Metabolic syndrome characterized by obesity, hyperglycemia and liver steatosis is becoming prevalent all over the world. Herein, a water insoluble polysaccharide (WIP) was isolated and identified from the sclerotium of Poria cocos, a widely used Traditional Chinese Medicine. WIP was confirmed to be a (1-3)-β-D-glucan with an average Mw of 4.486 × 10 Da by NMR and SEC-RI-MALLS analyses. Furthermore, oral treatment with WIP from P. cocos significantly improved glucose and lipid metabolism and alleviated hepatic steatosis in ob/ob mice. 16S DNA sequencing analysis of cecum content from WIP-treated mice indicated the increase of butyrate-producing bacteria Lachnospiracea, Clostridium. It was also observed that WIP treatment elevated the level of butyrate in gut, improved the gut mucosal integrity and activated the intestinal PPAR-γ pathway. Fecal transplantation experiments definitely confirmed the causative role of gut microbiota in mediating the benefits of WIP. It is the first report that the water insoluble polysaccharide from the sclerotium of P. cocos modulates gut microbiota to improve hyperglycemia and hyperlipidemia. Thereby, WIP from P. cocos, as a prebiotic, has the potential for the prevention or cure of metabolic diseases and may elucidate new mechanism for the efficacies of this traditional herbal medicine on the regulation of lipid and glucose metabolism.
Animals ; Bacteria ; classification ; genetics ; isolation & purification ; metabolism ; Butyrates ; metabolism ; Fatty Liver ; drug therapy ; Fungal Polysaccharides ; chemistry ; pharmacology ; therapeutic use ; Gastrointestinal Microbiome ; drug effects ; genetics ; Hyperglycemia ; drug therapy ; Hyperlipidemias ; drug therapy ; Intestines ; drug effects ; microbiology ; Male ; Metabolic Syndrome ; drug therapy ; Mice ; Mice, Obese ; Prebiotics ; Wolfiporia ; chemistry

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.
Animals ; Artemisia ; chemistry ; Atherosclerosis ; drug therapy ; genetics ; metabolism ; Cholesterol ; metabolism ; Cholesterol 7-alpha-Hydroxylase ; genetics ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hyperlipidemias ; drug therapy ; genetics ; metabolism ; Hypolipidemic Agents ; administration & dosage ; Liver ; drug effects ; metabolism ; Male ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Receptors, Cytoplasmic and Nuclear ; antagonists & inhibitors ; genetics ; metabolism ; Sterol Regulatory Element Binding Protein 1 ; genetics ; metabolism ; Triglycerides ; metabolism

Oleanolic acid (OA) is a pentacyclic triterpenoid compound extracted from olea europaeal, a traditional Chinese medicine herb. OA has been used in the clinic as a hepatoprotective medicine in China since 1970s. In our previous study, we observed that OA could ameliorate hyperlipidemia in animal models. In the present study, we conducted a small-scale clinical trial to evaluate the hypolipidemia effect of OA in hyperlipidemic patients. Hyperlipidemic patients were administrated with OA for four weeks (4 tablets once, three times a day). The blood samples of the patients were collected before and after OA treatment. The biological parameters were measured. Furthermore, three patients' blood samples were studied with DNA microarray. After OA administration, the TC, TG, and HDLC levels in serum decreased significantly. DNA microarray analysis results showed that the expressions of 21 mRNAs were significantly changed after OA treatment. Bioinformatics analysis showed 17 mRNAs were up-regulated and 4 mRNAs were down-regulated significantly after OA treatment. Five mRNAs (CACNA1B, FCN, STEAP3, AMPH, and NR6A1) were selected to validate the expression levels by qRT-PCR. Therefore, OA administration differentially regulated the expression of genes involved in lipid metabolism. The data showed a clinical evidence that OA could improve hyperlipidemia and also unveiled a new insight into the molecular mechanisms underlying the pharmacological effect of OA on hyperlipidemia.
China ; Computational Biology ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; drug effects ; Humans ; Hyperlipidemias ; blood ; drug therapy ; genetics ; metabolism ; Lipid Metabolism ; drug effects ; Male ; Middle Aged ; Oleanolic Acid ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; Treatment Outcome

