Fucosylated chondroitin sulfate oligosaccharides from Isostichopus badionotus regulates lipid disorder in C57BL/6 mice fed a high-fat diet
Introduction
Dyslipidemia has been a serious risk for human health by causing serious consequences. Over nutrition, such as Western diet, is a major contributor to dyslipidemia (Cordain et al., 2005). In addition, excessive energy intake often brings other complications such as obesity, inflammation, and nonalcoholic fatty liver disease (NAFLD). Diets typically high in animal fats, high in simple sugars and low in plant-based fibers, are referred to as a high-fat diet (HFD). HFD is often used in most studies to mimic diseases related to dyslipidemia (Noeman, Hamooda, & Baalash, 2011; Wang et al., 2017a). Dyslipidemia is characterized by elevated concentrations of serum triglycerides (TG), total cholesterol(TC), and low-density lipoprotein cholesterol (LDL-C) (Kotani, Serban, Penson, Lippi, & Banach, 2016). Adipose tissue and liver are the most important energy tissues and organs for lipid metabolism. Excessive energy intake will disturb the normal function of adipose tissue and liver (Kakimoto & Kowaltowski, 2016; Ouchi, Parker, Lugus, & Walsh, 2011) by influencing expression of genes related to energy metabolism. Thus, it is very important to maintain the normal function of adipose tissue and liver.
Polysaccharides have powerful effects on regulating dyslipidemia (Cao et al., 2016; Pan et al., 2016). Extensive evidence indicates that polysaccharides can regulate lipid metabolism through multi-functional roles. Polysaccharide from Angelica sinensis can reduce lipid accumulation and inflammatory response caused by HFD (Wang et al., 2015). Chitosan reduces energy intake by promoting fecal TC, TG, and total bile acid (TBA) excretion in vivo (Zhang, Zhang, Mamadouba, & Xia, 2012). This may result from the lipid-binding ability of chitosan, as a type of a cationic polysaccharide (Wydro, Krajewska, & Ha̧C-Wydro, 2007). Fucoidan can reverse the disorders related to protein expression caused by over nutrition, such as normalizing PI3K/PKB/GSK-3β signaling in liver tissue (Wang et al., 2016) and GLUT4/PI3K/PKB in adipose tissue (Huang et al., 2016). Glycosaminoglycans from crickets can affect liver gene expression profiling in rats on a HFD and exert antilipidemic effects (Ahn, Hwang, Kim, & Park, 2016). Most studies on the effects of glycans on lipid disorders have been focused on polysaccharides. However, to the best of our knowledge, there is a very limited research involving the impact of glycans on lipid disorders at the oligosaccharides level.
Fucosylated chondroitin sulfate (fCS) from sea cucumbers is a kind of glycosaminoglycan composed of alternating β-D-glucuronic acid and N-acetyl-β-D-galactosamine units with α-L-fucose branches. The most attractive property of fCS is their specific repeating oligosaccharide units and their unique sulfation patterns. This family of glycosaminoglycans has been extensively studied for its anticoagulant and antithrombotic activities for its sulfation (Chen et al., 2011). In addition, fCS also demonstrates health benefits in energy metabolism by normalizing the function of adipose tissues and liver (Hu et al., 2013) and inhibiting lipid disorders caused by over nutrition (Wu et al., 2016). Recently, depolymerized fCS (DfCS) from sea cucumbers has attracted increasing attention due to its reduced adverse effects on anticoagulation, compared to polysaccharides (Li et al., 2016). We have applied a modified controllable Fenton-system to obtain fCS oligosaccharides from Isostichopus badionotus with minimal impact on the main repeating structure and have named this oligosaccharide fraction DfCS-Ib (Li et al., 2017). The anticoagulant activity of DfCS-Ib has reduced side effects suggesting its potential therapeutic application (Li et al., 2017). However, the effects of DfCS-Ib on lipid metabolism remain undefined.
In the present study, DfCS-Ib prepared by our formerly reported method (Li et al., 2016), was explored for lipid regulation. The hypolipidemic activity of DfCS-Ib was investigated from lipid profile, inflammatory cytokines, and liver and epididymal fat histology. Related mRNA expression of adipose tissues and transcriptome analysis of liver were used here to reveal the possible mechanisms of DfCS-Ib effects on lipid metabolism disorders.
Section snippets
Materials
Sea cucumbers Isostichopus badionotus (from Western Atlantic Ocean) were purchased from a local market in Qingdao, Shandong, China.
Preparation of sea cucumber oligosaccharides
Crude chondroitin sulfate from Isostichopus badionotus (fCS-Ib) was prepared and purified based on a previously described method (Chen et al., 2012). DfCS-Ib from Isostichopus badionotus was prepared by a newly developed method of oxidative degradation based on a previous report (Li et al., 2016). Reaction conditions were pH 6, 200 mM H2O2, 2 mM Cu2+ and temperature
Effects of DfCS-Ib on body weight, liver weight, kidney weight, epididymal fat mass and food intake
The mice were fed with a HFD containing 45% fat for six weeks to build a hyperlipidemic model, which leading to significant gain in body, liver, kidney and epididymal fat weight compared with animals fed chow feeding (Fig. 1). Weight gain of the HFD group was 4.36 ± 0.92 g (Fig. 1a), twice of the control group (2.28 ± 0.63 g, P < 0.05 compared to HFD group). The body weight gains of simvastatin, DfCS-Ib-L (20 mg/kg), and DfCS-Ib-H (40 mg/kg) treated animals showed no significant difference with
Further discussion for possible mechanism of DfCS-Ib on lipid disorders
In the present work, even low-doses of DfCS-Ib could alleviate damage with the same power simvastatin. DfCS-Ib can restore lipid profile, alleviate mild inflammation, inhibit adipocyte hypertrophy, and maintain normal histomorphology of liver caused by HFD. Former studies reported that sulfated polysaccharides such as carrageenan and its low molecular weight carrageenan derivatives can be proinflammatory agent (Tobacman, Bhattacharyya, Borthakur, & Dudeja, 2008). Our results showed that DfCS-Ib
Conclusions
Although fucosylated chondroitin sulfate oligosaccharides have been investigated extensively for its anticoagulation activity (Zhao et al., 2015), their effects on the dyslipidemia caused by HFD has not yet been defined. Our study supports the argument that HFD can result in many metabolic diseases such as lipid disorders, obesity, chronic inflammation and non-alcoholic fatty liver disease (NAFLD). DfCS-Ib supplementation significantly suppresses high-fat diet induced lipids disorders such as
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