High-cholesterol Feeding Research Articles

Paternal hypercholesterolemia elicits sex-specific exacerbation of atherosclerosis in offspring.

Emerging studies suggest that various parental exposures affect offspring cardiovascular health, yet the specific mechanisms, particularly the influence of paternal cardiovascular disease (CVD) risk factors on offspring cardiovascular health, remain elusive. The present study explores how paternal hypercholesterolemia affects offspring atherosclerosis development using the LDL receptor-deficient (LDLR-/-) mouse model. We found that paternal high-cholesterol diet feeding led to significantly increased atherosclerosis in F1 female, but not male, LDLR-/- offspring. Transcriptomic analysis highlighted that paternal hypercholesterolemia stimulated proatherogenic genes, including Ccn1 and Ccn2, in the intima of female offspring. Sperm small noncoding RNAs (sncRNAs), particularly transfer RNA-derived (tRNA-derived) small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), contribute to the intergenerational transmission of paternally acquired metabolic phenotypes. Using a newly developed PANDORA-Seq method, we identified that high-cholesterol feeding elicited changes in sperm tsRNA/rsRNA profiles that were undetectable by traditional RNA-Seq, and these altered sperm sncRNAs were potentially key factors mediating paternal hypercholesterolemia-elicited atherogenesis in offspring. Interestingly, high-cholesterol feeding altered sncRNA biogenesis-related gene expression in the epididymis but not testis of LDLR-/- sires; this may have led to the modified sperm sncRNA landscape. Our results underscore the sex-specific intergenerational effect of paternal hypercholesterolemia on offspring cardiovascular health and contribute to the understanding of chronic disease etiology originating from parental exposures.

Directly Measuring Atherogenic Lipoprotein Kinetics in Zebrafish with the Photoconvertible LipoTimer Reporter.

Lipoprotein kinetics are a crucial factor in understanding lipoprotein metabolism since a prolonged time in circulation can contribute to the atherogenic character of apolipoprotein-B (ApoB)-containing lipoproteins (B-lps). Here, we report a method to directly measure lipoprotein kinetics in live developing animals. We developed a zebrafish geneticly encoded reporter, LipoTimer, in which endogenous ApoBb.1 is fused to the photoconvertible fluorophore Dendra2 which shift its emission profile from green to red upon UV exposure. By quantifying the red population of ApoB-Dendra2 over time, we found that B-lp turnover in wild-type larvae becomes faster as development proceeds. Mutants with impaired B-lp uptake or lipolysis present with increased B-lp levels and half-life. In contrast, mutants with impaired B-lp triglyceride loading display slightly fewer and smaller-B-lps, which have a significantly shorter B-lp half-life. Further, we showed that chronic high-cholesterol feeding is associated with a longer B-lp half-life in wild-type juveniles but does not lead to changes in B-lp half-life in lipolysis deficient apoC2 mutants. These data support the hypothesis that B-lp lipolysis is suppressed by the flood of intestinal-derived B-lps that follow a high-fat meal.

Fish oil consumption prevents hepatic lipid accumulation induced by high-cholesterol feeding in obese KK mice.

Fish oil (FO) is rich in the n-3 polyunsaturated fatty acids. It has been demonstrated that FO intake possesses lipid-lowering properties. Conversely, a high-cholesterol (CH) diet promotes lipid accumulation in the liver and induces fatty liver. This study investigated the effects of FO feeding on hepatic lipid accumulation induced by high-cholesterol feeding in KK mice. All experimental diets had a fat energy ratio of 25%, the SO group had all fat sources as safflower oil (SO), the 12.5 FO group had half of the SO replaced with FO, and the 25 FO group had all of the SO replaced with FO, each with or without 2 weight % (wt%) cholesterol (SO/CH, 12.5 FO/CH, and 25 FO/CH groups, respectively), for 8 weeks. The hepatic triglyceride and total cholesterol levels were significantly lower in the 25 FO/CH group than in the SO/CH group. The hepatic mRNAs of fatty acid synthesis-related genes were downregulated by the FO feeding groups. In view of importance to establish the benefit of FO for preventing severe NAFLD, our results suggest that FO intake prevents excessive hepatic fat accumulation induced by a high-cholesterol diet in obese KK mice through the inhibition of fatty acid synthesis.

