Dyslipidemia In Mice Research Articles

From Cells‐to‐Organism: Impact of Dyslipidemia on Inwardly Rectifying K+ Channels and Cerebral Vascular Function

Recent studies have noted that dyslipidemia can diminish dilatory function of resistance arteries by altering the activity of ion channels that set membrane potential. Focusing on the cerebral circulation, this study determined whether inwardly rectifying K+ (KIR) channels are targeted early in dyslipidemia and if alterations impact blood flow control. Experiments began at the cellular level (patch‐clamp electrophysiology) and then were extended to isolated arteries (pressure myography) and whole animals (arterial spin‐labelling magnetic resonance imaging). Initial lipid analysis confirmed the dyslipidemic state of LDLR−/− (normal chow) and C57BL/6 mice fed a high‐cholesterol high‐fat (HFHC) diet for 8 weeks; note aortic plaque formation was absent in these animal models. Patch‐clamp electrophysiology revealed a marked reduction in endothelial but not smooth muscle KIR activity in both dyslipidemic models. Flow activation of KIR was also reduced in endothelial cells from LDLR−/− and HFHC mice. However, endothelial KIR activity was recovered in dyslipidemic mice by depleting the plasma membrane of cholesterol. Consistent with these cellular changes, we observed diminished shear‐induced vasodilation in cerebral arteries isolated from dyslipidemic animals. To our surprise, these cellular/tissue level changes didn’t alter cerebral blood flow at baseline or in response to a blood pressure challenge (phenylephrine injection through a peritoneal catheter, 0.816 mg/kg). The maintenance of blood flow control was observed across a full range of structures including the cortex, cerebral nuclei, hippocampus, thalamus, hypothalamus and midbrain. In closing, our findings highlight that while KIR channel function is targeted early on in dyslipidemia, compensatory mechanisms can maintain brain blood flow to preserve neurological function.Support or Funding InformationCanadian Institutes of Health Research

High-intensive therapeutic lowering of systemic cholesterol does not ameliorate osteoarthritis development in knee joints of humanized dyslipidemic mice

Purpose: High systemic cholesterol levels are associated with osteoarthritis (OA) development. Novel therapeutic high-intensive cholesterol-lowering therapies have recently been shown to diminish western type diet (WTD) induced atherosclerosis. Here, we investigated the potency of these therapeutic cholesterol-lowering strategies to attenuate OA development in dyslipidemic APOE*3Leiden.CETP mice.

Hypericin attenuates nonalcoholic fatty liver disease and abnormal lipid metabolism via the PKA-mediated AMPK signaling pathway in vitro and in vivo

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and constitutes a major risk factor for progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC). The occurrence of NAFLD is closely associated with abnormal lipid metabolism and implies a high risk of type 2 diabetes and cardiovascular disease. Therefore, specific and effective drugs for the prevention and treatment of NAFLD are necessary. Hypericin (HP) is one of the main active ingredients of Hypericum perforatum L., and we previously revealed its protective role in islet β-cells and its effects against type 2 diabetes. In this study, we aimed to explore the preventive and therapeutic effects of HP against NAFLD and the underlying mechanisms in vitro and in vivo. Here, we demonstrated that HP improved cell viability by reducing apoptosis and attenuated lipid accumulation in hepatocytes both in vitro and in vivovia attenuating oxidative stress, inhibiting lipogenesis and enhancing lipid oxidization. Thus, HP exhibited significant preventive and therapeutic effects against HFHS-induced NAFLD and dyslipidemia in mice. Furthermore, we demonstrated that HP directly bound to PKACα and activated PKA/AMPK signaling to elicit its effects against NAFLD, suggesting that PKACα is one of the drug targets of HP. In addition, the enhancing effect of HP on lipolysis in adipocytes through the activation of PKACα was also elucidated. Together, the conclusions indicated that HP, of which one of the targets is PKACα, has the potential to be used as a preventive or therapeutic drug against NAFLD or abnormal lipid metabolism in the future.

