Increased Plasma Cholesterol Levels Research Articles

A polyphenol-rich plant extract prevents hypercholesterolemia and modulates gut microbiota in western diet-fed mice.

Totum-070 is a combination of five plant extracts enriched in polyphenols to target hypercholesterolemia, one of the main risk factors for cardiovascular diseases. The aim of this study was to investigate the effects of Totum-070 on cholesterol levels in an animal model of diet-induced hypercholesterolemia. C57BL/6JOlaHsd male mice were fed a Western diet and received Totum-070, or not, by daily gavage (1g/kg and 3g/kg body weight) for 6 weeks. The Western diet induced obesity, fat accumulation, hepatic steatosis and increased plasma cholesterol compared with the control group. All these metabolic perturbations were alleviated by Totum-070 supplementation in a dose-dependent manner. Lipid excretion in feces was higher in mice supplemented with Totum-070, suggesting inhibition of intestinal lipid absorption. Totum-070 also increased the fecal concentration of short chain fatty acids, demonstrating a direct effect on intestinal microbiota. The characterization of fecal microbiota by 16S amplicon sequencing showed that Totum-070 supplementation modulated the dysbiosis associated with metabolic disorders. Specifically, Totum-070 increased the relative abundance of Muribaculum (a beneficial bacterium) and reduced that of Lactococcus (a genus positively correlated with increased plasma cholesterol level). Together, these findings indicate that the cholesterol-lowering effect of Totum-070 bioactive molecules could be mediated through multiple actions on the intestine and gut microbiota.

Transcriptomics and metabolomics reveal the regulation of reproductive performance and egg quality of blotched snakehead Channa maculata broodstock induced by a high protein diet

To evaluate the effects of dietary protein on reproductive performance, egg quality and larval health of the blotched snakehead Channa maculata, three groups were designed: a high protein group (HP) with 48% protein content, a low protein group (LP) with 44% protein content, and a control group (C) fed with commercial feed containing 40% protein. The results demonstrated that the HP diet significantly enhanced maternal absolute fecundity, egg size and offspring health; however, it had no impact on fertilization rate and hatching rate. The maternal plasma levels of 11-ketotestosterone, 17β-estradiol, and vitellogenin in the HP group were found to be significantly higher compared to those in the C group. Plasma SOD activity and T-AOC capacity in the HP group were significantly higher than those in the C group, while MDA content showed an opposite trend. The trend of T-AOC in 7 days post-hatching larvae exhibited a consistent pattern with that observed in the maternal. Metabolomics and transcriptomics results indirectly indicated that the differences in reproductive and egg quality of the broodstock were associated with the regulation of arachidonic acid metabolism, steroid hormone biosynthesis, cholesterol metabolism, glycerophospholipid metabolism, and glycerolipid metabolism. The expression levels of star, zp3, foxo3, tgf-β, ghr, igf, cyp17a1, and cyp19a1 genes associated with reproduction and were significantly upregulated in the HP group. By depleting the abundance of metabolites in key pathway such as the pentose phosphate pathway, glycolysis/gluconeogenesis, nicotinate and nicotinamide metabolism, vitamin B6 metabolism within the ovary, there is an elevation in arachidonic acid metabolite abundance, thereby facilitating ovarian maturation and regulating egg quality. In conclusion, the high protein diet may affect the reproductive process and egg quality by inducing an upregulation of TGF-beta signaling pathway and ovarian steroidogenesis and arachidonic acid metabolism, leading to increased plasma cholesterol levels and enhanced steroid hormone synthesis.

Chronic Exposure of 5‐Alpha Reductase Inhibitor in Young Male Rats Induces Not Only Metabolic Disturbance, But Also Depressive‐Like Behaviors as Similar with Obese Condition