Safe and effective dosage combination of purple sweet potato extract and red fruit oil extract as antioxidant and hypolipidemic in rats given high cholesterol feed

Safe and effective dosage combination of purple sweet potato extract and red fruit oil extract as antioxidant and hypolipidemic in rats given high cholesterol feed

Red dragon (Hylocereus polyrhizus) fruit peel extract increased the motility and viability of spermatozoa of hypercholesterolemic rats (Rattus norvegicus)

This study aims to determine the effect of red dragon (Hylocereus polyrhizus) fruit peel extract (RDFPE) on spermatozoa motility and viability of hypercholesterolemic rats (Rattus norvegicus) as a model. Twenty male rats were randomly divided into negative control (NC), positive control (PC), treatment 1 (T1), treatment 2 (T2), and treatment 3 (T3) groups. All rats were given 2 mL of high cholesterol feed orally every day for 28 days. On day-15, all rats were measured for their blood cholesterol levels, followed by treatment for 14 days. Rats in the NC, PC, T1, T2, and T3 groups were treated with 1% Na-CMC, Simvastatin 10 mg/kg BW, and RDFPE of 500, 750, and 1000 mg/kg BW, respectively. On day-29, all rats were sacrificed to evaluate spermatozoa viability and motility. The results showed that spermatozoa viability and motility in the hypercholesterolemic rats (NC) group were the lowest (p <0.05) among the groups. Treatment of hypercholesterolemic rats with Simvastatin 10 mg/kg BW (PC) group showed higher (p <0.05) spermatozoa viability and motility compared to the NC group. RDFPE dose of 1000 mg/kg BW (T3 group) resulted in higher (p <0.05) spermatozoa viability and motility compared to other RDFPE doses (T1 and T2) and the control (NC) groups, and it was similar (p >0.05) compared with the Simvastatin treated (PC) group. It could be concluded that the administration of 1000 mg/kg BW ethanolic extract of red dragon fruit (Hylocereus polyrhizus) peel increased the viability and motility of spermatozoa of hypercholesterolemic rats (Rattus norvegicus) which were the same as the group of rats given Simvastatin 10 mg/kg BW.

Red dragon (Hylocereus polyrhizus) fruit peel extract increased the motility and viability of spermatozoa of hypercholesterolemic rats (Rattus norvegicus)

This study aims to determine the effect of red dragon (Hylocereus polyrhizus) fruit peel extract (RDFPE) on spermatozoa motility and viability of hypercholesterolemic rats (Rattus norvegicus) as a model. Twenty male rats were randomly divided into negative control (NC), positive control (PC), treatment 1 (T1), treatment 2 (T2), and treatment 3 (T3) groups. All rats were given 2 mL of high cholesterol feed orally every day for 28 days. On day-15, all rats were measured for their blood cholesterol levels, followed by treatment for 14 days. Rats in the NC, PC, T1, T2, and T3 groups were treated with 1% Na-CMC, Simvastatin 10 mg/kg BW, and RDFPE of 500, 750, and 1000 mg/kg BW, respectively. On day-29, all rats were sacrificed to evaluate spermatozoa viability and motility. The results showed that spermatozoa viability and motility in the hypercholesterolemic rats (NC) group were the lowest (p <0.05) among the groups. Treatment of hypercholesterolemic rats with Simvastatin 10 mg/kg BW (PC) group showed higher (p <0.05) spermatozoa viability and motility compared to the NC group. RDFPE dose of 1000 mg/kg BW (T3 group) resulted in higher (p <0.05) spermatozoa viability and motility compared to other RDFPE doses (T1 and T2) and the control (NC) groups, and it was similar (p >0.05) compared with the Simvastatin treated (PC) group. It could be concluded that the administration of 1000 mg/kg BW ethanolic extract of red dragon fruit (Hylocereus polyrhizus) peel increased the viability and motility of spermatozoa of hypercholesterolemic rats (Rattus norvegicus) which were the same as the group of rats given Simvastatin 10 mg/kg BW.

Hyperlipidaemia elicits an atypical, T helper 1-like CD4+ T-cell response: a key role for very low-density lipoprotein.

Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells. In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane stiffening and a reduction in lipid rafts. To further detail this response in vivo, T cells of mice lacking the LDL receptor (LDLr), which develop a strong increase in VLDL cholesterol and triglyceride levels upon high cholesterol feeding were investigated. CD4+ T cells of hyperlipidemic Ldlr-/- mice exhibited an increased expression of the C-X-C-chemokine receptor 3 (CXCR3) and produced more interferon-γ (IFN-γ). Gene set enrichment analysis identified IFN-γ-mediated signaling as the most upregulated pathway in hyperlipidemic T cells. However, the classical Th1 associated transcription factor profile with strong upregulation of Tbet and Il12rb2 was not observed. Hyperlipidemia did not affect levels of the CD4+ T cell's metabolites involved in glycolysis or other canonical metabolic pathways but enhanced amino acids levels. However, CD4+ T cells of hyperlipidemic mice showed increased cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with inflammatory T cell activation. Hyperlipidemia, and especially its VLDL component induces an atypical Th1 response in CD4+ T cells. Underlying mechanisms include CD36 mediated uptake of VLDL, and an altered AA/DHA ratio.

Effect of liver X receptor agonist TO901317 on cognitive function in APP/PS1 double transgenic mice with Alzheimer's disease and the underlying mechanism.

The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily, and LXR-β is an important receptor for cholesterol content in brain cells. LXR-β/retinoic X receptor (RXR-α)/ATP binding cassette transporter A1 (ABCA1) cholesterol transmembrane transport system is closely related to the occurrence and development of Alzheimer's disease (AD). LXR agonist TO901317 can affect the accumulation of β- amyloid protein in the brain tissue of APP/PS1 double transgenic AD mice. However, the molecular mechanism is not clarified in detail. This study aims to evaluate the effects of LXR agonist TO901317 on the cognitive function of AD mice fed with high cholesterol diet, and to explore its possible mechanism from the perspective of cholesterol metabolism. Twenty four male 6-month-old APP/PS1 double transgenic AD mice were randomly divided into 4 groups, 6 mice in each group: a control group (fed with normal diet), a cholesterol rich diet (CRD) group, a TO901317 group (fed with CRD combined with TO901317), and a GSK2033 group (fed with CRD combined with TO901317 and LXR antagonist GSK2033). The mice were fed with pellet feed made of high cholesterol feed, mixed with lard, egg yolk powder, and cod liver oil twice a day. TO901317 and GSK2033 were dissolved and diluted to a final concentration at 0.03%. The drugs were given to the mice daily through gastric tube according to their body weight. Meanwhile, the mice in the drug group were fed with high cholesterol diet . After feeding for 3 months, Morris water maze was used to observe the changes of spatial exploration and memory ability of AD mice in each group. The contents of TC, LDL, and HDL in serum of mice in each group were detected by cholesterol enzyme colorimetry, and the differences among the groups were compared. The expression of Aβ42 in the brain of AD mice was detected by ELISA. Western blotting was used to detect the protein levels of LXR-β, RXR-α, ABCA1, and Caveolin-1 in the brain of each group. Morris water maze results showed that the times, distance and the duration of mice crossing the platform in the CRD group were significantly decreased compared with the control group (all P<0.05), while these three figures in TO901317 group were significantly increased compared with the CRD group (all P<0.05). Compared with the TO901317 group, there was a decrease of these figures in the GSK2033 group (all P<0.05). The serum TC and LDL levels in the CRD group were significantly higher than those in the control group, while HDL levels were significantly lower (all P<0.001). The figures of the TC and LDL contents level in the TO901317 group were lower than those in the CRD group, while HDL levels were higher (all P<0.001). Compared with TO901317 group, the contents of the TC and LDL in GSK2033 group were significantly increased, while HDL content was significantly decreased (all P<0.001). ELISA results showed that the production of Aβ42 peptides in the brain of CRD group was the highest while the content in the TO901317 group was significantly decreased (P<0.001), which was the lowest among the groups. The figure in the control group was close to the GSK2033 group. Western blotting results showed that the protein levels of LXR-β, RXR-α, and ABCA1 in the CRD group were significantly decreased compared with the control group, but the protein level of Caveolin-1 was increased (all P<0.01). After TO901317 treatment, the protein levels of LXR-β, RXR-α and ABCA1 were significantly increased, while the protein level of Caveolin-1 was decreased partially (all P<0.001). In the GSK2033 group, the effect of TO901317 on AD mice was partially reversed by GSK2033. Compared to TO901317 group, the protein levels of LXR-β, RXR-α, and ABCA1 showed a decrease trend, while the protein level of Caveolin-1 showed an increase state (all P<0.05). High cholesterol diet leads to severer spatial exploration, learning and memory impairment in transgenic AD mice, while the LXR agonist TO901317 attenuates this effect. The mechanism may be that TO901317 promotes cholesterol efflux by activating LXR-β/RXR-α/ABCA1 transmembrane transport system, reduces the expression of Caveolin-1, improves the composition of lipid raft, and ultimately reduces the production of Aβ42 in the brain.