PML-RARα interaction with TRIB3 impedes PPARγ/RXR function and triggers dyslipidemia in acute promyelocytic leukemia

Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy, the underlying mechanism and the lipid statuses of patients with newly diagnosed APL remain to be addressed.Methods: We conducted a retrospective study to investigate the lipid profiles of APL patients. PML-RARα transgenic mice and APL cells-transplanted mice were used to assess the effects of APL cells on the blood/liver lipid levels. Subsequently, gene set enrichment analysis, western blot and dual luciferase reporter assay were performed to examine the role and mechanism of PML-RARα and TRIB3 in lipid metabolism regulation in APL patients at pretreatment and after induction therapy.Results: APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy based on a retrospective study. Furthermore, APL cells caused secretion of triglycerides, cholesterol, and PCSK9 from hepatocytes and degradation of low-density lipoprotein receptors in hepatocytes, which elevated the lipid levels in APL cell-transplanted mice and Pml-Rarα transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RARα to inhibit PPARγ activity by interfering with the interaction of PPARγ and RXR and promoting PPARγ degradation. Thus, reduced PPARγ activity in APL cells decreased leptin but increased resistin expression, causing lipid metabolism disorder in hepatocytes and subsequent dyslipidemia in mice. Although arsenic/ATRA therapy degraded PML-RARα and restored PPARγ expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPARγ activity by disrupting the PPARγ/RXR dimer, which resulted in dyslipidemia in APL patients undergoing therapy. Indeed, the PPAR activator not only enhanced the anti-APL effects of arsenic/ATRA by suppressing TRIB3 expression but also reduced therapy-induced dyslipidemia in APL patients.Conclusion: Our work reveals the critical role of the PML-RARα/PPARγ/TRIB3 axis in the development of dyslipidemia in APL patients, potentially conferring a rationale for combining ATRA/arsenic with the PPAR activator for APL treatment.

Integrins α4β1 and αVβ3 are Reduced in Endothelial Progenitor Cells from Diabetic Dyslipidemic Mice and May Represent New Targets for Therapy in Aortic Valve Disease

Diabetes reduces the number and induces dysfunction in circulating endothelial progenitor cells (EPCs) by mechanisms that are still uncovered. This study aims to evaluate the number, viability, phenotype, and function of EPCs in dyslipidemic mice with early diabetes mellitus and EPC infiltration in the aortic valve in order to identify possible therapeutic targets in diabetes-associated cardiovascular disease. A streptozotocin-induced diabetic apolipoprotein E knock-out (ApoE−/−) mouse model was used to identify the early and progressive changes, at 4 or 7 days on atherogenic diet after the last streptozotocin or citrate buffer injection. Blood and aortic valves from diabetic or nondiabetic ApoE−/− animals were collected. EPCs were identified as CD34 and vascular endothelial growth factor receptor 2 positive monocytes, and the expression levels of α4β1, αVβ3, αVβ5, β1, αLβ2, α5 integrins, and C-X-C chemokine receptor type 4 chemokine receptor on EPC surface were assessed by flow cytometry. The number of CD34 positive cells in the aortic valve, previously found to be recruited progenitor cells, was measured by fluorescence microscopy. Our results show that aortic valves from mice fed 7 days with atherogenic diet presented a significantly higher number of CD34 positive cells compared with mice fed only 4 days with the same diet, and diabetes reversed this finding. We also show a reduction of circulatory EPC numbers in diabetic mice caused by cell senescence and lower mobilization. Dyslipidemia induced EPC death through apoptosis regardless of the presence of diabetes, as shown by the higher percent of propidium iodide positive cells and higher cleaved caspase-3 levels. EPCs from diabetic mice expressed α4β1 and αVβ3 integrins at a lower level, while the rest of the integrins tested were unaffected by diabetes or diet. In conclusion, reduced EPC number and expression of α4β1 and αVβ3 integrins on EPCs at 4 and 7 days after diabetes induction in atherosclerosis-prone mice have resulted in lower recruitment of EPCs in the aortic valve.

