RESUMO
Hyperlipidaemia is a recognised risk factor for cardiovascular disease. In this study, the antihyperlipidaemic properties of spirulina (Arthrospira platensis, strain S2 from Serbia) were tested in adult Wistar rats before and after induction of hypercholesterolaemia by a high-fat diet (HFD) to compare the preventive with the curative effect. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT) and aspartate transaminase (AST) levels were measured in the blood samples. The chemical composition (lipids, proteins and cholesterol) and the content of bile acids in the faeces of the animals were also analysed. Feeding rats with an atherogenic diet for 10 weeks led to the successful development of hyperlipidaemia, as serum TC and LDL-C levels as well as lipids, cholesterol and bile acids in the animals' faeces were significantly increased. Pre- and post-treatment with spirulina led to a reduction in serum LDL, TC and ALT levels. Administration of spirulina resulted in both a significant increase in primary bile acids excretion and a decrease in bile acids metabolism, with pre-treatment being more effective than post-treatment in some cases. These results suggest that increased excretion of bile acids as well as an effect on the gut microbiota may be the mechanism responsible for the anti-hyperlipidaemic activity of the tested spirulina strain.
Assuntos
Ácidos e Sais Biliares , Dieta Hiperlipídica , Fezes , Hipercolesterolemia , Ratos Wistar , Spirulina , Animais , Dieta Hiperlipídica/efeitos adversos , Hipercolesterolemia/etiologia , Ácidos e Sais Biliares/metabolismo , Masculino , Fezes/microbiologia , Fezes/química , Ratos , Colesterol/sangue , LDL-Colesterol/sangue , Probióticos/farmacologia , Aspartato Aminotransferases/sangue , Alanina Transaminase/sangue , HDL-Colesterol/sangue , Lipídeos/sangue , Modelos Animais de DoençasRESUMO
Scope: fructose consumption from added sugars correlates with the epidemic rise in MetS and CVD. Maternal fructose intake has been described to program metabolic diseases in progeny. However, consumption of fructose-containing beverages is allowed during gestation. Cholesterol is also a well-known risk factor for CVD. Therefore, it is essential to study Western diets which combine fructose and cholesterol and how maternal fructose can influence the response of progeny to these diets. Methods and results: a high-cholesterol (2%) diet combined with liquid fructose (10%), as a model of an unhealthy Western diet, was administered to descendants from control and fructose-fed mothers. Gene (mRNA and protein) expression and plasma, fecal and tissue parameters of cholesterol metabolism were measured. Interestingly, progeny from fructose-fed dams consumed less liquid fructose and cholesterol-rich chow than males from control mothers. Moreover, descendants of fructose-fed mothers fed a Western diet showed an increased cholesterol elimination through bile and feces than males from control mothers. Despite these mitigating circumstances to develop a proatherogenic profile, the same degree of hypercholesterolemia and severity of steatosis were observed in all descendants fed a Western diet, independently of maternal intake. An increased intestinal absorption of cholesterol, synthesis, esterification, and assembly into lipoprotein found in males from fructose-fed dams consuming a Western diet could be the cause. Moreover, an augmented GLP2 signalling seen in these animals would explain this enhanced lipid absorption. Conclusions: maternal fructose intake, through a fetal programming, makes a Western diet considerably more harmful in their descendants than in the offspring from control mothers.