AbstractBackgroundFinasteride (FIN), a 5‐alpha reductase inhibitor (5‐ARIs), is one of the drugs approved for the treatment of androgenetic alopecia (AGA) and benign prostatic hyperplasia (BPH). AGA has been found to be associated with obesity. Obesity and AGA themselves often co‐occurs with anxiety and depression. Nevertheless, several studies reported adverse effects of FIN on anxiety and depression, especially in young men. A previous study also reported that FIN caused anxiety and depression in male rats; however, the effects of chronic FIN exposure in young obese condition has not been investigated.MethodTwenty male Wistar rats (8‐week‐old) were divided into two groups (N = 10/group) to feed with either normal diet (ND) or high‐fat diet (HFD) for 18 weeks. At week 13, rats in each dietary group were subdivided into two subgroups to treat with either vehicle as control or FIN (5 mg/kg/day) via oral gavage. At the end of the experimental protocol, the anxiety/depression‐like behaviors were measured using the Elevated‐Plus Maze (EPM) and the Splash Test (ST), while the Open‐Field Test (OFT) was examined for locomotor activity. In addition, blood in each rat was collected for determining the metabolic profiles.ResultHFD‐fed rats developed obesity and hypercholesterolemia, with an increase in systemic oxidative stress (Figure 1A‐C). Anxiety and depressive‐like behaviors were observed in vehicle‐treated HFD‐fed rats, as indicated by decreasing % preference index in the open arm of EPM and grooming time in ST (Figure 1D‐E). FIN treated ND‐fed rats also showed depression‐like behaviors, similar to those in vehicle‐treated HFD‐fed rats (Figure 1E). Although FIN increased plasma cholesterol levels in HFD‐fed rats, it did not aggravate anxiety and depression‐like behaviors in HFD‐fed rats. Regarding the locomotor activity, no significant difference was found among all groups. (Figure 1F).ConclusionAll of these findings suggest that FIN exposure induced metabolic disturbance, and depression‐like behaviors as similar to obesity without the aggravating effects of FIN and obesity on depressive‐like behaviors.

Atorvastatin mitigates memory deficits and brain monocyte infiltration in chronic hypercholesterolemia.

Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation induced by BBB dysfunction and monocyte infiltration might be responsible for neuron damage and cognitive impairment. Atorvastatin is a lipid-lowering drug that is widely applied for the treatment of cardiovascular diseases. However, the potential function of Atorvastatin in hypercholesterolemia-induced MCI remains uncertain. Our research will explore the potential therapeutic function of Atorvastatin in memory deficits induced by chronic hypercholesterolemia. ApoE-/- mice were utilized to mimic the state of chronic hypercholesterolemia and were divided into four groups. Animals in the WT and ApoE-/-groups were orally administered with normal saline, while WT mice in the Atorvastatin group and ApoE-/- mice in the ApoE-/-+ Atorvastatin group were orally administered with 10 mg/kg/day Atorvastatin. Markedly increased plasma cholesterol levels reduced RI in the long-term memory test and the spatial short-term memory test, declined mobility in the open field test, and downregulated PSD-95 and BDNF were observed in ApoE-/- mice, all of which were signally reversed by Atorvastatin. Moreover, the percentages of brain Ly6Chi CD45+ cells and CD3+ CD45+ cells, as well as the blood Ly6Chi CD45+ cells, plasma IL-12/IL-23 levels and IL-17 level were found notably increased in ApoE-/- mice, all of which were largely repressed by Atorvastatin. Lastly, the increased BBB permeability, decreased ZO-1 and occludin levels, and reduced KLF2 level were markedly abolished by Atorvastatin. Collectively, Atorvastatin mitigated memory deficits and brain monocyte infiltration in ApoE-/- mice.

Balancing dietary plant-based lipids and cholesterol to increase fillet omega-3 deposition in rainbow trout (Oncorhynchus mykiss) fed a diet without animal ingredients

