Department of Cell Biology, SUNY Downstate Medical Center, United States of America.
Fudan University, Shanghai, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 May;1866(5):158898. doi: 10.1016/j.bbalip.2021.158898. Epub 2021 Feb 2.
Sphingomyelin (SM) is one major phospholipids on lipoproteins. It is enriched on apolipoprotein B-containing particles, including very low-density lipoprotein (VLDL) and its catabolites, low-density lipoprotein (LDL). SM is synthesized by sphingomyelin synthase 1 and 2 (SMS1 and SMS2) which utilizes ceramide and phosphatidylcholine, as two substrates, to produce SM and diacylglyceride. SMS1 and SMS2 activities are co-expressed in all tested tissues, including the liver where VLDL is produced. Thus, neither Sms1 gene knockout (KO) nor Sms2 KO approach is sufficient to evaluate the effect of SMS on VLDL metabolism. We prepared liver-specific Sms1 KO/global Sms2 KO mice to evaluate the effect of hepatocyte SM biosynthesis in lipoprotein metabolism. We found that hepatocyte total SMS depletion significantly reduces cellular sphingomyelin levels. Also, we found that the deficiency induces cellular glycosphingolipid levels which is specifically related with SMS1 but not SMS2 deficiency. To our surprise, hepatocyte total SMS deficiency has marginal effect on hepatocyte ceramide, diacylglyceride, and phosphatidylcholine levels. Importantly, total SMS deficiency decreases plasma triglyceride but not apoB levels and reduces larger VLDL concentration. The reduction of triglyceride levels also was observed when the animals were on a high fat diet. Our results show that hepatocyte total SMS blocking can reduce VLDL-triglyceride production and plasma triglyceride levels. This phenomenon could be related with a reduction of atherogenicity.
鞘磷脂 (SM) 是脂蛋白上的一种主要磷脂。它富含载脂蛋白 B 颗粒，包括极低密度脂蛋白 (VLDL) 和其代谢产物，低密度脂蛋白 (LDL)。SM 由鞘磷脂合酶 1 和 2 (SMS1 和 SMS2) 合成，它利用神经酰胺和磷脂酰胆碱作为两种底物来产生 SM 和二酰基甘油。SMS1 和 SMS2 活性在所有测试的组织中均有表达，包括产生 VLDL 的肝脏。因此，既不能通过 Sms1 基因敲除 (KO) 也不能通过 Sms2 KO 方法来评估 SMS 对 VLDL 代谢的影响。我们制备了肝脏特异性 Sms1 KO/全局 Sms2 KO 小鼠，以评估肝细胞 SM 生物合成对脂蛋白代谢的影响。我们发现肝细胞总 SMS 耗竭显着降低细胞鞘磷脂水平。此外，我们发现该缺陷诱导细胞糖鞘脂水平升高，这与 SMS1 缺乏但与 SMS2 缺乏无关。令我们惊讶的是，肝细胞总 SMS 缺乏对肝细胞神经酰胺、二酰基甘油和磷脂酰胆碱水平几乎没有影响。重要的是，总 SMS 缺乏降低了血浆甘油三酯但不降低 apoB 水平并减少了更大的 VLDL 浓度。当动物食用高脂肪饮食时，也观察到甘油三酯水平降低。我们的结果表明，肝细胞总 SMS 阻断可减少 VLDL-甘油三酯的产生和血浆甘油三酯水平。这种现象可能与致动脉粥样硬化性降低有关。
