In Vivo Lipid-lowering Effect And Mechanism Of Chitosan Oligosaccharide(M_w≤1000 Da) Particles

Hyperlipidemia(HLP), characterized by the abnormal levels of serum lipids, is a kind of general and abnormal lipid metabolic diseases that damage the human health seriously and also has been considered as one of the important risk factors for cardiovascular disease(CVD) such as atherosclerosis(AS) and coronary heart disease(CHD), etc. With the transformation of modern human life-style, HLP has become one of the public health problems worldwide. Currently, the main treatment for HLP is chemotherapies, which present a number of adverse reactions(ADRs) at the same time. Therefore, It’s highly necessary for us to explore the hypolipidemic drugs characterized as safety, affectivity and fewer ADRs.Chitosan oligosaccharides(COS), as the natural derivatives of chitosan(CTS) that is the only alkaline polysaccharide in nature, generally prepared by enzyme hydrolysis method or chemical degradation method, is characterized by absorbing easily, high activity and few ADRs. In our previous study, we have studied systematically the lipid-lowering activity. However, its poor solubility, absorption and drug ability limit its activity and pharmaceutical value greatly. We chose chitosan oligosaccharides(Mw≤3000) particles(COS3000) for the hypolipidemic experiments latterly, the results showed that though the solubility and absorption of COS3000 were improved to some extent, its biological activity has not been adequately met our desirable effect.In this study, we firstly established Sprague-Dawley(SD) rat hyperlipidemic model induced by a high-fat diet to investigate the lipid-lowering effect of chitosan oligosaccharides particles(Mw≤1000, COST). The rats were randomly divided into six parallel groups for the experiment: the control group(NF), the hyperlipidemic model group(HF), the positive drug Simvastatin(SV) group as well as the high(COST-H), middle(COST-M) and low(COST-L) dose COST groups. There were 10 rats in every group, which were used for model-building and preventing experiment in the following six weeks. The results showed that COST can decrease dose-dependently body weight gain, fat/body ratio, Lee’s index and visceral indices as well as suppress the growth of adipocytes, presenting certain anti-obese effect. At the same time, COST can effectively lower the serum TC, TG and LDL-C level, and increase liver TC, TG and total bile acids(TBA) concentrations as well as further promote the excretion of TC, TG and TBA via feces, which is contributing to its hypolipidemic effect. In addition, COST also improved dose-dependently the activity of superoxide dismutase(SOD) and reduced remarkably the contents of serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT), displaying the obvious pharmacological actions for anti-oxidation and hepatic protection.To further explore the pharmacological mechanism of COST in lipid-lowering activity, we detected the m RNA expressions of hepatic lipase(HL) and peroxisome proliferators activated receptor-α(PPARα), which are the two of the important cytokines in liver relating to lipid metabolism. The results indicated that COST can significantly increase the expressions of liver PPARα and HL m RNA. Therefore, after the remedy of COST, the improvement of SD rats’ lipid metabolism is realized by the fact that COST can promote liver PPARα level and indirectly up-regulate liver HL expression, which further better hepatic lipid metabolism.