The Nonproteolytic Intracellular Domain of Membrane-Type 1 Matrix Metalloproteinase Coordinately Modulates Abdominal Aortic Aneurysm and Atherosclerosis in Mice-Brief Report.

MT1-MMP (membrane-type 1 matrix metalloproteinase, MMP-14) is a transmembrane-anchored protein with an extracellular proteinase domain and a cytoplasmic tail devoid of proteolytic functions but capable of mediating intracellular signaling that regulates tissue homeostasis. MT1-MMP extracellular proteolytic activity has been shown to regulate pathological remodeling in aortic aneurysm and atherosclerosis. However, the role of the nonproteolytic intracellular domain of MT1-MMP in vascular remodeling in abdominal aortic aneurysms (AAA) is unknown. We generated a mutant mouse that harbors a point mutation (Y573D) in the MT1-MMP cytoplasmic domain that abrogates the MT1-MMP signaling function without affecting its proteolytic activity. These mice and their control wild-type littermates were subjected to experimental AAA modeled by angiotensin II infusion combined with PCSK9 (proprotein convertase subtilisin/kexin type 9) overexpression and high-cholesterol feeding. The mutant mice developed more severe AAA than the control mice, with concomitant generation of intraaneurysmal atherosclerotic lesions and dramatically increased macrophage infiltration and elastin degradation. Aortic lesion-associated and bone marrow-derived macrophages from the mutant mice exhibited an enhanced inflammatory state and expressed elevated levels of proinflammatory Netrin-1, a protein previously demonstrated to promote both atherosclerosis and AAA. Our findings show that the cytoplasmic domain of MT1-MMP safeguards from AAA and atherosclerotic plaque development through a proteolysis-independent signaling mechanism associated with Netrin-1 expression. This unexpected function of MT1-MMP unveils a novel mechanism of synchronous onset of AAA and atherogenesis and highlights its importance in the control of vascular wall homeostasis.

PCSK9 deficiency results in a specific shedding of excess LDLR in female mice only: Role of hepatic cholesterol

PCSK9 promotes the lysosomal degradation of cell surface LDL receptor (LDLR). We analyzed how excess LDLR generated by PCSK9 deficiency is differently handled in male and female mice to possibly unveil the mechanism leading to the lower efficacy of PCSK9 mAb on LDL-cholesterol levels in women. Analysis of intact or ovariectomized PCSK9 knockout (KO) mice supplemented with placebo or 17β-estradiol (E2) demonstrated that female, but not male mice massively shed the soluble ectodomain of the LDLR in the plasma. Liver-specific PCSK9 KO or alirocumab-treated WT mice exhibit the same pattern. This shedding is distinct from the basal one and is inhibited by ZLDI-8, a metalloprotease inhibitor pointing at ADAM10/ADAM17. In PCSK9 KO female mice, ZLDI-8 raises by 80 % the LDLR liver content in a few hours. This specific shedding is likely cholesterol-dependent: it is prevented in PCSK9 KO male mice that exhibit low intra-hepatic cholesterol levels without activating SREBP-2, and enhanced by mevalonate or high cholesterol feeding, or by E2 known to stimulate cholesterol synthesis via the estrogen receptor-α. Liver transcriptomics demonstrates that critically low liver cholesterol in ovariectomized female or knockout male mice also hampers the cholesterol-dependent G2/M transition of the cell cycle. Finally, higher levels of shed LDLR were measured in the plasma of women treated with PCSK9 mAb. PCSK9 knockout female mice hormonally sustain cholesterol synthesis and shed excess LDLR, seemingly like women. In contrast, male mice rely on high surface LDLR to replenish their stocks, despite 80 % lower circulating LDL.

