Hypolipidemic effect and gut microbiota regulation of Gypenoside aglycones in rats fed a high-fat diet.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynostemma pentaphyllum (Thunb.) Makino has traditional applications in Chinese medicine to treat lipid abnormalities. Gypenosides (GPs), the main bioactive components of Gynostemma pentaphyllum, have been reported to exert hypolipidemic effects through multiple mechanisms. The lipid-lowering effects of GPs may be attributed to the aglycone portion resulting from hydrolysis of GPs by the gut microbiota. However, to date, there have been no reports on whether gypenoside aglycones (Agl), the primary bioactive constituents, can ameliorate hyperlipidemia by modulating the gut microbiota. AIM OF THE STUDY: This study explored the potential therapeutic effects of gypenoside aglycone (Agl) in a rat model of high-fat diet (HFD)-induced hyperlipidemia. METHODS: A hyperlipidemic rat model was established by feeding rats with a high-fat diet. Agl was administered orally, and serum lipid levels were analyzed. Molecular techniques, including RT-polymerase chain reaction (PCR) and fecal microbiota sequencing, were used to investigate the effects of Agl on lipid metabolism and gut microbiota composition. RESULTS: Agl administration significantly reduced serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) and mitigated hepatic damage induced by HFD. Molecular investigations have revealed the modulation of key lipid metabolism genes and proteins by Agl. Notably, Agl treatment enriched the gut microbiota with beneficial genera, including Lactobacillus, Akkermansia, and Blautia and promoted specific shifts in Lactobacillus murinus, Firmicutes bacterium CAG:424, and Allobaculum stercoricanis. CONCLUSION: This comprehensive study established Agl as a promising candidate for the treatment of hyperlipidemia. It also exhibits remarkable hypolipidemic and hepatoprotective properties. The modulation of lipid metabolism-related genes, along with the restoration of gut microbiota balance, provides mechanistic insights. Thus, Agl has great potential for clinical applications in hyperlipidemia management.

Hypolipidemic Effect of Rice Bran Oil Extract Tocotrienol in High-Fat Diet-Induced Hyperlipidemia Zebrafish (Danio Rerio) Induced by High-Fat Diet.

In recent years, the potent influence of tocotrienol (T3) on diminishing blood glucose and lipid concentrations in both Mus musculus (rats) and Homo sapiens (humans) has been established. However, the comprehensive exploration of tocotrienol's hypolipidemic impact and the corresponding mechanisms in aquatic species remains inadequate. In this study, we established a zebrafish model of a type 2 diabetes mellitus (T2DM) model through high-fat diet administration to zebrafish. In the T2DM zebrafish, the thickness of ocular vascular walls significantly increased compared to the control group, which was mitigated after treatment with T3. Additionally, our findings demonstrate the regulatory effect of T3 on lipid metabolism, leading to the reduced synthesis and storage of adipose tissue in zebrafish. We validated the expression patterns of genes relevant to these processes using RT-qPCR. In the T2DM model, there was an almost two-fold upregulation in pparγ and cyp7a1 mRNA levels, coupled with a significant downregulation in cpt1a mRNA (p < 0.01) compared to the control group. The ELISA revealed that the protein expression levels of Pparγ and Rxrα exhibited a two-fold elevation in the T2DM group relative to the control. In the T3-treated group, Pparγ and Rxrα protein expression levels consistently exhibited a two-fold decrease compared to the model group. Lipid metabolomics showed that T3 could affect the metabolic pathways of zebrafish lipid regulation, including lipid synthesis and decomposition. We provided experimental evidence that T3 could mitigate lipid accumulation in our zebrafish T2DM model. Elucidating the lipid-lowering effects of T3 could help to minimize the detrimental impacts of overfeeding in aquaculture.