Effect of Camellia sinensis teas on left ventricular hypertrophy and insulin resistance in dyslipidemic mice.

The control of dyslipidemia using plants is an important subject of studies since it has numerous benefits in cardiovascular protection. The objective of this study was to evaluate the effect of three Camellia sinensis L. teas (green, red, and white) on left ventricular hypertrophy and insulin resistance in low-density lipoprotein receptor knockout (LDLr-/-) mice fed a high-fat diet. The LDLr-/- mice were divided into four experimental groups: Group C: standard feed; Group CT: standard feed and three teas, Group HL: high-fat feed; HLT Group: high-fat feed and three teas. The three types of tea (green, red, and white) originated from different processing of the Camellia sinensis L. plant, and were administered associated once a day at a dose of 25 mg/kg by gavage for 60 days. The teas partially prevented hyperlipidemia, the decrease of the serum levels of high-density lipoproteins (HDL), insulin resistance, and increased C-reactive protein (CRP) levels, and completely prevented left ventricular hypertrophy in LDLr -/- mice of the HLT group. In conclusion, the three Camellia sinensis L. teas used to control genetic dyslipidemia associated with a high-fat diet can be used as an auxiliary treatment associated with the control of lipid intake, thus promoting cardiac protection against hyperlipidemia.

Ezetimibe ameliorates lipid accumulation during adipogenesis by regulating the AMPK-mTORC1 pathway.

Adipogenesis, a critical process that converts adipocyte precursors into adipocytes, is considered a potential therapeutic target for the treatment of obesity. Ezetimibe, a drug approved by the United States Food and Drug Administration, is used for the treatment of hypercholesterolemia. Recently, it was reported to ameliorate high fat diet-induced dyslipidemia in mice and reduce lipid accumulation in hepatocytes through the activation of AMPK. However, the anti-adipogenic effects of ezetimibe and the underlying molecular mechanism have not yet been elucidated. Here, we found that ezetimibe reduced lipid accumulation via activating AMPK during the early phase of adipogenesis. We also observed that ezetimibe inhibited peroxisome proliferator-activated receptor γ, which is a major transcription factor of adipogenesis. Furthermore, ezetimibe-mediated AMPK activation reduced lipid accumulation by inhibiting mTORC1 signaling, leading to the downregulation of lipogenesis-related genes. Mitotic clonal expansion, required for adipogenesis, accelerates cell cycle progression and cell proliferation. We additionally observed that ezetimibe prevented the progression of mitotic clonal expansion by arresting the cell cycle at the G0/G1 phase, which was followed by the inhibition of cell proliferation. Collectively, ezetimibe-mediated inhibition of adipogenesis is dependent on the AMPK-mTORC1 pathway. Thus, we suggest that ezetimibe might be a promising drug for the treatment of obesity.

Atherogenic lipid stress induces platelet hyperactivity through CD36-mediated hyposensitivity to prostacyclin: the role of phosphodiesterase 3A.