We hypothesized that a low phytosterol oil, such as soybean oil, in combination with an α-linolenic acid (ALA) rich oil, such as linseed oil, and supplemental cholesterol could effectively replace fish oil in salmonid feeds. As such, the primary objective was to blend soybean oil with linseed oil and supplemental cholesterol to maintain fish growth and increase de novo production of the omega-3 fatty acids (n-3 FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in trout muscle, since EPA and DHA have been identified as beneficial nutrients in human nutrition, and farmed seafood must meet consumer needs and expectations. To accomplish this, we used soy oil for its low phytosterol properties in combination with linseed oil for its n-3 FA content, with and without cholesterol to improve utilization. Upon conclusion of the study, our results did not support our hypothesis. Trout fed plant-based diets containing any amount of soy oil had reduced growth performance. Only fish fed the plant-based diet with 100% linseed oil plus supplemental cholesterol grew as well as both control groups, fishmeal/fish oil and plant meal/fish oil. Dietary cholesterol supplementation increased plasma cholesterol levels and EPA in fillets (P < 0.05). Two-way ANOVA demonstrated that growth performance and muscle EPA content were significantly increased in fish fed cholesterol-supplemented diets. However, expression of genes involved in fatty acid biosynthesis were not enhanced by cholesterol, suggesting a potential disconnect between gene expression and functional activity. Although our hypothesis failed and soybean oil was found to be less accepted by the fish, resulting in lower growth and feed intake, we were successful in developing a high soy-protein diet (35%) with all-plant ingredients using linseed oil and supplemental cholesterol that resulted in equal fish performance to fish fed a fishmeal/fish oil control diet. More research is needed to identify a cost-effective EPA/DHA source to meet consumer needs and expectations for n-3 FA in trout fillets.

Glial cell reactivity drives cognitive decline in LDLr‐/‐ mice: experimental evidences

AbstractBackgroundFamilial hypercholesterolemia (FH) is a clinical condition characterized by increased plasma cholesterol levels, due to a mutation in the gene encoding the low‐density lipoprotein receptor (LDLr) in cells [Brown and Goldstein, 1984]. Importantly, clinical evidence indicates that FH negatively affects cognition and favors the development of neuropathologies [Ariza et al., 2016; Zambón et al, 2010], however, the mechanisms behind this relationship are still not fully understood. In this study we aimed to investigate the role of glial cell reactivity on the cognitive deficits related to the FH, as well as the possible neuroprotective effect of a pharmacological inhibitor of microglial cell activation.MethodFirstly, male 3‐months‐old and 14‐months‐old C57BL/6 wild‐type and LDLr knockout mice (LDLr‐/‐) mice brains were prepared for the evaluation of glial cell morphology by immunofluorescence. In addition, the mice’s hippocampus was removed to measure the immune content of synaptic and tight‐junctions proteins. Moreover, male and female 6‐months‐old C57BL/6 wild‐type and LDLr‐/‐ mice were treated with minocycline (50 mg/kg) or vehicle (saline) for four weeks. Afterwards, mice were submitted to behavioral tests.ResultMiddle‐aged LDLr‐/‐ mice (14‐months‐old) exhibited increased microgliosis in hippocampus, which was correlated with morphological change of microglial cells and astrocytes in this same brain region. Also, middle‐aged LDLr‐/‐ mice presented a reduction in the immune content of synaptophysin‐1 in the hippocampus. Moreover, young adult (3‐months‐old) LDLr‐/‐ mice exhibited reduced immune content of PSD95 in the hippocampus. Finally, the administration of minocycline to 6‐months‐old LDLr‐/‐ mice ameliorated the performance of hypercholesterolemic mice in hippocampal‐dependent memory tasks, without modifying their locomotor activity and metabolic parameters.ConclusionTaken together, our results demonstrated that FH alters the glial cell reactivity, which was associated with changes in synaptic proteins in the hippocampus. In addition, the pharmacological modulation of microglial cell reactivity ameliorated the hippocampal‐dependent memory in LDLr‐/‐ mice, suggesting that increased glial cell reactivity is a key event for HF‐related cognitive deficits.

Abstract 321: Altered Epha2 Signaling In Non-alcoholic Fatty Liver Disease Progression