The anti-hyperlipidemic effects of Poria cocos (Schw.) Wolf extract: Modulating cholesterol homeostasis in hepatocytes via PPARα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Poria cocos (Schw.) Wolf (Polyporaceae, P.cocos), which is born on the pine root, has a history of more than two thousand years of medicine in China. P.cocos was first recorded in the Shennong's Herbal Classic, studies have proved its lipid-lowering effect. AIM OF STUDY: The aim of study was to investigate the underlying mechanism of P.cocos extract on hyperlipidemia. MATERIALS AND METHODS: Male Sprague-Dawley (SD) rats aged 9-12 weeks were intraperitoneally (IP) injected with Triton-WR 1339 to establish an acute hyperlipidemia model. At 0 h and 20 h after the model was established, low and high doses of P.cocos extract or simvastatin were given twice. After 48 h, the rats were sacrificed, and liver and serum samples were collected for analysis. The cell model was constructed by treating L02 cells with 1% fat emulsion-10% FBS-RPMI 1640 medium for 48 h. At the same time, low and high doses of P.cocos extract and simvastatin were administered. Oil red O staining was used to evaluate the lipid accumulation in the cells, and H&E staining was used to evaluate the liver lesions of rats. Real-time quantitative PCR and western blotting were used to detect the expressions of lipid metabolism-related genes. RESULTS: P.cocos extract relieved lipid accumulation in vitro and alleviated hyperlipidemia in vivo. Both gene and protein expressions of peroxisome proliferator-activated receptor α (PPARα) were shown to be up-regulated by P.cocos extract. Additionally, P.cocos extract down-regulated the expressions of fatty acid synthesis-related genes sterol regulatory element-binding protein-1 (SREBP-1), Acetyl-CoA Carboxylase 1 (ACC1) and fatty acid synthase (FAS), while up-regulated the expressions of cholesterol metabolism-related genes liver X receptor-α (LXRα), ATP-binding cassette transporter A1 (ABCA1), cholesterol 7alpha-hydroxylase (CYP7A1) and low density lipoprotein receptor (LDLR), which were reversed by the treatment with the PPARα inhibitor GW6471. CONCLUSION: P.cocos extract ameliorates hyperlipidemia and lipid accumulation by regulating cholesterol homeostasis in hepatocytes through PPARα pathway. This study provides evidence that supplementation with P.cocos extract could be a potential strategy for the treatment of hyperlipidemia.

Saponins from Chenopodium quinoa Willd. husks alleviated high-fat-diet-induced hyperlipidemia via modulating the gut microbiota and multiple metabolic pathways.

BACKGROUND: Hyperlipidemia is characterized by abnormally elevated blood lipids. Quinoa saponins (QS) have multiple pharmacological activities, including antitumor, bactericidal and immune-enhancing effects. However, the lipid-lowering effect and mechanisms of QS in vivo have been scarcely reported. METHODS: The effect of QS against hyperlipidemia induced by high-fat diet in rats was explored based on gut microbiota and serum non-targeted metabolomics. RESULTS: The study demonstrated that the supplementation of QS could reduce serum lipids, body weight, liver injury and inflammation. 16S rRNA sequencing demonstrated that QS mildly increased alpha-diversity, altered the overall structure of intestinal flora, decreased the relative richness of Firmicutes, the ratio of Firmicutes/Bacteroidetes (P < 0.05) and increased the relative richness of Actinobacteria, Bacteroidetes, Bifidobacterium, Roseburia and Coprococcus (P < 0.05). Simultaneously, metabolomics analysis showed that QS altered serum functional metabolites with respect to bile acid biosynthesis, arachidonic acid metabolism and taurine and hypotaurine metabolism, which were closely related to bile acid metabolism and fatty acid ß-oxidation. Furthermore, QS increased protein levels of farnesoid X receptor, peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase 1, which were related to the screened metabolic pathways. Spearman correlation analysis showed that there was a correlation between gut microbiota and differential metabolites. CONCLUSION: QS could prevent lipid metabolism disorders in hyperlipidemic rats, which may be closely associated with the regulation of the gut microbiota and multiple metabolic pathways. This study may provide new evidence for QS as natural active substances for the prevention of hyperlipidemia. © 2023 Society of Chemical Industry.

Active peptides from Eupolyphaga sinensis walker attenuates experimental hyperlipidemia by regulating the gut microbiota and biomarkers in rats with dyslipidemia.

Eupolyphaga sinensis Walker (ESW) is a traditional Chinese medicine formulation used to treat hyperlipidemia. However, the hypolipidemic effect of the active peptides from E. sinensis Walker (APE) is incompletely understood. We studied the hypolipidemic effect of APE and explored the impact of APE on the gut microbiota (GM) in rats suffering from hyperlipidemia. APE was prepared by enzymatic digestion, and its structure was characterized using various methods. The anti-hyperlipidemic activity of APE was assessed using a high-fat diet (HFD)-induced model in zebrafish and rats. In rats, HFD administration caused abnormalities of lipid metabolism and disturbances of the GM and amino acid (AA) profile in plasma. The abundance of bacteria of the phyla Firmicutes and Bacteroides was increased significantly (p < 0.05), and the relative abundance of Lactobacillus species and Clostridium species was decreased significantly (p < 0.05). HFD therapy affected the levels of 12 AAs in vivo: 10 AAs showed increased levels and two AAs had decreased levels (p < 0.05). Similar results were demonstrated in an experiment on fecal microbiota transplantation. APE treatment dose-dependently decreased lipid factors and liver damage (p < 0.05). Sequencing of the 16 S rRNA gene indicated that APE improved the intestinal-flora structure of rats with HL markedly, and increased the relative abundance of Lactobacillus species and Clostridium species. Metabolomics analysis indicated that APE could alter the levels of 10 AAs affected by HFD consumption. Spearman correlation analysis revealed that gamma-aminobutyric acid (GABA) could be a crucial metabolite, and Lactobacillus species and Clostridium species might be important bacteria for the action of APE against hyperlipidemia. We speculate that APE exhibited an anti-hyperlipidemic effect by regulating GABA synthesis in the presence of Lactobacillus species and Clostridium species.