Assuntos
Colesterol , Dieta Ocidental , Frutose , Animais , Frutose/efeitos adversos , Frutose/administração & dosagem , Feminino , Masculino , Ratos , Dieta Ocidental/efeitos adversos , Gravidez , Colesterol/metabolismo , Colesterol/sangue , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Fenômenos Fisiológicos da Nutrição Materna , Fígado/metabolismo , Hipercolesterolemia/metabolismo , Hipercolesterolemia/etiologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: In Morocco carob fruits are used traditionally to treat hypercholesterolemia, diabetes and related diseases. AIMS: This study was designed to evaluate the hypolipidemic activity of Ceratonia siliqua green pods extract and its fractions in Triton WR-1339 and high fat/cholesterol diet (HFCD) induced hyperlipidemia mice, as well as their ability to prevent lipoproteins oxidation in vitro. MATERIALS AND METHODS: High performance liquid chromatography (HPLC) analysis was used to determine the phenolic composition of the immature carob pods extract (HWCE). Antioxidant activities were evaluated using the DPPH radical scavenging test as well as MDA measurement in oxidized lipoprotein rich plasma. Plasma lipids, glucose and biliary total cholesterol, as well as lipids level in liver and feces, were analyzed. The acute oral toxicity was performed in mice single dosed with the HWCE at 2000 and 5000 mg/kg body weight. RESULTS: HPLC analysis shows that gallic acid is the main phenolic compound in the HWCE. The acute oral toxicity assessment revealed that the HWCE is not toxic (LD50 is greater than 5000 mg/kg body weight). In the acute hypolipidemic study, mice treated with the HWCE and its fractions exhibited a significant (P < 0.001) reduction in plasma total cholesterol (TC), triglycerides (TG) and low density lipoprotein-cholesterol (LDL-C) levels. Importantly, immature carob aqueous extract was more effective in lowering mice hypercholesterolemia than its fractions. Indeed, mice fed the HFCD for 12 weeks showed a significant raise in plasma TC, TG and LDL-C, as well as in hepatic and fecal TC and TG levels. The HWCE at 100 and 200 mg/kg body weight significantly (P < 0.001) reversed the plasmatic levels of these lipid parameters, increased plasma HDL-C level, reduced hepatic lipids accumulation, but increased cholesterol level in the bile and fecal lipids excretion. The HWCE decreased also the atherogenic index, the LDL-C/HDL-C ratio and plasma glucose level after 12 weeks' experiment. On the other hand, the HWCE was more effective in preventing mice lipoprotein-rich plasma oxidation than its fractions, with a concentration-dependent manner. CONCLUSION: C. siliqua green fruits extract could be effective in preventing atherosclerosis and related cardiovascular complications through the inhibition of lipoprotein oxidation and cholesterol clearance.
Assuntos
Aterosclerose , Fabaceae , Galactanos , Hipercolesterolemia , Hiperlipidemias , Mananas , Gomas Vegetais , Camundongos , Animais , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , LDL-Colesterol , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Metabolismo dos Lipídeos , Hiperlipidemias/tratamento farmacológico , Triglicerídeos/metabolismo , Fígado , Lipoproteínas , Aterosclerose/tratamento farmacológico , Peso Corporal , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/metabolismoRESUMO
There is increasing evidence that hypercholesterolemia has an intrauterine developmental origin. However, the pathogenesis of fetal-originated is still lacking in a theoretical system, which makes its clinical early prevention and treatment difficult. It has been found that an adverse environment during pregnancy (e.g., xenobiotic exposure) may lead to changes in fetal blood cholesterol levels through changing maternal cholesterol metabolic function and/or placental cholesterol transport function and may also directly affect the liver cholesterol metabolic function of the offspring in utero and continue after birth. Adverse environmental conditions during pregnancy may also raise maternal glucocorticoid levels and promote the placental glucocorticoid barrier opening, leading to fetal overexposure to maternal glucocorticoids. Intrauterine high-glucocorticoid exposure can alter the liver cholesterol metabolism of offspring, resulting in an increased susceptibility to hypercholesterolemia after birth. Abnormal epigenetic modifications are involved in the intrauterine programming mechanism of fetal-originated hypercholesterolemia. Some interventions targeted at pregnant mothers or offspring in early life have been proposed to effectively prevent and treat the development of fetal-originated hypercholesterolemia. In this paper, the recent research progress on fetal-originated hypercholesterolemia was reviewed, with emphasis on intrauterine maternal glucocorticoid programming mechanisms, in order to provide a theoretical basis for its early clinical warning, prevention, and treatment.