Prostacyclin (PGI2) controls platelet activation and thrombosis through a cyclic adenosine monophosphate (cAMP) signaling cascade. However, in patients with cardiovascular diseases this protective mechanism fails for reasons that are unclear. Using both pharmacological and genetic approaches we describe a mechanism by which oxidized low density lipoproteins (oxLDL) associated with dyslipidemia promote platelet activation through impaired PGI2 sensitivity and diminished cAMP signaling. In functional assays using human platelets, oxLDL modulated the inhibitory effects of PGI2, but not a phosphodiesterase (PDE)-insensitive cAMP analog, on platelet aggregation, granule secretion and in vitro thrombosis. Examination of the mechanism revealed that oxLDL promoted the hydrolysis of cAMP through the phosphorylation and activation of PDE3A, leading to diminished cAMP signaling. PDE3A activation by oxLDL required Src family kinases, Syk and protein kinase C. The effects of oxLDL on platelet function and cAMP signaling were blocked by pharmacological inhibition of CD36, mimicked by CD36-specific oxidized phospholipids and ablated in CD36−/− murine platelets. The injection of oxLDL into wild-type mice strongly promoted FeCl3-induced carotid thrombosis in vivo, which was prevented by pharmacological inhibition of PDE3A. Furthermore, blood from dyslipidemic mice was associated with increased oxidative lipid stress, reduced platelet sensitivity to PGI2 ex vivo and diminished PKA signaling. In contrast, platelet sensitivity to a PDE-resistant cAMP analog remained normal. Genetic deletion of CD36 protected dyslipidemic animals from PGI2 hyposensitivity and restored PKA signaling. These data suggest that CD36 can translate atherogenic lipid stress into platelet hyperactivity through modulation of inhibitory cAMP signaling.

Capsaicin alleviates lipid metabolism disorder in high beef fat-fed mice

This study was designed to evaluate the preventive mechanisms of capsaicin on beef fat-induced lipid metabolism disorder, oxidative stress and dysbacteriosis in mice. Mice were fed a control diet or a 30% beef-fat diet (BF) with or without 0.001% capsaicin for 12 weeks. The consumption of a BF with capsaicin effectively inhibited obesity and dyslipidemia in mice. Consumption of capsaicin improved the oxidative stress by reducing the hepatic malonaldehyde content and elevating the glutathionperoxidase activity. GC–MS analysis showed that the acetic acid content in the cecum was significantly increased by capsaicin supplementation. The enteric microflora species was not changed significantly by the consumption of capsaicin in BF-fed mice. The alleviation of dyslipidemia might be because capsaicin enhanced the antioxidant activity and elevated the enteric acetic acid levels in high beef fat-fed mice. Our results suggest that the ingestion of capsaicin might be an effective strategy for preventing beef fat-induced hyperlipidemia.

An Inhibitor of Activated Blood Coagulation Factor X Shows Anti-Endothelial Senescence and Anti-Atherosclerotic Effects

Background: Coagulant factor Xa inhibitors (XaIs) are prescribed for patients with atrial fibrillation for years. Methods: Human umbilical venous endothelial cells (HUVECs) were cultured with or without (w/wo) a XaI (rivaroxaban) under high glucose (HG: 22 mM). Endothelial senescence was investigated by assessing senescence-associated-β-galactosidase (SA-β-gal), p53, and telomere length. Endothelial function and atherosclerosis were examined by nitric oxide-related-products (NOx: NO₂^– and NO₃^–), O₂^–, endothelial NO synthase (eNOS), NADPH oxidase (p22^phox), and ICAM1. PAR1 (protease-activated receptor 1) and PAR2, which were reported to regulate eNOS phosphorylation, were inhibited by small interfering RNAs (siRNAs). Thirty-two male dyslipidemic type 2 diabetic rats (ZFDM LepR^fa/fa) were fed a high-cholesterol diet w/wo XaI (50 µg/day/kg) for 1–4 weeks. Results: SA-β-gal, p53, p21, and p16^INK4a were increased by HG and restored by XaI (50 nM) in HUVECs. XaI restored telomerase activity and preserved telomere length. XaI suppressed O₂^–, p22^phox, and ICAM1 and restored NOx and eNOS. XaI decreased PAR1 following elevation by HG, which was confirmed by PAR1 siRNA and PAR2 siRNA. In in vivo experiments, plasma glucose, total cholesterol, and triglycerides were increased for 4 weeks but were not changed by XaI. XaI decreased SA-β-gal and telomerase and preserved telomere length in the aortic endothelium. XaI activated eNOS, inhibited p22^phox, increased plasma NOx, and decreased O₂^–. Conclusion: Rivaroxaban prevents replicative senescence in HUVECs and aortic endothelial cells in dyslipidemic diabetic mice. It restores endothelial function and prevents the progression of atherosclerosis.