Polymethoxyflavones in citrus extract has a beneficial effect on hypercholesterolemia rats by promoting liver cholesterol metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperlipidemia is characterized by the disorder of lipid metabolism accompanied by oxidative stress damage, and low-grade inflammation, with the pathway of cholesterol and bile acid metabolic are an important triggering mechanism. Polymethoxyflavones (PMFs) are the active constituents of Aurantii Fructus Immaturus, which have many biological effects, including anti-inflammatory, antioxidant activities, anti-obesity, suppressing adipogenesis in adipocytes, and ameliorate type 2 diabetes, with potential roles for regulation of lipid metabolism. However, its associated mechanisms on hyperlipidemia remain unclear. AIM OF THE STUDY: This study aims to identify the anti-hypercholesterolemia effects and mechanisms of PMFs in a hypercholesterolemia model triggered by high-fat compounds in an excessive alcohol diet (HFD). MATERIALS AND METHODS: A hypercholesterolemia rat model was induced by HFD, and PMFs was intragastric administered at 125 and 250 mg/kg daily for 16 weeks. The effects of PMFs on hypercholesterolemia were assessed using serum lipids, inflammatory cytokines, and oxidative stress levels. Hematoxylin & eosin (H&E) and Oil Red O staining were performed to evaluate histopathological changes in the rat liver. The levels of total cholesterol (TC) and total bile acid (TBA) in the liver and feces were determined to evaluate lipid metabolism. RAW264.7 and BRL cells loaded with NBD-cholesterol were used to simulate the reverse cholesterol transport (RCT) process in vitro. The signaling pathway of cholesterol and bile acid metabolic was evaluated by Western Blotting (WB) and qRT-PCR. RESULTS: Lipid metabolism disorders, oxidative stress injury, and low-grade inflammation in model rats were ameliorated by PMFs administration. Numerous vacuoles and lipid droplets in hepatocytes were markedly reduced. In vitro experiments results revealed decreased NBD-cholesterol levels in RAW264.7 cells and increased NBD-cholesterol levels in BRL cells following PMFs intervention. PMFs upregulated the expression of proteins associated with the RCT pathway, such as LXRα, ABCA1, LDLR, and SR-BI, thereby promoting TC entry into the liver. Meanwhile, the expression of proteins associated with cholesterol metabolism and efflux pathways such as CYP7A1, CYP27A1, CYP7B1, ABCG5/8, ABCB1, and BSEP were regulated, thereby promoting cholesterol metabolism. Moreover, PMFs treatment regulated the expression of proteins related to the pathway of enterohepatic circulation of bile acids, such as ASBT, OSTα, NTCP, FXR, FGF15, and FGFR4, thereby maintaining lipid metabolism. CONCLUSIONS: PMFs might ameliorate hypercholesterolemia by promoting the entry of cholesterol into the liver through the RCT pathway, followed by excretion via metabolism pathways of cholesterol and bile acid. These findings provide a promising therapeutic potential for PMFs to treat hypercholesterolemia.

Totum-070, a Polyphenol-Rich Plant Extract, Prevents Hypercholesterolemia in High-Fat Diet-Fed Hamsters by Inhibiting Intestinal Cholesterol Absorption.

Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide, and hypercholesterolemia is a central risk factor for atherosclerosis. This study evaluated the effects of Totum-070, a plant-based polyphenol-rich supplement, in hamsters with high-fat diet (HFD)-induced dyslipidemia. The molecular mechanisms of action were explored using human Caco2 enterocytes. Totum-070 supplementation reduced the total cholesterol (-41%), non-HDL cholesterol (-47%), and triglycerides (-46%) in a dose-dependent manner, compared with HFD. HFD-induced hepatic steatosis was also significantly decreased by Totum-070, an effect associated with the reduction in various lipid and inflammatory gene expression. Upon challenging with olive oil gavage, the post-prandial triglyceride levels were strongly reduced. The sterol excretion in the feces was increased in the HFD-Totum-070 groups compared with the HFD group and associated with reduction of intestinal cholesterol absorption. These effects were confirmed in the Caco2 cells, where incubation with Totum-070 inhibited cholesterol uptake and apolipoprotein B secretion. Furthermore, a microbiota composition analysis revealed a strong effect of Totum-070 on the alpha and beta diversity of bacterial species and a significant decrease in the Firmicutes to Bacteroidetes ratio. Altogether, our findings indicate that Totum-070 lowers hypercholesterolemia by reducing intestinal cholesterol absorption, suggesting that its use as dietary supplement may be explored as a new preventive strategy for cardiovascular diseases.