Assuntos
Hipercolesterolemia , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Feminino , Hipercolesterolemia/prevenção & controle , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Glucocorticoides/metabolismo , Placenta/metabolismo , Colesterol , Epigênese Genética , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To investigate the relationships of low-density lipoprotein cholesterol and statin usage with pseudarthrosis following single-level posterior or transforaminal lumbar interbody fusion (PLIF/TLIF). SUMMARY OF BACKGROUND DATA: Hypercholesterolemia can lead to atherosclerosis of the segmental arteries, which branch into vertebral bone through intervertebral foramina. According to the vascular hypothesis of disc disease, this can lead to ischemia of the lumbar discs and contribute to lumbar degenerative disease. Yet, little has been reported regarding the effects of cholesterol and statins on the outcomes of lumbar fusion surgery. MATERIALS AND METHODS: TriNetX, a global federated research network, was retrospectively queried to identify 52,140 PLIF/TLIF patients between 2002 and 2021. Of these patients, 2137 had high cholesterol (≥130 mg/dL) and 906 had low cholesterol (≤55 mg/dL). Perioperatively, 18,275 patients used statins, while 33,415 patients did not. One-to-one propensity score matching for age, sex, race, and comorbidities was conducted to balance the analyzed cohorts. The incidence of pseudarthrosis was then assessed in the matched cohorts within the six-month, one-year, and two-year postoperative periods. RESULTS: After propensity score matching, high-cholesterol patients had greater odds of developing pseudarthrosis six months [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.28-2.33], one year (OR: 1.59, 95% confidence interval (CI): 1.20-2.10), and two years (OR: 1.57, 95% CI: 1.20-2.05) following a PLIF/TLIF procedure. Patients with statin usage had significantly lower odds of developing pseudarthrosis six months (OR: 0.74, 95% CI: 0.69-0.79), one year (OR: 0.76, 95% CI: 0.71-0.81), and two years (OR: 0.77, 95% CI: 0.72-0.81) following single-level PLIF/TLIF. CONCLUSIONS: The findings suggest that patients with hypercholesterolemia have an increased risk of developing pseudarthrosis following PLIF/TLIF while statin use is associated with a decreased risk. The data presented may underscore an overlooked opportunity for perioperative optimization in lumbar fusion patients, warranting further investigation in this area.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Pseudoartrose , Fusão Vertebral , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Retrospectivos , Vértebras Lombares/cirurgia , LDL-Colesterol , Pseudoartrose/epidemiologia , Pseudoartrose/etiologia , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/etiologia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodosRESUMO
INTRODUCTION: Liver transplantation (LTx) is the only successful treatment for end-stage liver disease. The results of liver transplantation depend not only on graft survival but may be also affected by superimposed cardiovascular morbidities. The aim of this retrospective study was to assess the prevalence of lipid disorders as one of the important cardiovascular risk factors in patients before and after successful LTx. MATERIAL AND METHODS: One hundred eleven patients who underwent liver transplantation because of liver cirrhosis and survived at least 2 years with functioning graft between November 2005 and May 2014 were included in this retrospective analysis. The mean age of the patients at the time of liver transplantation was 49.7±12.2 years. The prevalence of dyslipidemia was assessed before and two years after liver transplantation. This was analyzed in relation to the etiology of liver disease, including alcohol toxicity, viral or autoimmune diseases. RESULTS: The prevalence of hypertriglyceridemia before and after LTx was 13.5% and 40.5%, respectively (P<0.001). Similarly, hypercholesterolemia was noted in 17.1% and 51.4% respectively (P<0.001). The annual incidence of hypertriglyceridemia and hypercholesterolemia during the first two years after LTx was 16.2% and 20.7%, respectively. The prevalence of hypertriglyceridemia (18.5% vs 66.7%, P<0.001) and hypercholesterolemia (29.6% vs 70.0%, P=0.002) was significantly lower in patients with the autoimmune cause of liver cirrhosis in comparison to patients with the alcoholic liver disease. CONCLUSIONS: The prevalence of dyslipidemia is increased after liver transplantation. The prevalence of dyslipidemia may be related to the cause of liver injury before LTx.