Worsening of Oxidative Stress, DNA Damage, and Atherosclerotic Lesions in Aged LDLr-/- Mice after Consumption of Guarana Soft Drinks.

Background Excessive consumption of soft drinks (SD) has become a health problem worldwide due to its association with related cardiovascular diseases. We investigated the possible impacts associated with the consumption of Brazilian guarana (normal and zero) SD in dyslipidemic mice, thus mitigating potential clinical confounders such as poor-quality diet, lifestyle, body composition, and/or comorbidities. Methods Sixteen-month-old LDLr−/− mice were divided into the following groups: (1) control; (2) GSD: normal guarana SD; and (3) Z-GSD: zero guarana SD. All were fed ad libitum, and blood pressure was measured noninvasively. After 8 weeks, aorta, blood, liver, and stomach samples were collected for histological and biochemical analyses. Results Guarana soft drinks increased atherosclerosis (~60%) and were associated with hypercholesterolemia, hypertension, oxidative stress, DNA fragmentation, and apoptosis (~2-fold) of blood cells, besides presenting an increase in liver and gastric damage even in normoglycemia. Interestingly, Z-GSD did not cause the aforementioned changes, except in hemodynamic and renal parameters. Conclusions Chronic administration of GSD is prooxidative, compromising the cardiovascular, gastric, and hepatic systems; the effects are due at least in part to free sugar consumption but not to guarana extract per se.

Suppression of Hepatic Lipogenesis and Enhancement of β-oxidation in Skeletal Muscle by Betulinic Acid Lead to the Reduction of Body Adiposity and Dyslipidemia in Mice (P21-043-19)

ObjectivesBetulinic acid (BA) exists as a lipophilic conformation in nature, rich in fruits and vegetables, especially the bark of birch wood. Beneficial effects of BA on cancer, oxidative stress, and inflammation were previously reported. Studies of BA for anti-obesity and dyslipidemia have been recently emerged, however the outcomes are still not conclusive. We tested if BA improves obesity and/or dyslipidemia by incorporated mechanism of liver and skeletal muscle in vivo. MethodsFive-week-old male C57BL/6 mice were fed Western type diet (45% kcal from fat with 1.25% cholesterol) ad libitum for 12 weeks. Mice were allocated into five groups: (−) control, BA 5 mg/kg, BA 15 mg/kg, BA 25 mg/kg, and fenofibrate as a (+) control. BA was orally administered every day. For proved phenotype alteration, we analyzed mRNA and protein expressions linked to lipogenesis and β-oxidation. ResultsGrowth performance including final body weight, weight gain, and feed intake were not altered by BA. Body fat mass was decreased by all BA treated groups (P < 0.01) without changes of lean mass. Energy expenditure contributed by β-oxidation was increased by BA 25 (P < 0.001). Serum lipid profiles including triglyceride, free fatty acid, total cholesterol, and LDL cholesterol were significantly improved by all BA treated groups (P < 0.001). Lipid accumulation in the liver was reduced by BA 15 and 25 (all P < 0.001). The mRNA expressions of Acc1and Scd1were dose-dependently suppressed by betulinic acid in liver (P < 0.05). SREBP1 was diminished by BA treated groups (all P < 0.05). FAS showed reduced tendency by BA (P = 0.06). In protein levels, ACC1 and SCD1 were inhibited by BA treated groups (P < 0.001 and P < 0.05). FAS and SREBP1 tended to be reduced by BA (P = 0.40 and P = 0.70). LPL and CPT1, β-oxidation markers in skeletal muscle, were activated by BA 25 (P < 0.001 and P < 0.01). The activation of CPT1 was influenced by stimulating of AMPK-pT172 and ACC1-pS79 (all P < 0.05). Taken together, BA inhibitedde novolipogenesis in the liver and upregulated key proteins related to β-oxidation in skeletal muscle, contributing to the prevention of obesity and dyslipidemia. ConclusionsWe suggest that BA is a potent nutraceutical for prevention and treatment of chronic metabolic diseases including obesity and dyslipidemia. Funding SourcesNational Research Foundation of Korea.