Interventional hepatic apoC-III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering.

Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved.

Long non‐coding RNA HULC protects against atherosclerosis via inhibition of PI3K/AKT signaling pathway

AbstractStudies on the roles of long non‐coding RNA in atherosclerosis (AS) have been extensively explored. However, the action of lncRNA highly upregulated in liver cancer (HULC) in AS still needs in‐depth investigations. Hence, this study is launched towards the translation of HULC‐oriented mechanism in AS. Mouse AS models were established by high cholesterol and high fat feeding. AS mice were injected with restored HULC or phosphatidylinositide 3‐kinase/protein kinase B (PI3K/AKT) signaling pathway inhibitor to explore their roles in AS. Blood lipid, inflammation and oxidative stress were detected as well as HULC, PI3K, phosphated‐PI3K (p‐PI3K), AKT, p‐AKT, and aortic vascular cell apoptosis were determined. HULC was poorly expressed, p‐PI3K and p‐AKT were highly expressed in AS. HULC inhibited the PI3K/AKT signaling pathway. In AS, by inhibition of PI3K/AKT signaling pathway, restored HULC restrained atherosclerotic plaque formation, alleviated aortic intimal damage and reduced collagen fiber content in aorta, down‐regulated blood lipid levels, and inhibited inflammation, oxidative stress and aortic vascular cell apoptosis. Our study elucidates that HULC alleviates AS via inhibition of the PI3K/AKT signaling pathway, which provides a potential biomarker for treatment of AS.

Effect of Parkia speciosa Hassk Peels Extract on Total Cholesterol Levels of Hypercholesterolemia Rats

Background: This research aimed to examine the secondary metabolites in the ethanol extract of Parkiaspeciosa Hassk peels and determine the effect of the P. speciosa Hassk peels on the reduction in totalcholesterol levels of male hypercholesterolemia white rats.Methods: Thirty white male rats were divided into six treatment groups (n=5): Group I: normal control(0.5% CMC Na suspension), Group II: negative control (high cholesterol feed), Group III: positive control(suspension simvastatin), Group IV, V, VI: hypercholesterolemia rat received P. speciosa Hassk shell at doseof 300, 400, and 500 mg/kg BW orally for 14 days. The total cholesterol levels were measured on days 0,14, 28, 35.Results: Quantitative test showed that the ethanol extract of P. speciosa peels contained 0.21% alkaloids(w/w), 8.34% flavonoids (w/w), 4.21% tannins (w/w) and 0.18% saponins (w/w). The ethanol extract of P.speciosa peels at a dose of 300 mg/kg BW was able to reduce total cholesterol levels in hypercholesterolemiawhite mice (52 mg/dL).Conclusion: The ethanol extract of P. speciosa peels can be considered as an effective treatment forhyperlipidemia disease.

Pengaruh Ekstrak Etanol Daun Kenikir (Cosmos caudatus) terhadap Kadar Glutathion Dan Interleukin 6 Serum Tikus Wistar Jantan yang Diberi Pakan Tinggi Kolesterol

Chronic dyslipidemia, especially in hypercholesterolemia, can directly disrupt endothelial cell function through increased formation of oxidized LDL which will stimulate an inflammatory response including interleukin 6 (IL-6) release. For this reason, it is necessary to have anti-inflammation that can reduce the effects of hypercholesterolemia on blood vessels. Polyphenols have anti-inflammatory effects and kenikir leaves are vegetables that are rich in polyphenols. This study aims to prove the effect of kenikir leaf (Cosmos caudatus) ethanol extract on IL-6 levels of serum of male Wistar rats fed high cholesterol. The method used is a true experimental study with a Post-test Only Control Group Design. Samples using 24 male rats were divided into 4 groups DS, DTK, Ss, and Cc. DTK, Ss and Cc groups were given high cholesterol feed for 20 weeks. In the 17th to 20th weeks the Ss group was given additional simvastatin and the Cc group was given an additional extract of Cosmos caudatus leaf. Whereas the DS group was only given standard feed for 20 weeks. After 20 weeks all rats in all four groups were examined serum GSH and IL-6 levels. The results showed the highest GSH serum levels average in Cc with p-value=0,016 but not different from Ss. IL-6 serum levels in DTK were higher than those of the other three groups and were significantly different with p-value=0,035. The difference occurs between DTK and DS, Ss and Cc, not different between DS, Ss and Cc. The ethanol extract of kenikir leaf influences the serum IL-6 levels of male Wistar rats fed high cholesterol.