Assuntos
Hipercolesterolemia , Hipertrigliceridemia , Transplante de Fígado , Humanos , Adulto , Pessoa de Meia-Idade , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Hipercolesterolemia/etiologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/cirurgia , Hipertrigliceridemia/etiologia , LipídeosRESUMO
Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide, and hypercholesterolemia is a central risk factor for atherosclerosis. This study evaluated the effects of Totum-070, a plant-based polyphenol-rich supplement, in hamsters with high-fat diet (HFD)-induced dyslipidemia. The molecular mechanisms of action were explored using human Caco2 enterocytes. Totum-070 supplementation reduced the total cholesterol (-41%), non-HDL cholesterol (-47%), and triglycerides (-46%) in a dose-dependent manner, compared with HFD. HFD-induced hepatic steatosis was also significantly decreased by Totum-070, an effect associated with the reduction in various lipid and inflammatory gene expression. Upon challenging with olive oil gavage, the post-prandial triglyceride levels were strongly reduced. The sterol excretion in the feces was increased in the HFD-Totum-070 groups compared with the HFD group and associated with reduction of intestinal cholesterol absorption. These effects were confirmed in the Caco2 cells, where incubation with Totum-070 inhibited cholesterol uptake and apolipoprotein B secretion. Furthermore, a microbiota composition analysis revealed a strong effect of Totum-070 on the alpha and beta diversity of bacterial species and a significant decrease in the Firmicutes to Bacteroidetes ratio. Altogether, our findings indicate that Totum-070 lowers hypercholesterolemia by reducing intestinal cholesterol absorption, suggesting that its use as dietary supplement may be explored as a new preventive strategy for cardiovascular diseases.
Assuntos
Aterosclerose , Hipercolesterolemia , Hiperlipidemias , Cricetinae , Animais , Humanos , Hipercolesterolemia/etiologia , Extratos Vegetais/farmacologia , Extratos Vegetais/metabolismo , Dieta Hiperlipídica/efeitos adversos , Polifenóis/farmacologia , Polifenóis/metabolismo , Células CACO-2 , Mesocricetus , Colesterol/metabolismo , Hiperlipidemias/metabolismo , Triglicerídeos/metabolismo , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Aterosclerose/metabolismo , Fígado/metabolismoRESUMO
OBJECTIVE: Although it has been suggested that one-anastomosis gastric bypass (OAGB) is metabolically superior to the "gold standard," i.e., Roux-en-Y gastric bypass (RYGB), there is little robust evidence to prove it. Because this result may arise from the typically longer length of bypassed intestine in OAGB, here, the authors standardized the bypass length in RYGB and OAGB and compared weight loss and metabolic outcomes in a randomized controlled trial. METHODS: The authors randomized 121 bariatric patients to RYGB (n = 61) or OAGB (n = 60) in two Finnish University Hospitals and measured weight; body composition; metabolic features (insulin sensitivity, lipids, inflammation, nutrition); and comorbidities before and 6 and 12 months after the operation. RESULTS: Total weight loss was similar in RYGB and OAGB at 6 months (mean: 21.2% [95% CI: 19.4-23.0] vs. 22.8% [95% CI: 21.5-24.1], p = 0.136) and 12 months (25.4% [95% CI: 23.4-27.5] vs. 26.1% [95% CI: 24.2-28.9], p = 0.635). Insulin sensitivity, lipids, and inflammation improved similarly between the groups (p > 0.05). Remission of type 2 diabetes and hypercholesterolemia was marked and similar (p > 0.05) but the use of antihypertensive medications was lower (p = 0.037) and hypertension tended to improve more (p = 0.053) with RYGB versus OAGB at 12 months. Higher rates of vitamin D-25 deficiency (p < 0.05) and lower D-25 levels were observed with OAGB versus RYGB throughout the follow-up (p < 0.001). No differences in adverse effects were observed. CONCLUSIONS: RYGB and OAGB were comparable in weight loss, metabolic improvement, remission of diabetes and hypercholesterolemia, and nutrition at 1-year follow-up. Vitamin D-25 deficiency was more prevalent with OAGB, whereas reduction in antihypertensive medications and hypertension was greater with RYGB. There is no need to change the current practices of RYGB in favor of OAGB.
