释 义 n. 非诺贝特
例 句 Objective To discuss the value of simvastatin plus fenofibrate for the treatment of mixed hyperlipemia. 目的探讨辛伐他汀联合非诺贝特治疗混合性高脂血症的价值。
作者： Laurits J Holml
A perturbed serum lipidome has been detected in children and NOD mice who later develop type 1 diabetes. However, there is a lack of studies looking at pancreas lipid composition in relation to type 1 diabetes. We have previously shown that individuals with newly diagnosed type 1 diabetes have abnormal islet sphingolipid metabolism. In this study, we sought to further investigate the effects of fenofibrate, a regulator of lipid metabolism that has previously been shown to prevent diabetes and inflammation in the pancreas of NOD mice. Using MS, we found that fenofibrate treatment led to a specific increase in very-long-chain sphingolipids, predominantly C24. We observed no change in total ceramide levels, as the increase in C24 was associated with a corresponding decrease in C16 and C18. The altered chain length composition is critical, as the proapoptotic properties of ceramide are greatly dependent on the length of the lipid chain. C24 ceramide is an important component of myelin sheaths with essential roles in neuronal and metabolic health, whereas C16 ceramide promotes apoptosis and is associated with mitochondrial dysfunction and insulin resistance. Hence, our results suggest that fenofibrate creates a more beneficial ceramide composition in the pancreas. The function of sulfatide is equally dependent on lipid chain length, with C16 regulating insulin secretion and proinsulin folding, while C24 is an immune regulator. Furthermore, C24:1 sulfatide has been shown to induce transcription of the gene encoding indoleamine 2,3-dioxygenase 1, an important regulator of autoimmunity with reduced expression in individuals with newly diagnosed type 1 diabetes. The increase in C24:0 and C24:1 sulfatide is, thus, likely to create a more anti-inflammatory environment. This increase might be a direct explanation for the diabetes-protective effect of fenofibrate, as injections of C24:0 sulfatide have been shown to reduce diabetes incidence in NOD mice. The progression into diabetes is associated with decreased levels of GPLs in NOD mice, suggesting that the reduced level of GPLs in fenofibrate-treated mice might be disadvantageous. On the other hand, we found increased amounts of lysoGPL, of which LPC is an inducer of insulin secretion. The increased PC:PE ratio signals a changed membrane permeability, which could influence cytokine signalling; however, an increased ratio is also linked to endoplasmic reticulum stress. A limitation of this study is the lack of a ‘normal’ pancreatic lipidome from non-diabetic mice, thus making the global biological effects of the observed changes hard to predict. It is difficult to find an appropriate control as different mouse strains have very different pancreatic lipidomes. A recent study found that the genetically closely related NODSCID mouse (which does not develop diabetes) has a very different pancreatic lipidome to the NOD mouse, making it a bad model with which to compare. We are therefore at high risk of drawing different conclusions depending on which mouse strain we define as ‘normal’.