SAT-LB95 Low Density Lipoprotein Receptor and Proprotein Convertase Subtilisin/Kexin Type 9 Kinetics Using Heavy Water (2H2O) Labeling and Mass Spectrometry

Abnormally high blood cholesterol levels in low density lipoprotein (LDL) increases the risk of heart disease. Cell surface receptors such as LDL-receptors (LDLr) regulate the clearance of LDL from blood circulation. As cholesterol levels decrease, cells promote cholesterol synthesis and cholesterol uptake by increasing LDLr expression. Another regulatory protein of plasma cholesterol clearance is proprotein convertase subtilisin/kexin type 9 (PCSK9). It is secreted from the liver into circulation where it can bind to and target LDLr to the lysosome for subsequent degradation. The current model of cholesterol regulation describes how increased cholesterol content down-regulates the number of LDLr promoted by PCSK9 mediated degradation, however minimal knowledge is not known about LDLr and PCSK9 kinetics using heavy water labeling, and how cholesterol enriched diet affects LDLr and PCSK9 kinetics in vivo. Therefore, our objective(s) were to establish a method 1) to measure the kinetics of LDLr and PCSK9 via stable isotopic metabolic labeling with heavy water (2H2O) in vivo 2) to further test established models of cholesterol metabolic regulation on LDLr and PCSK9 turnover after feeding mice a cholesterol enriched diet. We hypothesize that a cholesterol enriched diet will decrease both LDLr and PCSK9 synthesis rates. In order to test this, mice were fed a cholesterol enrich diet for 1 week and metabolically labeled with heavy water (2H2O) up to 36 hours. LDLr and PCSK9 were immunoprecipitated from liver and deuterium incorporation into LDLr and PCSK9 were measured via mass spectrometry. Our results revealed high cholesterol feeding down-regulated cholesterol synthesis and LDLr fractional synthesis rate decreased from 10.0% to 6% per hour. PCSK9 concentration also decreased from 1 to 0.2 (ng/ml / total mg protein), but the synthesis rate increased from 9.0%/day in control mice to 19.5%/day in high cholesterol diet. These results suggest high cholesterol feeding increases PCSK9 synthesis that potentially depletes the intracellular pool to target LDLr to the lysosome thus decreasing LDLr turnover. This research provides a flux-based approach to measure the kinetics of LDLr and PCSK9 for a molecular based kinetic insight of their functions in physiology, disease and therapy.

Pengaruh Ekstrak Daun Pedada (Sonneratia caseolaris) Sebagai Antihiperkolesterolmia Pada Mencit (Mus musculus)

Abstract. This study was conducted to determine the effect of extract leaf pedada (Sonneratia caseolaris) to total cholesterol levels of mice (Mus musculus) male ICR strain. Leaf pedada extracted using 96% methanol by maceration. This study is a completely randomized design (CRD), which consists of 5 treatments and 5 replicates the normal group (distilled water), positive group (Simvastatin), a group of leaf pedada extract at a dose of 125, 250 and 500 mg / kg. The extract was dissolved using Carboxy Methyl Cellulose (CMC) 0.5% and given orally in mice which had previously been given a high cholesterol feed. The results showed the methanol extract of leaves cemba with the dose of 500 mg/kg hads the highest effectiveness in lowering total cholesterol levels in mice which have hypercholesterolemia with a 30,20 % percentage drop. These results indicate that of the giving leaf extract pedada (Sonneratia caseolaris) able to lower total cholesterol levels of mice (Mus musculus) male hypercholesterolaemia.Keywords: Antihipercholesterolemia, total cholesterol, Methanol extract of leaf pedada (Sonneratia caseolaris), mice (Mus musculus) ICR male.