Herbal medicine formula Huazhuo Tiaozhi granule ameliorates dyslipidaemia via regulating histone lactylation and miR-155-5p biogenesis.

BACKGROUND: Huazhuo Tiaozhi granule (HTG) is a herbal medicine formula widely used in clinical practice for hypolipidaemic effects. However, the molecular mechanisms underlying dyslipidaemia treatment have not been well elucidated. RESULTS: A significant reduction in the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) was observed in the serum of patients with dyslipidaemia after HTG treatment, without disruption in the levels of aspartate transaminase (AST), alanine transaminase (ALT), urea nitrogen (BUN), and creatinine (Cr). The dyslipidaemia rat model was induced by a high-fat diet and treated with Xuezhikang (0.14 g/kg/d) or HTG (9.33 g crude herb/kg/day) by gavage for 8 weeks. Body weight and liver index were markedly decreased in dyslipidaemic rats after treatment with Xuezhikang or HTG. HTG administration markedly ameliorated hyperlipidaemia by decreasing the levels of TC and LDL-C in serum and hepatic lipid accumulation. In vitro, lipid accumulation in LO2 and HepG2 cells was alleviated by serum treatment with HTG. High lactylation was observed in 198 proteins, including lactylation of histone H2B (K6), H4 (K80). Deep sequencing of microRNAs showed that miR-155-5p was significantly downregulated. CONCLUSIONS: This study demonstrates that HTG is an effective and safe formula for treating dyslipidaemia, which promotes lactylation in hepatocytes, and the retardation of miR-155-5p biogenesis.

Highland barley attenuates high fat and cholesterol diet induced hyperlipidemia in mice revealed by 16S rRNA gene sequencing and untargeted metabolomics.

AIMS: In this study, highland barley (HB), HB bran (HBB) and whole grain HB (WGHB) alleviating hyperlipemia and liver inflammation in high fat and cholesterol diet (HFCD) mice was investigated. METHODS: All 50 ICR mice were randomly allocated to 5 treatment groups: Normal control group, HFCD group, HB group, HBB group and WGHB group. The serum lipid profiles, liver and epididymal adipocyte histology, gut microbiota and untargeted metabolomics were adopted. KEY FINDINGS: The results suggested that HB especially HBB supplement could obviously decrease BW and BWG. Serum lipid profiles showed that HB especially HBB decreased TG, TC, LDL-C, ALT and AST levels while increased HDL-C level. Liver and epididymal adipocyte H&E staining also confirmed that hepatic injury and adipose accumulation were alleviated by HB especially HBB. Gut microbiota analysis indicated that HBB increased Bacteroidetes/Firmicutes ratio, Lactobacillus and Akkermansia muciniphila abundances while decreased Proteobacteria and Shigella abundances. Untargeted metabolomics results showed that HBB significantly increased deoxycholic acid levels compared with HFCD mice and HBB regulated arachidonic acid metabolism pathway. SIGNIFICANCE: The obtained results provided important information about the processing of highland barley to retain its hypolipidemic effect and improve its acceptability and biosafety, and had a guiding effect on the development of HB products.

Polyphenol-rich extract from loquat fruit peel prevents hyperlipidemia and hepato-nephrotoxicity in mice: in vivo study and in silico prediction of possible mechanisms involving identified polyphenols and/or their circulating metabolites.

Hyperlipidemia is the most well-known cause of metabolic complications and tissue toxicity such as liver steatosis, atherosclerosis and obesity. This study aims to evaluate the preventive effect of loquat fruit peel extract (PE) against tyloxapol-induced hyperlipidemia and related tissue lipotoxicity in mice. The in vivo study was conducted on mice injected daily with tyloxapol at 100 mg per kg B.W. and treated simultaneously with the PE at concentrations of 100 and 200 mg kg-1 or fenofibrate for 28 days. Plasma and tissue lipid biochemical analyses were undertaken using enzymatic methods. The antioxidative stress was revealed by measuring the malondialdehyde content and activities of superoxide dismutase and catalase as well as the scavenging activity against lipoperoxyl radicals. The PE significantly prevented oxidative stress and restored lipid metabolism, plasma glucose, body weight, organ relative mass and biomarkers of hepato-nephrotoxicity as well as the histological structure of the liver and kidneys. It contains five major polyphenols, namely, ferulic acid, caffeic acid, neochlorogenic acid, chlorogenic acid and quercetin. According to molecular docking analysis, these compounds and their circulating metabolites could interact with major proteins implicated in lipid metabolism and oxidative stress. Overall, the study suggests that PE could prevent hyperlipidemia and related toxic tissue complications.