Vasoreactivity of isolated aortic rings from dyslipidemic and insulin resistant inducible nitric oxide synthase knockout mice

Recent study from this lab indicated enhanced susceptibility of iNOS KO mice for diet induced obesity (DIO) and systemic insulin resistance (IR) as compared to C57BL/6 (WT) mice. The present study investigates aortic vasoreactivity in high fat diet (HFD) induced insulin resistant iNOS KO mice.WT and iNOS KO mice were fed with 45% HFD/10% LFD for ten weeks. Systemic IR was assessed via measurement of circulating lipids, glucose, and insulin; while phenylephrine (PE)/acetylcholine (ACh) induced responses were monitored in the isolated aortic rings. To understand the mechanism, qPCR or Western blotting experiments were performed in aorta and Ea.hy926 cells. After 10 weeks of HFD feeding, significant increase in the body weight/fat mass, augmented circulating lipids, glucose, insulin and inflammatory cytokines along with impaired acetylcholine induced aortic vasorelaxation and enhanced iNOS expression was observed in the aortic tissue of WT mice. In the aminoguanidine (AG, 20 mg/kg for 4 weeks) treated WT mice and also in iNOS KO mice, acetylcholine induced vasorelaxation was significantly preserved. Further, acetylcholine mediated vasorelaxation correlated with increased eNOS phosphorylation at Ser1177 residue in the iNOS KO mice and same was also observed in the iNOS silenced Ea.hy926 cells. Moreover, treatment of Ea.hy926 cells with palmitic acid or TNFα also caused a significant decrease in eNOS activity, which was reversed in iNOS silenced Ea.hy926 cells suggesting the role of iNOS in the reduction of eNOS activity. The study thus implies a critical role of iNOS in vascular diseases associated with dyslipidemia/IR.

MiR-96 and autophagy are involved in the beneficial effect of grape seed proanthocyanidins against high-fat-diet-induced dyslipidemia in mice.

We aimed to investigate the possible signaling pathways underlying the regulation of grape seed proanthocyanidins extracts (GSPE) on lipid metabolism. One hundred male C57BL/6 mice were divided into four groups: control group (normal diet), GSPE group (normal diet + GSPE), high-fat diet group (HFD), and high-fat diet plus GSPE (200mg/kg/day) group (HFD+GSPE). Mice received the diets for 180days. Body weight and serum lipid levels were measured. Autophagic flux characteristics, such as accumulation of lipids, mitochondria, and autophagosomes in the liver, were detected using transmission electron microscopy. Expression profile of microRNAs (miRNAs) in the liver was determined using RNA microarray and quantitative real time polymerase chain reaction (qRt-PCR). GSPE significantly decreased the weight gain, serum levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol but increased high-density lipoprotein cholesterol in the HFD mice. Autophagic flux was significantly increased by HFD but decreased by GSPE treatment. GSPE significantly attenuated HFD-induced miR-96 upregulation, which in turn reduced the expressions of miR-96 downstream molecules, FOXO1, mTOR, p-mTOR, and LC3A/B. These results suggested that the miR-96 is involved in the protective effect of GSPE against HFD-induced dyslipidemia. Possible mechanisms might be through mTOR and FOXO1, which facilitate autophagic flux for clearance of lipid accumulation.

Effects of Metformin Combined with Lactoferrin on Lipid Accumulation and Metabolism in Mice Fed with High-Fat Diet.