Background: Nonalcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease worldwide, results from diet-induced hepatic steatosis that can result in hepatocyte ballooning, inflammation and fibrosis driving nonalcoholic steatohepatitis (NASH). The Eph receptors, the largest family of receptor tyrosine kinases in the mammalian genome, affect inflammation and fibrosis in other model systems, and we have shown that EphA2 deletion reduces atherosclerosis despite increasing plasma cholesterol levels. While a GWAS study has linked EphA2 to NAFLD, the potential role of EphA2 in NAFLD has never been investigated. Methods: EphA2 expression and signaling was assessed in mice fed a high fat diet (HFD) for 8 and 24 weeks, in human liver samples from NASH patients, and in HuH7 cells treated with palmitic acid (FA), low density lipoprotein (LDL), and/or fructose. Global EphA2 KO mice were fed a HFD for 12 weeks followed by histological and molecular analyses. Results: Mice with early-stage non-alcoholic fatty liver disease (NAFLD) showed elevated EphA2 expression along with markers of EphA2 ligand-dependent signaling (EphA2 tyrosine phosphorylation). Consistently, HuH7 cells treated with FA, LDL, and/or fructose displayed a similar enhancement of EphA2 expression upon treatment. However, a mouse model of late-stage NASH exhibited reduced expression of the EphA2 ligand ephrinA1 and elevated markers of ligand-independent signaling (Ser897 phosphorylation). Similarly, human liver samples from NASH patients show reduced ephrinA1 expression and elevated markers of EphA2 ligand independent signaling. Consistent with a role for EphA2 in NAFLD/NASH, global EphA2 KO mice show significantly lower indices of NAFLD following high fat diet feeding, including reduced liver-to-body weight ratios, hepatic steatosis, and inflammation. Conclusion: Taken together, our data demonstrate that EphA2 expression and signaling are altered during NAFLD/NASH pathogenesis and suggest that EphA2 inhibition may reduce NAFLD/NASH disease progression.

Limb-girdle muscular dystrophy type 2B causes HDL-C abnormalities in patients and statin-resistant muscle wasting in dysferlin-deficient mice

Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Duchenne MD (DMD) are caused by mutations to the Dysferlin and Dystrophin genes, respectively. We have recently demonstrated in typically mild dysferlin- and dystrophin-deficient mouse models that increased plasma cholesterol levels severely exacerbate muscle wasting, and that DMD patients display primary dyslipidemia characterized by elevated plasma cholesterol and triglycerides. Herein, we investigate lipoprotein abnormalities in LGMD2B and if statin therapy protects dysferlin-deficient mice (Dysf) from muscle damage. Herein, lipoproteins and liver enzymes from LGMD2B patients and dysferlin-null (Dysf) mice were analyzed. Simvastatin, which exhibits anti-muscle wasting effects in mouse models of DMD and corrects aberrant expression of key markers of lipid metabolism and endogenous cholesterol synthesis, was tested in Dysf mice. Muscle damage and fibrosis were assessed by immunohistochemistry and cholesterol signalling pathways via Western blot. LGMD2B patients show reduced serum high-density lipoprotein cholesterol (HDL-C) levels compared to healthy controls and exhibit a greater prevalence of abnormal total cholesterol (CHOL)/HDL-C ratios despite an absence of liver dysfunction. While Dysf mice presented with reduced CHOL and associated HDL-C and LDL-C-associated fractions, simvastatin treatment did not prevent muscle wasting in quadriceps and triceps muscle groups or correct aberrant low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) protein expression. LGMD2B patients present with reduced serum concentrations of HDL-C, a major metabolic comorbidity, and as a result, statin therapy is unlikely to prevent muscle wasting in this population. We propose that like DMD, LGMD2B should be considered as a new type of genetic dyslipidemia.

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins.

The copper metabolism MURR1 domains/coiled-coil domain containing 22/coiled-coil domain containing 93 (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear. We here investigated the contribution of retriever to hepatocytic lipoprotein receptor recycling and plasma lipids regulation. Using somatic CRISPR/Cas9 gene editing, we generated liver-specific VPS35L or VPS26C-deficient mice. We determined total and surface levels of LDLR and LRP1 and plasma lipids. In addition, we studied the protein levels and composition of CCC and retriever. Hepatocyte VPS35L deficiency reduced VPS26C levels but had minimal impact on CCC composition. VPS35L deletion decreased hepatocytic surface expression of LDLR and LRP1, accompanied by a 21% increase in plasma cholesterol levels. Hepatic VPS26C ablation affected neither levels of VPS35L and CCC subunits, nor plasma lipid concentrations. However, VPS26C deficiency increased hepatic LDLR protein levels by 2-fold, probably compensating for reduced LRP1 functioning, as we showed in VPS26C-deficient hepatoma cells. Upon PCSK9 (proprotein convertase subtilisin/kexin type 9)-mediated LDLR elimination, VPS26C ablation delayed postprandial triglyceride clearance and increased plasma triglyceride levels by 26%. Our study suggests that VPS35L is shared between retriever and CCC to facilitate LDLR and LRP1 transport from endosomes to the cell surface. Conversely, retriever subunit VPS26C selectively transports LRP1, but not LDLR, and thereby may control hepatic uptake of postprandial triglyceride-rich lipoprotein remnants.