Marein reduces lipid levels via modulating the PI3K/AKT/mTOR pathway to induce lipophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: The capitulum of Coreopsis tinctoria Nutt. (CT, Xue-Ju in Chinese) is a precious medicine in Xinjiang Uygur Autonomous region of China. The Coreopsis tinctoria Nutt. is used to prevent and treat dyslipidemia, coronary heart disease, etc. Recent studies have shown that its extract has a pharmacological effect on hyperlipidemia and hyperglycemia. AIM OF THE STUDY: The study aimed to systematically evaluate the lipid-lowering activity of CT through a mice model of hyperlipidemia and a human hepatoma G2 (HepG2) cells model of lipid accumulation, and to investigate its main active components and mechanism. MATERIALS AND METHODS: Biochemical analysis of blood/liver lipids and liver histopathology were used to evaluate the effect of the aqueous extract of Coreopsis tinctoria Nutt. (AECT) on hyperlipidemia mice. High-performance liquid chromatography (HPLC) analysis was used to identify the main components in the AECT. Oil red O staining, immunofluorescence, western blotting, and determination of the total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were used to further study the effect and potential mechanism of the AECT main components on sodium oleate-induced lipid accumulation in HepG2 cells. RESULTS: We confirmed the lipid-lowering activity of the aqueous extract and further identified flavonoids as its main components. Among them, five Coreopsis tinctoria Nutt. flavonoids mixture (FM) significantly reduced lipid droplet area, lipid content, TC, TG, and LDL-C levels, and elevated HDL-C levels in HepG2 cells induced by sodium oleate. Furthermore, they increased lipophagy in HepG2 lipid-accumulating cells, while decreasing the ratio of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR. Most importantly, marein may be a key component. CONCLUSIONS: Our study demonstrated that AECT, with flavonoids as the main component, can improve diet-induced hyperlipidemia in obese mice. Among the main five flavonoids, marein plays a key role in promoting lipophagy by regulating the PI3K/AKT/mTOR pathway, resulting in a lipid-lowering effect.

Probio-X Relieves Symptoms of Hyperlipidemia by Regulating Patients' Gut Microbiome, Blood Lipid Metabolism, and Lifestyle Habits.

Hyperlipidemia is a key risk factor for cardiovascular disease, and it is associated with lipid metabolic disorders and gut microbiota dysbiosis. Here, we aimed to investigate the beneficial effects of 3-month intake of a mixed probiotic formulation in hyperlipidemic patients (n = 27 and 29 in placebo and probiotic groups, respectively). The blood lipid indexes, lipid metabolome, and fecal microbiome before and after the intervention were monitored. Our results showed that probiotic intervention could significantly decrease the serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol (P < 0.05), while increasing the levels of high-density lipoprotein cholesterol (P < 0.05) in patients with hyperlipidemia. Probiotic recipients showing improved blood lipid profile also exhibited significant differences in their lifestyle habits after the 3-month intervention, with an increase in daily intake of vegetable and dairy products, as well as weekly exercise time (P < 0.05). Moreover, two blood lipid metabolites (namely, acetyl-carnitine and free carnitine) significantly increased after probiotic supplementation cholesterol (P < 0.05). In addition, probiotic-driven mitigation of hyperlipidemic symptoms were accompanied by increases in beneficial bacteria like Bifidobacterium animalis subsp. lactis and Lactiplantibacillus plantarum in patients' fecal microbiota. These results supported that mixed probiotic application could regulate host gut microbiota balance, lipid metabolism, and lifestyle habits, through which hyperlipidemic symptoms could be alleviated. The findings of this study urge further research and development of probiotics into nutraceuticals for managing hyperlipidemia. IMPORTANCE The human gut microbiota have a potential effect on the lipid metabolism and are closely related to the disease hyperlipidemia. Our trial has demonstrated that 3-month intake of a mixed probiotic formulation alleviates hyperlipidemic symptoms, possibly by modulation of gut microbes and host lipid metabolism. The findings of the present study provide new insights into the treatment of hyperlipidemia, mechanisms of novel therapeutic strategies, and application of probiotics-based therapy.

Liver lipidomics analysis reveals the anti-obesity and lipid-lowering effects of gypnosides from heat-processed Gynostemma pentaphyllum in high-fat diet fed mice.