As a culinary and medicinal herb, rosemary is widely used. The present work aimed to investigate the effects of rosemary extracts on metabolic diseases and the underlying mechanisms of action. Liver cells stably expressing SREBP reporter were used to evaluate the inhibitory effects of different fractions of rosemary extracts on SREBP activity. The obese mice induced by Western-type diet were orally administered with rosemary extracts or vehicle for 7 weeks, the plasma and tissue lipids were analyzed. SREBPs and their target genes were measured by quantitative RT-PCR. We demonstrated that the petroleum ether sub-fraction of rosemary extracts (PER) exhibited the best activity in regulating lipid metabolism by inhibiting SREBPs, while water and n-BuOH sub-fraction showed the SREBPs agonist-effect. After PER treatment, there was a significant reduction of total SREBPs in liver cells. PER not only decreased SREBPs nuclear abundance, but also inhibited their activity, resulting in decreased expression of SREBP-1c and SREBP-2 target genes in vitro and in vivo. Inhibiting SREBPs by PER decreased the total triglycerides and cholesterol contents of the liver cells. In the mice fed with Western-type diet, PER treatment decreased TG, TC, ALT, glucose, and insulin in blood, and improved glucose tolerance and insulin sensitivity. Furthermore, PER treatment also decreased lipid contents in liver, brown adipose tissue, and white adipose tissue. Our results from the present study suggested that petroleum ether fraction of rosemary extracts exhibited the best potential of improving lipid metabolism by inhibiting SREBPs activity.
Alkanes ; chemistry ; Animals ; Cholesterol ; metabolism ; Hepatocytes ; drug effects ; metabolism ; Humans ; Hyperlipidemias ; drug therapy ; genetics ; metabolism ; Insulin ; metabolism ; Insulin Resistance ; Liver ; drug effects ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Petroleum ; analysis ; Plant Extracts ; administration & dosage ; chemistry ; isolation & purification ; Rosmarinus ; chemistry ; Sterol Regulatory Element Binding Protein 1 ; genetics ; metabolism ; Sterol Regulatory Element Binding Protein 2 ; genetics ; metabolism

BACKGROUND: Several studies have focused on the association between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism; however, the results are conflicting. The effects of statins show significant variability between individuals. This meta-analysis aimed to investigate the effects of the SLCO1B1 c.521T>C polymorphism on the lipid-lowering effects of statins. METHODS: We systematically searched PubMed and Web of Science to screen relevant studies. Meta-analysis was performed to identify the association between SLCO1B1 c.521 polymorphisms and the lipid-lowering effects of statinson the basis of the standard mean difference (SMD) and 95% confidence intervals (CIs). Additionally, we checked for heterogeneity (I 2) among studies and evidence of publication bias. We obtained eight studies including 2,012 wild genotype (T/T) and 526 variant genotype (T/C and C/C) cases. RESULTS: No significant difference was observed in the lipid-lowering efficacy of statins between the wildand variant genotypes of SLCO1B1, with a pooled SMD of 0.03 (95% CI: -0.07-0.13). Furthermore, there was no significant effect in the meta-analyses of the variant heterozygote, homozygote, and Chinese populations. Subgroup meta-analysis indicated that the timerequired for the statin to take effectdid notsignificantly affect the association between lipid-lowering efficacy of statins and SLCO1B1 c.521T>C polymorphism. However, thewild genotype improved the lipid-lowering efficacy of simvastatin with a pooled SMD of -0.26 (95% CI: -0.47- -0.05). CONCLUSIONS: No significant association was detected between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism, with the exception of simvastatin.
Alleles ; Databases, Factual ; Genotype ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Hyperlipidemias/drug therapy/genetics ; Polymorphism, Single Nucleotide ; Solute Carrier Organic Anion Transporter Family Member 1b1/*genetics