ANALYSIS OF APO-B SERUM LEVELS IN BALB/C MICE HYPERCHOLESTEROLEMIC AGAINST TEMULAWAK EXTRACT (Curcuma xanthoriza Roxb)

APO–B Serum levels is the most predictive value for the incidence of atherosclerosis and coronary heart disease. Curcuma xanthorrhiza Roxb contains curcumin, which can be used as an antioxidant, anti–inflammatory and antihypercholesterol. The mechanism of curcumin contained in ginger to reduce cholesterol is due to its function as a cholagoga or bile stimulant. This study aims to determine the effect of temulawak extract on the levels of APO–B Serum in hypercholesterolemia mice. This research were a true experimental study with a post–test only control group design carried out in February 2018. The extraction As much as 25 mice were divided into 5 groups where are group consisted of 5 mice. Positive control group (K+) were treated with high cholesterol feed and water, negative control group (K–) were given standard feed and water, treatment group 1 (P1) were given high cholesterol food and 25mg/kg BW of curcuma extract for 14 days, treatment group 2 (P2) were treated with foods high in cholesterol and 50mg/kg BW of curcuma extract for 14 days and treatment group 3 (P3) treated with high cholesterol and ginger extract 75mg/kg BW for 14 days. Examination of APO–B levels were measured using the spectrophotometric method. Data were analyzed using One–Way Anova. The results showed that the average of APO–B level at (K+) was 209.7 ± 1.02 mg / dL, at (K–) 115.3 ± 1.04 mg / dL, at (P1) 180.4 ± 1.07 mg / dL, at (P2) 147.6 ± 1.12 mg / dL, at (P3) 119.1 ± 1.10 mg / dL. Based on the results of statistical test it was found that there was a significant decrease in APO–B levels with p–value= 0.001 at alpha 0.05 (p &lt;α).

Bioengineered VEGF Therapy Following Angioplasty in Renovascular Disease: More and Better Microvessels

Asymmetric dimethylarginine (ADMA) is a pro‐atherogenic marker of endothelial dysfunction and inhibitor of endothelial nitric oxide synthase (eNOS) that may contribute to progression of renal injury. We designed a novel bioengineered fusion of an elastin‐like polypeptide with vascular endothelial growth factor (ELP‐VEGF). We showed that ELP‐VEGF therapy in renovascular disease (RVD) restores renal hemodynamics by improving microvascular (MV) rarefaction in the stenotic kidney. Our preliminary data suggest that co‐adjuvant ELP‐VEGF therapy with renal angioplasty (PTRAs) enhances renal recovery compared to PTRAs alone. We aimed to elucidate underlying mechanisms of renoprotection and test the hypothesis that co‐adjuvant ELP‐VEGF+PTRAs decreases ADMA and thus, its effects on eNOS inhibition, causing augmented renal bioavailability of NO and improvements of MV endothelial function, renal hemodynamics, and reversal of MV rarefaction.RVD was induced by unilateral renal artery stenosis and high cholesterol feeding in 14 pigs. Six weeks later, single‐kidney blood flow (RBF) and filtration (GFR) were quantified in vivo using multi‐detector CT at baseline and during an endothelium‐dependent challenge (with acetylcholine, Ach). Then pigs were randomized to either PTRAs+placebo or PTRAs followed by intra‐renal ELP‐VEGF therapy (RVD+PTRAs+ELP‐VEGF). Pigs were observed for four additional weeks; in vivo CT studies repeated, then pigs were euthanized, and ex vivo renal MV micro‐CT quantification, plasma ADMA concentration, and stenotic kidney eNOS, VEGF, and Flk‐1 expression were measured.Pre‐treatment renal hemodynamics were equally reduced and PTRAs similarly resolved renal artery stenosis in all pigs with RVD. However, PTRAs+ELP‐VEGF led to significantly greater recovery of RBF and GFR and responses to Ach than PTRAs alone. Improvements in renal function were accompanied by decreased plasma ADMA and enhanced stenotic kidney expression of eNOS, VEGF, and its Flk‐1 receptor, and improved MV density and remodeling (Figure).This study extends our previous findings by identifying a potential mechanism of enhanced renal recovery after combined PTRAs+ELP‐VEGF therapy. Reductions in circulating ADMA may have contributed to the improved renal expression of eNOS in tandem with VEGF therapy, resulting in augmented renal bioavailability of NO and ultimately improving functional and structural renal MV rarefaction. Furthermore, decreased ADMA may suggest a slowing down of the atherosclerotic process in the RVD kidney, which may have also helped contribute to the greater improvements in MV density and overall renal function after PTRAs+ELP‐VEGF therapy.Support or Funding InformationR41DK109737, R01HL095638, P01HL51971, P20GM104357, R01HL121527, EIA18490005, IPA34170267, and T32HL105324This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Ethanol Extract from Purple Eggplant Skin (Solanum melongena L) On Blood Glucose Levels and Pancreatic β Cells Regeneration on White Rats Male Hypercholesterolemia-Diabetic

