| During the past20years, the incidence of non-alcoholic fatty liver disease(NAFLD) has been increasing, and its pathogenesis, prevention and treatment wellstudied and have drawn much attention. The occurrence of NAFLD in metabolicsyndrome (MS) people was about5.6fold than that in people without MS. There isclose association between NAFLD and IR, the foundation of MS. The causalrelationship between NAFLD and IR is still controversial. Because people with MSare often accompanied by obesity or hyperlipidemia, both of which affect insulinsensitivity, either directly or indirectly. In this study, NAFLD model induced by oroticacid (OA) in rats, a fatty liver animal model without obesity and hyperlipidemia, isused to study the precedence relationship between NAFLD and IR to excludeinterference with obesity and hyperlipidemia. In addition, sea cucumber saponinis triterpenoid saponin, the major bioactive compound of sea cucumber. Andshort-time feeding of sea cucumber saponin showed significant preventive effect fromNAFLD. However, the development and utilization of saponin is limited by itshemolytic activity and toxicity. Previous works proved that the structural modificationof sea cucumber saponin through acidolysis significantly reduce the hemolyticactivity and toxicity. In this study, we first studied the mechanisms of NAFLD in thedevelopment of fatty liver by OA in rats. Secondly, sea cucumbers and its structuralmodifications are used to study the effects on lipid and glucose metabolisms in thismodel, providing a theoretical basis for the comprehensive development andutilization.Firstly, the causal relationship between NAFLD and IR was studied in thedevelopment of fatty liver induced by1%OA feeding in rats. It is found that, thehepatic lipid accumulation exacerbated with time, and in later stages of fatty liver,glucose intolerance appeared. The results of mechanism research showed that, inadvanced stages of NAFLD, OA enhanced hepatic lipogenesis by up-regulatingSREBP-1c and its target gene expression, impaired insulin signaling transductionpathway through down-regulating the gene and protein expression of major signalingmolecules, especially the protein expression of t-Akt, p-Akt(ser473), and disturbedglucose metabolism by suppressing hepatic gluconeogenesis and promotingexpression of GLUT2protein, finally inducing hepatic glycogen storage in rats. In aword, the NAFLD preceded IR, and chronic NAFLD may cause IR directly.Secondly, sea cucumber saponin was used to prepare the structural modificationof sea cucumber saponin, desulfurization saponin and saponin aglycone, by hydrolysis using strong acid and dilute acid. Then, sea cucumber saponin, desulfurizationsaponin and saponin aglycone (0.03%) were added to the standard chow with1%OAto investigate the preventive effect on NAFLD. The results showed that the seacucumber saponin, desulfurization saponin, the saponin aglycone all reduced thesignificantly increases of hepatic TG and TC content induced by OA, and thepreventive effects exhibited no difference.Finally，the therapeutic effects of the saponins were further studied by feeding0.04%all the sea cucumber saponins and starfish saponin for8w, after1%OAfeeding for6w to induce fatty liver in rats. On one hand, all the used saponinssignificantly attenuated the excessive accumulation of hepatic TG and TC induced byOA. Among that, the therapeutic effect of saponin aglycone on NAFLD was the best.On the other hand, both of sea cucumber saponin and starfish saponin accelerated theexudation of insulin, suppressed the increase of serum glucose level, significantlyimproving glucose intolerance in the glucose tolerance test.This is the first time to study the precedence relationship between NAFLD andIR in the development of NAFLD induced by OA in rats, compared the preventiveeffect on NAFLD of sea cucumber saponins and its modifications, and the therapeuticeffect on NAFLD of chronic sea cucumber saponins and starfish saponins in rats,providing a scientific basis for the process of marine saponins. |
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