Metformin (Met) and lactoferrin (Lf) both exhibit beneficial effects on body weight management and lipid accumulation. However, the synergistical action of Met and Lf remains unclear. In this study, 64 mice were divided into five groups, namely, the control group, high-fat diet (HFD group), HFD with Met (Met group), Lf (Lf group), and a combination of Met and Lf (Met + Lf group). Met (200 mg/kg body weight) and Lf (2 g/100 mL) were administrated in drinking water. The experiment lasted for 12 weeks. Body weight, serum, and hepatic lipids were determined. Histology of the liver and perirenal fat was observed. Protein expression related to hepatic lipid metabolism was also measured. HFD significantly increased body weight, visceral fat weight, and lipid profiles, which lead to obesity and dyslipidemia in mice. Compared with the HFD group, the treatments significantly decreased body weight and Lee’s index (body mass index of mice) with the lowest values in the Met + Lf group. The treatments also decreased the weight of visceral fat, and improved circulating lipid profile and the ability for regulating glucose intake. The adipocyte size and serum TC level were significantly lower in the Met + Lf group as compared with those in the Met or Lf group. The treatments alleviated hepatic lipid accumulation, especially in the Met + Lf group. For protein expression, the p-AMPK/AMPK ratio, a key kinase-regulating cellular energy homeostasis, was significantly higher in the Met + Lf group than the ratio in the HFD group. Similarly, the treatments significantly downregulated the protein expression of lipogenic enzymes (FAS, ACC, and SREBP-1) and upregulated the protein expression of lipolytic enzyme (ATGL). The protein expression of HMGCoAR, which is an important rate limiting enzyme in cholesterol biosynthesis, was only significantly lower in the Met + Lf group than in the HFD group. In conclusion, Met and Lf, either alone or in combination, prevented HFD-induced obesity and improved lipid metabolism.

Ameliorating effects of Sporidiobolus pararoseus extract on dyslipidemia in mice with high fat diet induced obesity.

The study investigated how an extract of Sporidiobolus pararoseus (S.p.) affects lipid metabolism in Kunming mice that were obese as a result of being fed a high-fat diet; the control group were administered Max EPA fish oil. Ten mice were randomly selected from a pool of 60 mice for the control group and the remaining 50 mice were fed with a high-fat diet to establish a dyslipidemia model. After 4 weeks, these 50 mice were randomly distributed among 5 groups: high-fat model group; Max EPA group; and 3 groups of mice fed different doses of S.p. extract (low dose, medium dose, and high dose). After 8 weeks, the mice were sacrificed and the relevant parameters were measured. Compared with the high-fat model group, the group administered the high dose of S.p. extract showed significantly decreased body mass and serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol, and increased levels of high-density lipoprotein cholesterol. The results from RT-PCR showed that the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthesis enzyme, and acetyl-CoA carboxylase was lower in the groups supplemented with S.p. extract than in the high-fat model group, whereas the expression of carnitine palmitoyltransferase 1 was higher in the group supplemented with S.p. extract than in the high-fat model group. Our results suggest that taking S.p. extract could benefit patients with dyslipidemia. Therefore, S.p. extract should be developed as a dietary supplement to improve lipid metabolism in obese people.

Paeoniflorin regulates GALNT2-ANGPTL3-LPL pathway to attenuate dyslipidemia in mice

N-acetylgalactosaminyltransferase 2-Angiopoietin-like protein 3-lipoprotein lipase (GALNT2-ANGPTL3-LPL) pathway may be a useful pharmacologic objective for dyslipidemia. The present study was conducted to test the effect of paeoniflorin, a monoterpene Glycoside, on dyslipidemia in mice. Fifty mice were randomly divided into five groups (n = 10): three groups of apolipoprotein E-null (ApoE-/-) mice treated with paeoniflorin (10 or 20 or 30 mg/kg/day), untreated ApoE-/- mice group, and C57BL/6J control group. Six weeks after treatment, expression of hepatic ANGPTL3, hepatic GALNT2 and adipose tissue LPL, lipid levels in the liver and blood were quantified. Treatment with paeoniflorin (10 or 20 or 30 mg/kg) obviously down-regulated expression of ANGPTL3 and up-regulated expressions of GALNT2 and LPL concomitantly with elevated plasma high-density lipoprotein cholesterol level, reduced plasma concentrations of low-density lipoprotein cholesterol, total cholesterol, triglyceride, malonaldehyde, and 8-isoprostane. The present results suggest that paeoniflorin regulates GALNT2-ANGPTL3-LPL pathway to attenuate dyslipidemia in mice.

