引起的线粒体损伤，诱导其产生将减轻损伤。 这将在3个目标中进行测试：1-确定肝细胞中SPTLC 3上调的机制，以及如何 这改变了鞘脂谱，2-确立了SPTLC 3和d16-鞘脂在线粒体自噬中的作用， 线粒体功能和调节核受体转录因子3-评估的影响 对肝细胞特异性Sptlc 3敲除小鼠进行酒精喂养。这个项目的深远目标是 寻求基于操纵肝细胞中非典型鞘脂代谢的ALD的未来治疗。

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.