Assuntos
Diabetes Mellitus Tipo 2 , Derivação Gástrica , Hipercolesterolemia , Hipertensão , Resistência à Insulina , Obesidade Mórbida , Humanos , Derivação Gástrica/efeitos adversos , Obesidade Mórbida/cirurgia , Diabetes Mellitus Tipo 2/cirurgia , Diabetes Mellitus Tipo 2/etiologia , Hipercolesterolemia/cirurgia , Hipercolesterolemia/etiologia , Anti-Hipertensivos , Hipertensão/etiologia , Redução de Peso , Inflamação/etiologia , Vitamina D , Lipídeos , Estudos Retrospectivos , GastrectomiaRESUMO
Platelet activation and proprotein convertase subtilisin kexin 9 (PCSK9) play pivotal roles in the progression of atherosclerosis to cardiovascular events. It has been reported that hyperlipidemia, a well-documented risk factors for cardiovascular diseases, tends increase platelet activation and PCSK9 expression. However, little is known about this specific mechanism, particularly how nutrition affects platelet activation and PCSK9 levels in hyperlipidemia conditions. This study aimed to assess how a high-fat diet influences platelet activation, its association with PCSK9, and the effects on blood pressure in an animal model. Here, male Wistar rats were divided into four groups, subjected to different high-fat diets for ten weeks with varying nutrient components. The results showed that high-fat diet-induced hypercholesterolemia and hypertriglyceridemia significantly increased the plasma levels of ß-thromboglobulin (ß-TG), p-selectin, and platelet factor 4 (PF-4). The blood pressure readings were also elevated post high-fat diet induction. Interestingly, the group with the highest percentage of saturated fatty acid and trans-fat exhibited the highest PCSK9 levels, along with the highest increase in plasma cholesterol, triglycerides, and platelet activation parameters. These findings confirm that high-fat diet-induced hypercholesterolemia and hypertriglyceridemia stimulate platelet activity and PCSK9 levels. Moreover, our results suggest that PCSK9, implicated in hypercholesterolemia and hypertriglyceridemia, may synergistically mediate platelet hyperactivity, aligning with clinical studies. Notably, our results highlight the association between a high-fat diet and PCSK9, providing insights for drug discovery targeting platelet activation in atherosclerosis-induced cardiovascular diseases.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Hipercolesterolemia , Hiperlipidemias , Hipertrigliceridemia , Animais , Ratos , Masculino , Pró-Proteína Convertase 9 , Hipercolesterolemia/etiologia , Dieta Hiperlipídica/efeitos adversos , Subtilisina , Ratos Wistar , Pró-Proteína Convertases/metabolismo , Aterosclerose/etiologia , Ativação PlaquetáriaRESUMO
PURPOSE: Hypercholesterolemia due to a high-cholesterol diet is linked to numerous diseases and may lead to male infertility. However, the underlying mechanism remains unknown. The maintenance of male fertility requires intact testicular structures (including seminiferous tubules and mesenchyme) and functioning cells (Leydig cells, Sertoli cells and germ cells, etc.), production of appropriate concentrations of sex hormones, and cooperation among testicular cells. Thus, we considered whether male fertility declined as the structure and function of testicular cells were altered in rats on a high-cholesterol diet. METHODS: Male Sprague Dawley rats were fed either a standard or a high-cholesterol diet for 16 weeks. Serum sex hormones, lipid components, semen quality, and fertility rate were assayed in the rats. The 3ß-hydroxysteroid dehydrogenase (3ß-HSD), Wilms tumor 1 (WT-1), and deleted in azoospermia-like (DAZL) were regarded as specific markers of Leydig, Sertoli, and germ cells in rats. In addition, the ultrastructure of the testis and expression levels of particular marker molecules of testicular cells were further investigated. RESULTS: Compared to rats fed on a regular diet, the serum testosterone levels and sperm progressive motility decreased in rats fed high cholesterol. Moreover, we observed a deformed nucleus, dilated smooth endoplasmic reticulum, and swollen mitochondria of Leydig cells and a schizolytic nucleus of Sertoli cells in rats on a high-cholesterol diet. The 3ß-HSD, WT-1, and DAZL protein expression levels were significantly reduced in rats on a high-cholesterol diet. CONCLUSIONS: Our results showed that a high-cholesterol diet adversely affected testosterone production and sperm progressive motility, possibly due to Leydig, Sertoli, and germ cell abnormalities.