Exposure to Ionizing Radiation Causes Endoplasmic Reticulum Stress in the Mouse Hippocampus.

It is well known that ionizing radiation-induced toxicity to normal tissue has functional consequences in the brain. However, the underlying molecular alterations have yet to be elucidated. We have previously reported cognitive impairments with concomitant changes in dendritic complexity, spine density and inflammation in mice at 6-24 weeks postirradiation. The goal of this study was to determine whether metabolic changes in the mouse hippocampus after whole-body (4 Gy) or cranial (9 Gy) X-ray irradiation might trigger some of the incipient changes contributing to the persisting pathology in the radiation-injured brain. Metabolomic and lipidomic profiling of hippocampal tissue revealed that radiation induced dyslipidemia in mice at two days and two weeks postirradiation. Strikingly, significant changes were also observed in metabolites of the hexosamine biosynthesis pathway, a finding that was further confirmed using orthogonal methodologies. We hypothesize that these changes in hexosamine metabolism could induce endoplasmic reticulum stress and contribute to radiation-induced cognitive impairments. Taken together, our results show that molecular phenotyping is a valuable approach to identify potentially detrimental pathway perturbations that manifest significantly earlier than gross structural and functional changes in the irradiated brain.

Physical exercise alters hepatic morphology of low-density lipoprotein receptor knockout ovariectomized mice.

To explore the effects of physical exercise on the liver of animals in menopause, we analyzed the histomorphometric parameters of the hepatic tissue in ovariectomized and dyslipidemic female mice. The animals were distributed in six groups (n = 5): sedentary control (SC), sedentary ovariectomized control (SOC), trained ovariectomized control (TOC), sedentary LDL knockout (LDL-S), sedentary ovariectomized LDL knockout (LDL-SO), and trained ovariectomized LDL knockout (LDL-TO). At the end of the experiment, the liver and the visceral adipose tissue (VAT) of animals were removed for morphometric and stereological studies. In the LDL-S and LDL-SO animals, both sedentary, results showed reduction in the area (µm2) and major and minor diameters (µm) of hepatocytes and reduction in the portions of large hepatocytes, and increase in the percentage of Kupffer cells. The trained group showed a tendency of increase in the area and diameter and in the percentage of hepatocytes, as well significant reduction in the percentage of Kupffer cells and interstitial tissue. We suggested that training can prevent cell and tissue damage caused by the process of increase in hepatic fat, lipoperoxidation, and tissue inflammation in animals with privation of estrogen and dyslipidemia, apparently reflecting a better metabolic response of the hepatic tissue in organisms undergoing training.

Tributyltin exposure induces gut microbiome dysbiosis with increased body weight gain and dyslipidemia in mice

Gut microbiome dysbiosis plays a profound role in the pathogenesis of obesity and tributyltin (TBT) has been found as an environmental obesogen. However, whether TBT could disturb gut microbiome and the relationship between obesity induced by TBT exposure and alteration in gut microbiota are still unknown. In order to assess the association between them, mice were exposed to TBTCl (50 μg kg−1) once every three days from postnatal days (PNDs) 24 to 54. The results demonstrated that TBT exposure resulted in increased body weight gain, lager visceral fat accumulation and dyslipidemia in male mice on PND 84. Correspondingly, 16S rRNA gene sequencing revealed that TBT treatment decreased gut microbial species and perturbed the microbiome composition in mice. Furthermore, Pearson’s corelation coefficient analysis showed a significantly negative correlation between the body weight and the alpha diversity of gut microbiome. These results suggested that TBT exposure could induce gut microbiome dysbiosis in mice, which might contribute to the obesity pathogenesis.