BACKGROUND: In traditional Chinese medicine, Gynostemma pentaphyllum (G. pentaphyllum) is widely used to treat conditions associated with hyperlipidemia, and its therapeutic potential has been demonstrated in numerous studies. However, the mechanism of lipid metabolism in hyperlipidemic by G. pentaphyllum, especially heat-processed G. pentaphyllum is not yet clear. PURPOSE: The aim of this study was to investigate the therapeutic mechanism of gypenosides from heat-processed G. pentaphyllum (HGyp) in hyperlipidemic mice by means of a lipidomics. METHODS: The content of the major components of HGyp was determined by ultra-performance liquid chromatography-electrospray ionization ion trap mass spectrometry (UPLC-ESI-MS). An animal model of hyperlipidaemia was constructed using C57BL/6J mice fed with high-fat diet. HGyp was also administered at doses of 50, 100 and 200 mg/kg, all for 12 weeks. Serum parameters were measured, histological sections were prepared and liver lipidome analysis using UPLC-MS coupled with multivariate statistical analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to analyze the genes and proteins associated with lipid lowering in HGyp. RESULTS: HGyp reduced body weight, serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) and hepatic lipid accumulation in hyperlipidemic obese mice. To explore specific changes in lipid metabolism in relation to HGyp administration, lipid analysis of the liver was performed. Orthogonal partial least squares discriminant analysis (OPLS-DA) score plots showed that HGyp altered lipid metabolism in HFD mice. In particular, fatty acids (FA), triglycerides (DG), TG and ceramides (CER) were significantly altered. Eleven lipids were identified as potential lipid biomarkers, namely TG (18:2/20:5/18:2), TG (18:2/18:3/20:4), DG (18:3/20:0/0:0), Cer (d18:1/19:0), Cer (d16:1/23:0), Ceramide (d18:1/9Z-18:1), PS (19:0/18:3), PS (20:2/0:0), LysoPC (22:5), LysoPE (0:0/18:0), PE (24:0/16:1). Western blot and qRT-PCR analysis showed that these metabolic improvements played a role by down-regulating genes and proteins related to fat production (SREBP1, ACC1, SCD1), up-regulating genes and proteins related to lipid oxidation (CPTA1, PPARα) and lipid transport decomposition in the bile acid pathway (LXRα, PPARγ, FXR, BSEP). CONCLUSION: The lipid-lowering effect of gypenosides from heat-processed G. pentaphyllum is regulate lipid homeostasis and metabolism.

Effect of Copper Exposure on the Cholesterol Metabolism in Broiler Liver.

Copper (Cu) is a kind of widely used dietary supplement in poultry production, and a common environmental pollutant at the same time. Excess Cu exposure has been reported to accumulate in the liver and induce cytotoxicity, but the effect of Cu toxicity on hepatic cholesterol metabolism is still uncertain. Herein, we aimed to reveal the effect of excess Cu on the liver and primary hepatocytes of broilers at various concentrations. We found that 110 mg/kg Cu supplement remarkably increased blood cholesterol levels by detecting serum TC, LDL-C, and HDL-C in the broilers, while there was no significant difference in 220 and 330 mg/kg Cu supplements. In addition, high Cu exposure resulted in severe hepatic steatosis and hepatic cord derangement in the broilers. Oil red O staining of primary hepatocytes showed that Cu treatment caused intracellular neutral lipid accumulation. However, the hepatic TC content indicated a downward trend in both liver tissues and hepatocytes after Cu exposure. Furthermore, the expression of cholesterol metabolism-related indicators (SREBP2, HMGCR, LDLR, and CYP7A1) was notably decreased in the Cu-treated groups. While the expression of the key enzyme of cholesterol esterification (ACAT2) did not change significantly. Taken together, our findings preliminarily revealed excess Cu-induced hepatic cholesterol metabolism dysfunction, providing a deeper understanding of the molecular mechanisms of Cu-induced hepatotoxicity.

Black rice regulates lipid metabolism, liver injury, oxidative stress and adipose accumulation in high-fat/cholesterol diet mice based on gut microbiota and untargeted metabonomics.

Black rice displays a series of properties including regulating lipid metabolism and attenuating liver injury. Our study aimed to investigate the effect of Zixiangnuo black rice (ZG), peeled rice (ZPG), rice bran (ZBG) on lipid metabolism, liver inflammation, gut microbiota and metabolite profiles in high-fat/cholesterol (HFCD) diet mice. A total of five treatment groups were fed a normal control diet or a HFCD with or without Highland barley (HB) supplementation for 10 weeks. The results showed that ZBG significantly improved lipid parameters, liver function and injury and blood glucose indexes related to hyperlipidemia compared with HFCD group. ZBG recovered the disorder of gut microbiota by increasing Bacteroidetes/Firmicutes ratio and Lactobacillus abundance, and decreasing Proteobacteria abundance. ZBG enhanced the levels of six short chain fatty acids. Fecal metabolomics analysis showed that the important differential metabolites between ZBG and HFCD group were Deoxycholic acid and Myclobutanil, and metabolic pathways were Arachidonic acid metabolism and ABC transporters. Results suggested that BR or bran were effective dietary candidates to ameliorate hyperlipidemia.