Assuntos
Hipercolesterolemia , Doenças Testiculares , Humanos , Masculino , Ratos , Animais , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Análise do Sêmen , Ratos Sprague-Dawley , Sêmen , Testículo/fisiologia , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Testosterona , Doenças Testiculares/etiologia , Dieta , ColesterolRESUMO
BACKGROUND: Obesity has reached epidemic proportions among adolescents. Methods, such as bariatric surgery, have become the most effective treatment for patients with classes III and IV obesity. AIM: To evaluate weight loss, comorbidity remission, and long-term results of bariatric surgery in adolescents. METHODS: Study with adolescent patients undergoing bariatric surgery, evaluating laboratory tests, comorbidities, and the percentage of excess weight loss in the preoperative period and at one, two, and five years postoperatively. RESULTS: A total of 65 patients who met the inclusion criteria, with a mean age of 18.6 years, were included in the analysis. In the preoperative period, 30.8% of hypercholesterolemia, 23.1% of systemic arterial hypertension, and 18.4% of type 2 diabetes were recorded, with remission of these percentages occurring in 60, 66.7 and 83.4%, respectively. The mean percentage of excess weight loss was 63.48% after one year of surgery, 64.75% after two years, and 57.28% after five years. The mean preoperative total cholesterol level was 180.26 mg/dL, and after one, two, and five years, it was 156.89 mg/dL, 161.39 mg/dL, and 150.97 mg/dL, respectively. The initial mean of low-density lipoprotein was 102.19mg/dL and after five years the mean value reduced to 81.81 mg/dL. The mean preoperative glycemia was 85.08 mg/dL and reduced to 79.13 mg/dL after one year, and to 76.19 mg/dL after five years. CONCLUSIONS: Bariatric surgery is safe and effective in adolescents, with low morbidity, resulting in a loss of excess weight and long-term stability, improving laboratory tests, and leading to remission of comorbidities, such as diabetes mellitus, hypercholesterolemia, and systemic arterial hypertension.
Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Hipercolesterolemia , Hipertensão , Laparoscopia , Obesidade Mórbida , Humanos , Adolescente , Diabetes Mellitus Tipo 2/cirurgia , Seguimentos , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/etiologia , Hipercolesterolemia/cirurgia , Obesidade/cirurgia , Resultado do Tratamento , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipertensão/cirurgia , Redução de Peso , Laparoscopia/métodos , Obesidade Mórbida/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: Hypercholesterolemia is associated with tendon pathology, but the reasons underpinning this relationship are not well understood. Cholesterol can accumulate in the tendon non-collagenous matrix which may affect both global and local tissue mechanics. Changes to the local strain environment within tendon may have significant implications for mechanosensitive tenocytes. Here, we investigated the association between elevated blood cholesterol and presence of tendon lipids in the Achilles tendon. We expected lipids to be localised in the proteoglycan-rich inter-sub-tendon matrix (ISTM), therefore we also sought to examine the impact of this on the biomechanical and viscoelastic properties of the ISTM. METHODS: The Achilles tendons of 32 young wild-type (SD) and 32 apolipoprotein E knock-out rats (ApoE-/-) were harvested at 15.6 ± 2.3 weeks of age. 32 specimens underwent histological examination to assess the distribution of lipids throughout sub-tendons and ISTM. The remaining specimens were prepared for biomechanical testing, where the ISTM between the gastrocnemius and soleus sub-tendons was subjected to shear load mechanical testing. A sub-set of tests were video recorded to enable a strain analysis. RESULTS: ApoE-/- serum cholesterol was double that of SD rats (mean 2.25 vs. 1.10 mg/ml, p < 0.001) indicating a relatively mild hypercholesterolemia phenotype. Nonetheless, we found histological evidence of esterified lipids in the ISTM and unesterified lipids in the sub-tendons, although the location or intensity of staining was not appreciably different between rat strains. Despite a lack of observable histological differences in lipid content between groups, there were significant differences in the mechanical and viscoelastic behaviour of the Achilles sub-tendon matrix. CONCLUSION: Even slightly elevated cholesterol may result in subtle changes to tendon biomechanical properties and hence injury risk. The young age of our cohort and the mild phenotype of our ApoE-/- rats are likely to have limited our findings and so we also conclude that the ApoE-/- rat model is not well suited for investigating the biomechanical impact of tendon xanthomas on Achilles sub-tendon function.