Effect of Probiotic from Different Sources on Lipid Profile and Sugar on Patients with Hypercholesterolemia

For managing the digestive tract and immune system, probiotic has been recommended more frequently as an effective therapy and are known as the agent of cholesterol-lowering. The definition of hypercholesterolemia is, increase of plasma cholesterol levels excessively above 200 mg/dL, the patients may have a strong risk to cardiovascular disease. The aims of this study is used different types of probiotic sources of treating patients with hypercholesterolemia with no cardiovascular disease for 30 days. The results show that, there are significant differences (p &lt; 0.05) between cholesterol, Low-density lipoprotein (LDL) and High-density lipoprotein (HDL) before and after the consumption of probiotics from different sources, while triglyceride and glucose show there are no significant differences after 30 days (p &gt; 0.05).

Abstract 104: R952Q Mutation In ApoE Receptor-2 Exacerbates Hypercholesterolemia And Accelerates Atherosclerosis Progression In Ldl Receptor-knockout Mice

Background and objective: Apolipoprotein E Receptor-2 (apoER2) is a type I transmembrane receptor in the LDL receptor family and is expressed in vascular smooth muscle cells (VSMC), endothelium, and macrophages. An apoER2 mutation referred to as ApoER2-R952Q (R952Q) is associated with elevated plasma triglyceride levels and increased risk of premature coronary artery disease and myocardial infarction. Disease phenotypes emerging from the loss of apoER2 have been established, with results showing that apoER2 inactivation accelerates atherosclerosis progression through macrophage-mediated lipid accumulation and VSMC senescence to accelerate necrosis. This study investigated the effects of the R952Q mutation and its influence on atherosclerosis. Approach and results: We generated R952Q-expressing mice using a CRISPR-directed approach. This mouse line was crossed with the LDL-receptor knockout mouse line ( Ldlr -/- ) and the progenies were fed a high cholesterol diet for 24 weeks. Results showed that R952Q mice were similar to apoER2 knockout mice in displaying increased lesion necrosis compared to Ldlr -/- mice with functional apoER2. However, R952Q mutant mice differed from apoER2 knockout mice, exhibiting increased lipid accumulation in the lesion area. Plasma cholesterol levels were also elevated in the R952Q mutant mice compared to their apoER2 knockout counterparts. Interestingly, unlike the apoER2 deficient VSMCs, the R952Q mutation did not affect VSMC proliferation and showed no signs of accelerated senescence. Thus, the accelerated atherosclerosis observed in the R952Q mutant mice is not due to smooth muscle cell defects, and possibly due to increased plasma cholesterol levels. Additional experiments performed via bone marrow transplant of control and R952Q cells into Ldlr -/- mice showed that the R952Q bone marrow recipients recapitulated the elevated plasma cholesterol levels phenotype of the R952Q mice, suggesting a novel mechanism by which the R952Q mutation in macrophages may accelerate atherosclerosis. Conclusion: The R952Q mutation in apoER2 accelerates atherosclerosis via a gain-of-function mechanism in macrophages with a unique phenotype that exacerbates hypercholesterolemia.

Prevention of Triglyceridemia by (Non-)Anticoagulant Heparin(oids) Does Not Preclude Transplant Vasculopathy and Glomerulosclerosis.