Traditional Chinese medicine (TCM) has definitely clinical effect in treating hyperlipidemia, but the action mechanism still need to be explored. Based on consulting Chinese Pharmacopoeia (2010), all the lipid-lowering Chinese patent medicines were analyzed by associated rules data mining method to explore high frequency herb pairs. The top three couplet medicines with high support degree were Puerariae Lobatae Radix-Crataegi Fructus, Salviae Miltiorrhizae Radix et Rhizoma-Crataegi Fructus, and Polygoni Multiflori Radix-Crataegi Fructus. The 20 main ingredients were selected from the herb pairs and docked with 3 key hyperlipidemia targets, namely 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), peroxisome proliferator activated receptor-α (PPAR-α ) and niemann-pick C1 like 1 (NPC1L1) to further discuss the molecular mechanism of the high frequency herb pairs, by using the docking program, LibDock. To construct evaluation rules for the ingredients of herb pairs, the root-mean-square deviation (RMSD) value between computed and initial complexes was first calculated to validate the fitness of LibDock models. Then, the key residues were also confirmed by analyzing the interactions of those 3 proteins and corresponding marketed drugs. The docking results showed that hyperin, puerarin, salvianolic acid A and polydatin can interact with two targets, and the other five compounds may be potent for at least one of the three targets. In this study, the multi-target effect of high frequency herb pairs for lipid-lowering was discussed on the molecular level, which can help further researching new multi-target anti-hyperlipidemia drug.
Asteraceae ; chemistry ; Drugs, Chinese Herbal ; chemistry ; metabolism ; Humans ; Hydroxymethylglutaryl CoA Reductases ; chemistry ; genetics ; metabolism ; Hyperlipidemias ; drug therapy ; enzymology ; genetics ; metabolism ; Hypolipidemic Agents ; chemistry ; metabolism ; Membrane Proteins ; chemistry ; genetics ; metabolism ; Molecular Docking Simulation ; PPAR alpha ; chemistry ; genetics ; metabolism ; Protein Binding ; Pueraria ; chemistry

Hyperlipidemia is a major factor causing coronary heart disease and atherosclerosis. The high-density lipoprotein cholesterol (HDL-C) is a major indicator for measuring lipid levels. However, there is no an effective medicine that can obviously increase HDL-C at present. According to previous laboratory studies, atractylodes macrocephalae extracts could significantly increase HDL-C level. In this study, the metabolic hyperlipidemia rat model was established by feeding high-sugar and fat diets and alcohol-drinking to explore the effect and mechanism of atractylodes macrocephalae extracts on hyperlipidemia rats. According to the findingins, different doses of atractylodes macrocephalae extracts could reduce the levels of TC, TG, LDL-C, ACAT and increase the contents of LCAT, HDL-C. Particularly, the atractylodes macrocephalae extracts (100 mg · kg(-1) group showed increase in HDL-C by about 50% and significant declines in HMG-CoA reductase, TC, TG. In conclusion, Atractylodes Macrocephelae Rhizoma extracts could effectively regulate the dyslipidemia of hyperlipidemia rats, especially on HDL-C. Its mechanism may be related to reduction in cholesterol synthesis by inhibiting HMG-CoA reductase in livers and increase in lipid metabolism and transport by regulating LCAT and ACAT levels.
Acyl Coenzyme A ; antagonists & inhibitors ; genetics ; metabolism ; Animals ; Atractylodes ; chemistry ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; administration & dosage ; Hyperlipidemias ; drug therapy ; enzymology ; metabolism ; Lipoproteins, HDL ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Rhizome ; chemistry ; Triglycerides ; metabolism

Rhubarb is a traditional Chinese medicine (TCM), wildly used in treating the disease of hyperlipidemia. However, its components are complicated, so that it is still difficult to clear the specific roles of its various components in blood lipids regulation in. So we decide to systematically study the anti- hyperlipidemia mechanism of rhubarb. We integrated multiple databases, based on entity grammar systems model, constructed molecular interaction network between the chemical constituents of rhubarb and hyperlipidemia. The network includes 231 nodes and 638 edges. Thus we infer the interactions of active targets and disease targets to clarify the anti-hyperlipidemia mechanism. And find that rhubarb can promote excretion of cholesterol; inhibit clotting factors and improve blood circulation; inhibit the release of inflammatory cytokines and maintain fat metabolism balance; inhibit cholesterol and triglyceride synthesis; and other ways to achieve lipid-lowering effect. Thus this study provides reference for novel drug development and component compatibility, and also gives a new way for the systematically study of acting mechanism of traditional Chinese medicine.
Animals ; Databases, Factual ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Gene Regulatory Networks ; drug effects ; Humans ; Hyperlipidemias ; drug therapy ; genetics ; metabolism ; Hypolipidemic Agents ; administration & dosage ; chemistry ; Lipid Metabolism ; Rheum ; chemistry ; Signal Transduction ; drug effects