Assuntos
Tendão do Calcâneo , Hipercolesterolemia , Ratos , Animais , Tendão do Calcâneo/lesões , Ratos Sprague-Dawley , Hipercolesterolemia/etiologia , Hipercolesterolemia/patologia , Fenômenos Biomecânicos , ColesterolRESUMO
Prion diseases are fatal and infectious neurodegenerative diseases that occur in humans and animals. They are caused by the misfolding of the cellular prion protein PrPc into the infectious isoform PrPSc. PrPSc accumulates mostly in endolysosomal vesicles of prion-infected cells, eventually causing neurodegeneration. In response to prion infection, elevated cholesterol levels and a reduction in membrane-attached small GTPase Rab7 have been observed in neuronal cells. Here, we investigated the molecular events causing an impaired Rab7 membrane attachment and the potential mechanistic link with elevated cholesterol levels in prion infection. We demonstrate that prion infection is associated with reduced levels of active Rab7 (Rab7.GTP) in persistently prion-infected neuronal cell lines, primary cerebellar granular neurons, and neurons in the brain of mice with terminal prion disease. In primary cerebellar granular neurons, levels of active Rab7 were increased during the very early stages of the prion infection prior to a significant decrease concomitant with PrPSc accumulation. The reduced activation of Rab7 in prion-infected neuronal cell lines is also associated with its reduced ubiquitination status, decreased interaction with its effector RILP, and altered lysosomal positioning. Consequently, the Rab7-mediated trafficking of low-density lipoprotein to lysosomes is delayed. This results in an impaired feedback regulation of cholesterol synthesis leading to an increase in cholesterol levels. Notably, transient overexpression of the constitutively active mutant of Rab7 rescues the delay in the low-density lipoprotein trafficking, hence reducing cholesterol levels and attenuating PrPSc propagation, demonstrating a mechanistic link between the loss of Rab7.GTP and elevated cholesterol levels.
Assuntos
Hipercolesterolemia , Proteínas Monoméricas de Ligação ao GTP , Doenças Priônicas , Animais , Camundongos , Colesterol/metabolismo , Ativação Enzimática , Retroalimentação , Hipercolesterolemia/etiologia , Hipercolesterolemia/fisiopatologia , Lipoproteínas LDL/metabolismo , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Neurônios/metabolismo , Doenças Priônicas/metabolismo , Príons/metabolismo , Proteínas PrPSc/genética , Proteínas PrPSc/metabolismoRESUMO
The functional characteristics of Lactobacillus johnsonii BFE6154, first isolated from Maasai traditional fermented milk, were previously identified in vitro, but its cholesterol-lowering properties have not been verified yet. In this study, we investigated the effect of L. johnsonii BFE6154 on cholesterol regulation and the mode of action. Stimulation of Caco-2 intestinal epithelial cells with L. johnsonii BFE6154 downregulated the gene expression of Niemann-Pick C1-like 1 (NPC1L1) through the activation of liver X receptor (LXR). Also, stimulation of HepG2 cells with the metabolites produced by L. johnsonii BFE6154 revealed an increase in the gene expression of low-density lipoprotein receptor (LDLR). Oral administration of L. johnsonii BFE6154 in mice receiving a high-fat and high-cholesterol diet (HFHCD), reduced total cholesterol and low-density lipoprotein-cholesterol (LDL) and increased high-density lipoprotein-cholesterol (HDL) in the blood, compared to the control. Diet-induced hypercholesterolemic mice receiving L. johnsonii BFE6154 showed a suppression of cholesterol absorption under the control of NPC1L1 in the intestine. Furthermore, L. johnsonii BFE6154 consumption ameliorated the hepatic cholesterol level and LDLR expression, which was reduced by HFHCD. These molecular modulations led to the increase of cholesterol excretion and the decrease of cholesterol levels in the feces and liver, respectively. Taken together, these results suggest that L. johnsonii BFE6154 may protect against diet-induced hypercholesterolemia through the regulation of cholesterol metabolism in the intestine and liver.