Background: In renal transplantation, chronic transplant dysfunction (CTD) is associated with increased PCSK9 and dyslipidemia. PCSK9 is an enzyme that increases plasma cholesterol levels by downregulating LDLR expression. We recently showed increased PCSK9–syndecan-1 interaction in conditions of proteinuria and renal function loss. Treatment with heparin(oids) might be a therapeutic option to improve dyslipidemia and CTD. We investigated the effects of (non-)anticoagulant heparin(oids) on serum lipids, syndecan-1 and PCSK9 levels, and CTD development. Methods: Kidney allotransplantation was performed from female Dark Agouti to male Wistar Furth recipients. Transplanted rats received daily subcutaneous injections of saline, unfractionated heparin, and RO-heparin or NAc-heparin (2 mg heparin(oid)/kg BW) until sacrifice after 9 weeks of treatment. Results: Saline-treated recipients developed hypertension, proteinuria, and loss of creatinine clearance (all p < 0.05 compared to baseline), along with glomerulosclerosis and arterial neo-intima formation. Saline-treated recipients showed significant increase in plasma triglycerides (p < 0.05), borderline increase in non-HDLc/HDLc (p = 0.051), and ∼10-fold increase in serum syndecan-1 (p < 0.05), without significant increase in serum PCSK9 at 8 weeks compared to baseline. Heparin and non-anticoagulant RO-heparin administration in transplanted rats completely prevented an increase in triglycerides compared to saline-treated recipients at 8 weeks (both p < 0.05). Heparin(oids) treatment did not influence serum total cholesterol (TC), plasma syndecan-1 and PCSK9 levels, creatinine clearance, proteinuria, glomerulosclerosis, and arterial neo-intima formation, 8 weeks after transplantation. Combining all groups, increased syndecan-1 shedding was associated with TC (r = 0.5; p = 0.03) and glomerulosclerosis (r = 0.53; p = 0.021), whereas the non-HDLc/HDLc ratio was associated with the neo-intimal score in the transplanted kidneys (r = 0.65; p < 0.001). Conclusion: Prevention of triglyceridemia by (non-)anticoagulant heparin(oids) neither influenced PCSK9/syndecan-1 nor precluded CTD, which however did associate with the shedding of lipoprotein clearance receptor syndecan-1 and the unfavorable cholesterol profile.

Antioxidative Potential of Terminalia catappa L. Leaves in Reducing Plasma Ox-Ldl in Atherosclerosis

Atherosclerosis is an illness due to plaque build-up in the artery. The plaque, mainly consisted of fat, cholesterol, calcium would harden and narrows the blood vessels, interfering with the blood distribution. Hypercholesterolemia is one of the main causes of atherosclerosis. Arterial endothelial permeability alterations due to increasing plasma cholesterol levels allow LDL-C to migrate into the artery, resulting in a series of vascular changes. Several complications of atherosclerosis includes cardiac arrest, stroke, even death. Due to its fatality and lack of symptoms, it is crucial to prevent atherosclerosis. Terminalia catappa L. has been recognized for its antioxidative properties. It contains flavonoids, especially quercetin that exhibited protective effects in the cardiovascular system as well as hinders cellular damage. Various studies had found that quercetin possess several atheroprotective qualities, reducing inflammation and cell damage caused by ox-LDL, lipid precipitation, atherosclerotic plaque, as well as serum levels of ox-LDL, LDL-C, IL-6, and. TNF-. Keywords: atherosclerosis, Terminalia catappa L. leaves, ox-LDL, antioxidant, CVD.

Sex differences in the response to circadian disruption in diurnal sand rats

ABSTRACT Most animal model studies on physiological functions and pathologies are conducted in males. However, diseases such as depression, type 2 diabetes (T2DM) and cardiovascular disease, all show different prevalence and characteristics in females and males. Moreover, most mammal studies are conducted in nocturnal mice and rats, while modelling diurnal humans. We therefore used male and female fat sand rats (Psammomys obesus), which are diurnal in the wild, as an animal model for T2DM, to explore the effects of mild circadian disruption on behavior, glucose tolerance, cholesterol and heart weight. We found significant differences between the sexes: on average, in response to short photoperiods (SP) acclimation, males showed higher levels of depression-like behavior, lower glucose tolerance, and increased plasma cholesterol levels compared with females, with no effect on heart/body weight ratio. Females, however did show an increase in heart/body weight ratio in response to SP acclimation. We also found that regardless of sex, arrhythmic animals showed higher blood glucose levels, cholesterol levels, heart/body weight ratio, and depressive-like behavior compared with rhythmic animals. Hence, we suggest that the expression of the Circadian Syndrome could be different between males and females. Additional work with females is required to clearly delineate the specific effects in both sexes, and promote sex-based health care, prevention measures and therapies.