Saikosaponins ameliorate hyperlipidemia in rats by enhancing hepatic lipid and cholesterol metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperlipidemia is the systemic manifestation of abnormal lipid metabolism, characterized by elevated circulating levels of cholesterol and triglyceride and a high risk of cardiovascular events. Radix Bupleuri (RB) is a traditional Chinese herbal product used to treat liver diseases. Our previous study demonstrated that Saikosaponins (SSs), the most potent bioactive ingredients in RB, ameliorate hepatic steatosis. However, whether SSs have anti-hyperlipidemia effects and plausible underlying mechanisms remain elusive. AIM OF THE STUDY: To comprehensively evaluate the lipid-lowering potential of SSs against hyperlipidemia in rats. MATERIALS AND METHODS: RNA sequencing and untargeted metabolomics approaches were applied to analyze the changes in the liver transcriptome and serum lipid profile in long-term high-fat diet feeding-induced hyperlipidemia rats in response to SSs or positive drug simvastatin (SIM) intervention. RESULTS: Our data revealed that SSs significantly alleviated HFD-induced hypertriglyceridemia and hypercholesterolemia. Combined with the analysis of gene ontology enrichment analysis and gene set enrichment analysis, we found that SSs remarkably repaired the unbalanced blood lipid metabolic spectrum in a dose-dependent manner by increasing the hepatic uptake of circulating fatty acids and facilitating mitochondrial respiration in fatty acid oxidation, comparable to SIM group. In addition, SSs markedly modulated cholesterol clearance by promoting intracellular cholesterol efflux, HDL remodeling, LDL particle clearance, and bile acid synthesis. SSs also efficiently protected the liver from lipid overload-related oxidative stress and lipid peroxidation, as well as substantially exaggerated inflammatory response. CONCLUSION: Our research not only unraveled the intricate mechanisms underlying the lipid-lowering functions of SSs but also provided novel perspectives on developing an SSs-based therapeutic strategy for the treatment of hyperlipidemia. CLASSIFICATION: Metabolism.

Overall metabolic network analysis of urine in hyperlipidemic rats treated with Bidens bipinnata L.

Hyperlipidemia has been highlighted as one of the most prominent and global chronic conditions nowadays. Bidens bipinnata L. (BBL), a folk medicine in contemporary China, has efficacy in the treatment of hyperlipidemia (HLP) in China. Although some physiological and pathological function parameters of hyperlipidemia have been investigated, little information about the changes in small metabolites in biofluids has been reported. In the present study, global metabolic profiling with high-performance liquid chromatography-linear ion trap/Orbitrap high-resolution mass spectrometry (HPLC-LTQ/Orbitrap MS) combined with a pattern recognition method was performed to discover the underlying lipid-regulating mechanisms of BBL on hyperlipidemic rats induced by high-fat diet (HFD). The total of four metabolites, up- or down-regulated (p < 0.05 or 0.01), were identified and contributed to the progression of hyperlipidemia. These promising identified biomarkers underpin the metabolic pathway, including glyoxylate and dicarboxylate metabolism, the TCA cycle, sphingolipid metabolism and purine metabolism. They are disturbed in hyperlipidemic rats, and are identified using pathway analysis with MetPA. The altered metabolite indices could be regulated closer to normal levels after BBL intervention. The results demonstrated that urinary metabolomics is a powerful tool in the clinical diagnosis and treatment of hyperlipidemia to provide information on changes in metabolite pathways.

Duyun compound green tea extracts regulate bile acid metabolism on mice induced by high-fat diet.