To study the effects of alkaloids from Coptidis Rhizoma on low-density lipoprotein receptor (LDLR) mRNA expression and antihyperlipedemic levels. The LDLR mRNA expression were detected by real time fluorescence quantitative PCR, and the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-c) and high-density lipoprotein cholesterol (HDL-c) in serum were measured at the first and last examination. The results show that, after the drug treatment, compared with the model group, each drug group showed a lipid-lowering effect. Especially, coptisine, palmatine, jatrorrhinze were significantly reduced TC, TG, LDL-c (P < 0.05, P < 0.01), and increased HDL-c (P < 0.01). In addition, they also increased mRNA expression of the LDLR in liver and HepG2 cells. The results showed that alkaloids from Coptidis Rhizoma can regulate lipid metabolism disorder, and coptisine have the best lipid-lowering effect.
Alkaloids ; administration & dosage ; Animals ; Cholesterol ; metabolism ; Cricetinae ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hyperlipidemias ; drug therapy ; genetics ; metabolism ; Hypoglycemic Agents ; administration & dosage ; Lipid Metabolism ; drug effects ; Lipids ; blood ; Lipoproteins, LDL ; metabolism ; Mesocricetus ; Receptors, Lipoprotein ; genetics ; metabolism ; Triglycerides ; metabolism

OBJECTIVETo investigate the anti-hyperlipidemic effects of apple polyphenols extract (APE) in Triton WR-1339-induced endogenous hyperlipidemic model.

METHODSFirstly, APE was isolated and purified from the pomace of Red Fuji Apple and contents of individual polyphenols in APE were determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Secondly, forty male National Institude of Health (NIH) mice were randomly divided into 5 groups with 8 animals in each group. The Fenofibrate Capsules (FC) group and APE groups received oral administration of respective drugs for 7 consecutive days. All mice except those in the normal group were intravenously injected through tail vein with Triton WR-1339 on the 6th day. Serum and livers from all the mice were obtained 18 h after the injection. The changes in serum total cholesterol (TC), triglyceride (TG), lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) were measured by respective kits. Finally, expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) mRNA was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS SERUM TC AND TG LEVELS SIGNIFICANTLY INCREASED IN TRITON WR-1339-INDUCED MODEL GROUP COMPARED WITH THE NORMAL GROUP (P<0.01). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY REDUCED THE SERUM LEVEL OF TG IN HYPERLIPIDEMIC MICE (P<0.01). SERUM LPL AND HTGL ACTIVITIES SIGNIFICANTLY DECREASED IN TRITON WR-1339-INDUCED MODEL GROUP COMPARED WITH THE NORMAL GROUP (P<0.05). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY ELEVATED THE SERUM ACTIVITY OF LPL IN HYPERLIPIDEMIC MICE (P<0.05 OR P<0.01). FURTHERMORE, COMPARED WITH THE NORMAL GROUP, HEPATIC MRNA LEVEL OF PPARα IN THE MODEL GROUP SIGNIFICANTLY DECREASED (P<0.01). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY ELEVATED THE EXPRESSION OF PPARα IN HYPERLIPIDEMIC MICE (P<0.05 OR P<0.01):

CONCLUSIONAPE could reduce TG level via up-regulation of LPL activity, which provides new evidence to elucidate the anti-hyperlipidemic effects of APE.

Animals ; Chlorogenic Acid ; pharmacology ; therapeutic use ; Cholesterol ; blood ; Flavonoids ; pharmacology ; therapeutic use ; Hyperlipidemias ; blood ; drug therapy ; enzymology ; pathology ; Hypolipidemic Agents ; pharmacology ; Lipoprotein Lipase ; blood ; genetics ; Male ; Mice ; PPAR alpha ; genetics ; metabolism ; Phytotherapy ; Polyethylene Glycols ; RNA, Messenger ; genetics ; metabolism ; Tannins ; pharmacology ; therapeutic use ; Triglycerides ; blood ; Up-Regulation ; drug effects