The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis

ObjectiveObesity-related chronic inflammation plays an important role in the development of Metabolic Associated Fatty Liver Disease (MAFLD). Although the contribution of the pro-inflammatory NF-κB signaling pathway to the progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is well-established, its role as an initiator of hepatic steatosis and the underlying mechanism remains unclear. Here, we investigated the hypothesis that the hepatocytic NF-κB signaling pathway acts as a metabolic regulator, thereby promoting hepatic steatosis development. MethodsA murine model expressing a constitutively active form of IKKβ in hepatocytes (Hep-IKKβca) was used to activate hepatocyte NF-κB. In addition, IKKβca was also expressed in hepatocyte A20-deficient mice (IKKβca;A20LKO). A20 is an NF-κB-target gene that inhibits the activation of the NF-κB signaling pathway upstream of IKKβ. These mouse models were fed a sucrose-rich diet for 8 weeks. Hepatic lipid levels were measured and using [1–13C]-acetate de novo lipogenesis and cholesterol synthesis rate were determined. Gene expression analyses and immunoblotting were used to study the lipogenesis and cholesterol synthesis pathways. ResultsHepatocytic NF-κB activation by expressing IKKβca in hepatocytes resulted in hepatic steatosis without inflammation. Ablation of hepatocyte A20 in Hep-IKKβca mice (IKKβca;A20LKO mice) exacerbated hepatic steatosis, characterized by macrovesicular accumulation of triglycerides and cholesterol, and increased plasma cholesterol levels. Both De novo lipogenesis (DNL) and cholesterol synthesis were found elevated in IKKβca;A20LKO mice. Phosphorylation of AMP-activated kinase (AMPK) - a suppressor in lipogenesis and cholesterol synthesis - was decreased in IKKβca;A20LKO mice. This was paralleled by elevated protein levels of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) and reduced phosphorylation of HMG-CoA reductase (HMGCR) both key enzymes in the cholesterol synthesis pathway. Whereas inflammation was not observed in young IKKβca;A20LKO mice sustained hepatic NF-κB activation resulted in liver inflammation, together with elevated hepatic and plasma cholesterol levels in middle-aged mice. ConclusionsThe hepatocytic IKK:NF-κB axis is a metabolic regulator by controlling DNL and cholesterol synthesis, independent of its central role in inflammation. The IKK:NF-κB axis controls the phosphorylation levels of AMPK and HMGCR and the protein levels of HMGCS1. Chronic IKK-mediated NF-κB activation may contribute to the initiation of hepatic steatosis and cardiovascular disease risk in MAFLD patients.

A High Fat/Cholesterol Diet Recapitulates Some Alzheimer's Disease-Like Features in Mice: Focus on Hippocampal Mitochondrial Dysfunction.

Ample evidence from clinical and pre-clinical studies suggests mid-life hypercholesterolemia as a risk factor for developing Alzheimer's disease (AD) at a later age. Hypercholesterolemia induced by dietary habits can lead to vascular perturbations that increase the risk of developing sporadic AD. To investigate the effects of a high fat/cholesterol diet (HFCD) as a risk factor for AD by using a rodent model of AD and its correspondent control (healthy animals). We compared the effect of a HFCD in normal mice (non-transgenic mice, NTg) and the triple transgenic mouse model of AD (3xTgAD). We evaluated cognitive performance in relation to changes in oxidative metabolism and neuron-derived nitric oxide (•NO) concentration dynamics in hippocampal slices as well as histochemical staining of markers of the neurovascular unit. In NTg, the HFCD produced only moderate hypercholesterolemia but significant decline in spatial memory was observed. A tendency for decrease in •NO production was accompanied by compromised mitochondrial function with decrease in spare respiratory capacity. In 3xTgAD mice, a robust increase in plasma cholesterol levels with the HFCD did not worsen cognitive performance but did induce compromise of mitochondrial function and significantly decreased •NO production. We found increased staining of biomarkers for astrocyte endfeet and endothelial cells in 3xTgAD hippocampi, which was further increased by the HFCD. A short term (8 weeks) intervention with HFCD can produce an AD-like phenotype even in the absence of overt systemic hypercholesterolemia and highlights mitochondrial dysfunction as a link between hypercholesterolemia and sporadic AD.