To observed secondary metabolite compounds in the purpleeggplant skin fruit ethanol extract, the effect and effective dose on blood glucose levels and regeneration of pancreatic s cells of white rats male Hypercholesterolemia-Diabetic. This research is a laboratory experiment with a Phytochemical assay using a specified reagent for the ethanol extract of purple eggplant skin. The effect and effective dose on blood glucose levels and regeneration of pancreatic s cells animal model using posttest randomized controlled-group design. A total of 30 rats were divided into six groups. Group I; normal control given standard feed: group II; negative control is given Na CMC 0.5%, high cholesterol feed and induced by streptozotocin 30 mg/kg BW; experimental groups were given extract of ethanol from purple eggplant skin each with dose 25, 50 and 100 mg/kg BW, high cholesterol feed, and streptozotocin 30 mg/kg BW. The data obtained were analyzed using one-way ANOVA test at 95% confidence level and continued with LSD Post Hoc test and description of histologic damage level of the pancreaswas analyzed by Kruskal-Wallis test followed by Mann-Whitney test for observed the difference between treatments. Extracts ethanol of purple eggplant skinaffect blood glucose levels and pancreatic s cell regeneration and an effective dose is a dose of 25 mg/kg body weight was the most effective extract.This research confirm that the ethanol extract from purple eggplant skin (Solanum melongena L) affect blood glucose levels and pancreatic s cell regeneration.

Evaluation of Reference Genes for Quantitative PCR in Four Tissues from Rabbits with Hypercholesterolaemia

Abstract Rabbit with hypercholesterolaemia is an important model for studying cholesterol metabolism disease. This study aimed to evaluate the expression stability of nine reference genes for quantitative PCR (qPCR) analysis in adrenal gland, liver, spleen, and kidney tissue from rabbits with hypercholesterolaemia. In total, 30 male Harbin Large White (HLW) rabbits were fed a normal feed (n = 15) or a high cholesterol feed (n = 15) for 8 weeks to induce hypercholesterolaemia. Nine reference genes were verified by qPCR using cDNA extracted from rabbit tissue samples. For qPCR analysis, reference genes were evaluated using the RefFinder and GeNorm algorithms. Overall, seven rabbits with hypercholesterolaemia were identified based on body weight and total cholesterol measurements. Combining the results of the RefFinder and GeNorm algorithms, the most stable reference genes were hypoxanthine phosphoribosyltransferase 1 (Hprt1) and eukaryotic translation elongation factor 1 alpha 1 (Eef1a1) in the adrenal gland, β-2-microglobulin (B2m) and glyceraldehyde-3-phosphate dehydrogenase (Gapdh) in the liver, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (Ywhaz) and Gapdh in the spleen, and peptidylprolyl isomerase (Ppia), β-actin (Actb), succinate dehydrogenase complex subunit A flavoprotein (Sdha), and B2m in the kidney. Taken together, our results confirmed that Hprt1 and Eef1a1, B2m and Gapdh, Ywhaz and Gapdh, and Ppia, Actb, Sdha, and B2m were the best reference genes for qPCR analyses in adrenal gland, liver, spleen, and kidney tissue, respectively, of rabbits with hypercholesterolaemia.