目的:鞘脂从头生物合成与非酒精性脂肪肝或肝脂肪变性有关。然而,机制尚不清楚。神经鞘磷脂合成酶(SMS),使用神经酰胺作为底物之一来生产鞘磷脂,位于鞘脂生物合成的十字路口。SMS具有两种异构体:SMS1和SMS2。SMS2是肝脏中的主要同工型。
结果:为了研究肝脏SMS2活性介导的鞘脂变化与肝脏脂肪变性之间的关系,我们使用了2种小鼠模型:Sms2肝脏特异性转基因和Sms2基因敲除小鼠。我们发现Sms2肝脏特异性转基因肝脏具有较低的神经酰胺和较高的鞘磷脂,而Sms2基因敲除的肝脏有较高的神经酰胺和较低的鞘磷脂。我们还发现肝脏Sms2过表达促进脂肪酸摄取和肝脏脂肪变性,而Sms2缺乏与各自的对照相比具有相反的作用。重要的是,对Huh7细胞补充外源性神经酰胺,人类肝癌细胞系,降低过氧化物酶体增殖物激活受体γ2及其靶基因的表达,Cd36和Fsp27。过氧化物酶体增殖物激活受体γ报告基因分析证实了这种现象。此外,过氧化物酶体增殖物激活受体γ拮抗剂治疗显着降低了Sms2肝脏特异性转基因肝脏中甘油三酯的积累。
结论:我们将这些作用归因于神经酰胺,它可以抑制过氧化物酶体增殖物激活受体γ2,从而降低Cd36和Fsp27的表达并减少肝脏脂肪变性。毕竟,肝脏中的SMS2抑制可以减少肝脏脂肪变性。
OBJECTIVE: Sphingolipid de novo biosynthesis is related to nonalcoholic fatty liver disease or hepatic steatosis. However, the mechanism is still unclear. Sphingomyelin synthase (SMS), using ceramide as one of the substrates to produce sphingomyelin, sits at the crossroads of sphingolipid biosynthesis. SMS has 2 isoforms: SMS1 and SMS2. SMS2 is the major isoform in liver.
RESULTS: To investigate the relationship between liver SMS2 activity-mediated sphingolipid changes and hepatic steatosis, we used 2 mouse models: Sms2 liver-specific transgenic and Sms2 knockout mice. We found that Sms2 liver-specific transgenic livers have lower ceramide and higher sphingomyelin, whereas Sms2 knockout livers have higher ceramide and lower sphingomyelin. We also found that liver Sms2 overexpression promoted fatty acid uptake and liver steatosis, whereas Sms2 deficiency had an opposite effect in comparison with their respective controls. Importantly, the exogenous ceramide supplementation to Huh7 cells, a human hepatoma cell line, reduced the expression of peroxisome proliferator-activated receptor γ2 and its target genes, Cd36 and Fsp27. Peroxisome proliferator-activated receptor γ reporter analysis confirmed this phenomenon. Furthermore, peroxisome proliferator-activated receptor γ antagonist treatment significantly decreased triglyceride accumulation in Sms2 liver-specific transgenic liver.
CONCLUSIONS: We attributed these effects to ceramide that can suppress peroxisome proliferator-activated receptor γ2, thus reducing the expression of Cd36 and Fsp27 and reducing liver steatosis. After all, SMS2 inhibition in the liver could diminish liver steatosis.