Cerebrotendinous xanthomatosis without neurological involvement.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism. Neurological symptoms are considered to be a clinical hallmark of untreated adult patients. We describe a 'milder CTX phenotype', without neurological involvement. We performed a retrospective patient file study in 79 genetically confirmed Dutch patients with CTX (55 patients aged≥21years) to study the clinical heterogeneity of CTX. We studied the frequency of adult patients with CTX without neurological involvement at diagnosis, in our Dutch cohort, and included a family from South Africa and patients from Italy, USA, Chile and Asia from the literature. In total, we describe 19 adult patients with CTX from 16 independent families, without neurological symptoms at diagnosis. A relatively small percentage (21%, n=4) had a history of cataract. The majority, 84% (n=16), presented with tendon xanthomas as the sole or predominant feature. The majority of patients showed increased plasma cholesterol levels. No correlation was found between this 'milder phenotype', the cholestanol levels and the CYP27A1 genotype. In addition, we describe three novel mutations in the CYP27A1 gene. This study shows the clinical heterogeneity of CTX, highlighting the existence of a 'milder phenotype', that is without neurological involvement at diagnosis. Adult patients with CTX may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia. It is important to realize that the absence of neurological symptoms does not rule out the development of future neurological symptoms. As CTX is a treatable disorder, early diagnosis and initiation of treatment when additional clinical signs occur is therefore essential.

Co-repressing immunometabolic processes in atherosclerosis

Cardiovascular disease is the primary cause of mortality in the world, and tightly associated with the metabolic syndrome, which is a cluster of interconnected metabolic dysfunctions including insulin resistance, obesity, hypertension and dyslipidaemias. These dysfunctions increase the risk of developing atherosclerosis and consequent cardiovascular diseases, such as myocardial infarction and stroke. Atherosclerosis is primarily triggered by increased plasma cholesterol levels and can be classified as an immunometabolic disease, a chronic disease that is affected by both metabolic and inflammatory triggers and/or mediators. These triggers and mediators activate common downstream pathways, including nuclear receptor signalling. Interestingly, specific cofactors that bind to these complexes act as immunometabolic integrators. This review provides examples of such co-regulator complexes, including nuclear sirtuins, nuclear receptor co-repressor 1 (NCOR1), nuclear receptor interacting protein 1 (NRIP1), and prospero homeobox 1 (PROX1). Their study might provide novel insight into mechanistic regulations and the identification of new targets to treat atherosclerosis.

Effect of Seaweed Ethanol Extract on Cholesterol Levels and Obesity in White Rats

Seaweed (EucheumaCottonii J. Agardh) is one of the biological resources found in coastal and marine areas. Seaweed contains secondary metabolites such as flavonoids, alkaloids, polyphenols and tannins which can reduce cholesterol levels in the blood. This study aims to determine the effect of seaweed ethanol extract on reducing cholesterol and obesity levels by comparing plasma cholesterol levels, body weight, and weight of vital organs (liver, kidneys and jantumg) of obese rats, mice given seaweed ethanol extract with normal mice . Rats were grouped randomly into 6 groups. group one was given 0.5% CMC Na, group two was given high fat diet food, group three was given simvastatin, group four was given seaweed ethanol extract 100 mg / kgbb, group five was given ethanol extract of seaweed 200 mg / kgbb and group six was given ethanol extract of seaweed 300 mg / kg with a long suspension of extract for 14 days. Measurement of cholesterol levels in the blood using the CHOD-PAP method, body weight and organs carried out by weighing. The results showed that seaweed ethanol extract has the effect of inhibiting an increase in plasma cholesterol levels and has anti-obesity potential at a dose of 300 mg / kgbb.

High Cholesterol Diet Exacerbates Blood-Brain Barrier Disruption in LDLr-/- Mice: Impact on Cognitive Function.

Background:Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr–/–), a mouse model of familial hypercholesterolemia.Objective:Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr–/–mice.Methods:Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/–mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi.Results:A tenfold elevation in plasma cholesterol levels of LDLr–/–mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr–/–mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr–/–mice treated with a hypercholesterolemic diet. The LDLr–/–mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr–/–mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice.Conclusion:Therefore, LDLr–/–mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.