Duyun compound green tea (DCGT) is a healthy beverage with lipid-lowering effect commonly consumed by local people, but its mechanism is not very clear. We evaluated the effect of DCGT treatment on bile acids (BA) metabolism of mice with high-fat diet (HFD) - induced hyperlipidaemia by biochemical indexes and metabolomics and preliminarily determined the potential biomarkers and metabolic pathways of hyperlipidaemia mice treated with DCGT as well as investigated its lipid-lowering mechanism. The results showed that DCGT treatment could reduce HFD - induced gain in weight and improve dyslipidaemia. In addition, a total of ten types of BA were detected, of which seven changed BA metabolites were observed in HFD group mice. After DCGT treatment, glycocholic acid, tauroursodeoxycholic acid and taurochenodeoxycholic acid were significantly down-regulated, while hyodeoxycholic acid, deoxycholic acid and chenodeoxycholic acid were markedly up-regulated. These results demonstrated that DCGT treatment was able to make the BA metabolites in the liver of hyperlipidaemia mice normal and alleviate hyperlipidaemia by regulating the metabolites such as glycocholic acid, tauroursodeoxycholic acid and taurochenodeoxycholic, as well as the BA metabolic pathway and cholesterol metabolic pathway involved.

Assessment of hypolipidemic and anti-inflammatory properties of walnut (Juglans regia) seed coat extract and modulates some metabolic enzymes activity in triton WR-1339-induced hyperlipidemia in rat kidney, liver, and heart.

Atherosclerosis and cognitive impairment are both influenced by hyperlipidemia. Due to their high margin of safety and low cost, natural chemicals have recently attracted particular attention in the context of the treatment of disease. Hence, the purpose of this study was to investigate the possible amendatory impact of ethanol extract walnut (Juglans regia) seed coat (E-WSC) on some metabolic enzymes (glutathione reductase (GR), paraoxonase-1 (PON1), aldose reductase (AR), sorbitol dehydrogenase (SDH), acetylcholinesterase (AChE), glutathione S-transferase (GST), and butyrylcholinesterase (BChE)) activity in the liver, kidney, and heart of rats with Triton WR-1339-induced hyperlipidemia. Rats were divided into five groups: control group, HL-Control group (Triton WR-1339 400 mg/kg, i.p administered group), E- WSC + 150 (150 mg/kg,o.d given group), E- WSC + 300 (E- WSC 300 mg/kg, o.d given group) and HL+ E-WSC + 300 (Group receiving E- WSC 300 mg/kg, o.d 30 min prior to administration of Triton WR-1339 400 mg/kg, i.p). In HL-Control, AR, SDH, and BChE enzyme activity was significantly increased in all tissues compared to the control, while the activity of other studied enzymes was significantly decreased. The effects of hyperlipidemia on balance were improved and alterations in the activity of the investigated metabolic enzymes were prevented by E-WSC. As a result, promising natural compounds that can be used as adjuvant therapy in the treatment of cognitive disorders and hyperlipidemia may be found in E-WSC powder.

Extraction of Naringin from Pomelo and Its Therapeutic Potentials against Hyperlipidemia.

Pomelo peel is a natural plant product with numerous pharmacological effects and is used in traditional Chinese medicine. In the present study, we extracted naringin from pomelo peel and aimed to decipher its therapeutic potential against hyperlipidemia. We used ultrasonic-assisted extraction to obtain naringin prior to identifying its structure, to evaluate its ability in binding sodium glycine cholate and sodium bovine cholate in vitro by simulating the gastrointestinal environment, so as to evaluate its blood lipid-lowering activity. The hyperlipidemia mouse model was established. Following the intragastric administration of naringin for 5 weeks, we measured the weight change, organ index, high-density lipoprotein cholesterol (HDL-C), serum total cholesterol (TC), serum triglycerides (TG), liver superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), low-density lipoprotein cholesterol (LDL-C) level, malondialdehyde (MDA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) level of mice in the normal control and high-fat diet groups in addition to the high-, medium-, and low-dose naringin groups. The pathological changes in the liver were observed under a light microscope. The total RNA of the liver was extracted, and the mRNA expression level of lipid metabolism-related factors in mouse liver was detected via a fluorescence quantitative polymerase chain reaction (PCR). Naringin significantly (p < 0.01) reduced the body weight, organ index, serum TG, LDL-C, and TC levels of hyperlipidemic mice, but increased the serum HDL-C levels (p < 0.01). Furthermore, naringin increased GSH Px and SOD activity (p < 0.01), while decreasing MDA, ALT, and AST levels, as well as the liver index (p < 0.01). There was no statistically significant difference in the brain, heart, spleen, kidney, and other indicators (p > 0.05). A histopathological analysis of mouse liver showed that naringin could alleviate the degenerative damage of fatty liver cells in hyperlipidemic mice. Naringin could significantly (p < 0.01) reduce the expression of FAS and SREBP-1c mRNA, and simultaneously increase PPARα mRNA expression. This study shows that naringin has the strong effect of lowering lipids and protecting the liver in hyperlipidemic mice. Our findings underscore the anti-hyperlipidemia potential of naringin and increase the scientific understanding of its anti-hyperlipidemia effects, that may lead to its potential application as a dietary strategy for hyperlipidemia management in the future.