Assuntos
Hipercolesterolemia , Lactobacillus johnsonii , Humanos , Camundongos , Animais , Hipercolesterolemia/etiologia , Hipercolesterolemia/terapia , Células CACO-2 , Proteínas de Membrana Transportadoras/metabolismo , Colesterol , Dieta , LDL-Colesterol/metabolismoRESUMO
Cholesterol is a lipid molecule of great biological importance to animal cells. Dysregulation of cholesterol metabolism leads to raised blood total cholesterol levels, a clinical condition called hypercholesterolemia. Evidence has shown that hypercholesterolemia is associated with the development of liver and heart disease. One of the mechanisms underlying heart and liver alterations induced by hypercholesterolemia is oxidative stress. In this regard, in several experimental studies, gold nanoparticles (AuNP) displayed antioxidant properties. We hypothesized that hypercholesterolemia causes redox system imbalance in the liver and cardiac tissues, and AuNP treatment could ameliorate it. Young adult male Swiss mice fed a regular rodent diet or a high cholesterol diet for eight weeks and concomitantly treated with AuNP (2.5 µg/kg) or vehicle by oral gavage. Hypercholesterolemia increased the nitrite concentration and glutathione (GSH) levels and decreased the liver's superoxide dismutase (SOD) activity. Also, hypercholesterolemia significantly enhanced the reactive oxygen species (ROS) and GSH levels in cardiac tissue. Notably, AuNP promoted the redox system homeostasis, increasing the SOD activity in hepatic tissue and reducing ROS levels in cardiac tissue. Overall, our data showed that hypercholesterolemia triggered oxidative stress in mice's liver and heart, which was partially prevented by AuNP treatment.
Assuntos
Hipercolesterolemia , Nanopartículas Metálicas , Camundongos , Animais , Masculino , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Ouro/metabolismo , Ouro/farmacologia , Ouro/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Colesterol , Estresse Oxidativo , Dieta , Fígado , Glutationa , Superóxido Dismutase/metabolismoRESUMO
High-density lipoproteins (HDL) undergo adverse remodeling and loss of function in the presence of comorbidities. We assessed the potential of lipid-lowering approaches (diet and rosuvastatin) to rescue hypercholesterolemia-induced HDL dysfunction. Hypercholesterolemia was induced in 32 pigs for 10 days. Then, they randomly received one of the 30-day interventions: (I) hypercholesterolemic (HC) diet; (II) HC diet + rosuvastatin; (III) normocholesterolemic (NC) diet; (IV) NC diet + rosuvastatin. We determined cholesterol efflux capacity (CEC), antioxidant potential, HDL particle number, HDL apolipoprotein content, LDL oxidation, and lipid levels. Hypercholesterolemia time-dependently impaired HDL function (−62% CEC, −11% antioxidant index (AOI); p < 0.01), increased HDL particles numbers 2.8-fold (p < 0.0001), reduced HDL-bound APOM (−23%; p < 0.0001), and increased LDL oxidation 1.7-fold (p < 0.0001). These parameters remained unchanged in animals on HC diet alone up to day 40, while AOI deteriorated up to day 25 (−30%). The switch to NC diet reversed HDL dysfunction, restored apolipoprotein M content and particle numbers, and normalized cholesterol levels at day 40. Rosuvastatin improved HDL, AOI, and apolipoprotein M content. Apolipoprotein A-I and apolipoprotein C-III remained unchanged. Lowering LDL-C levels with a low-fat diet rescues HDL CEC and antioxidant potential, while the addition of rosuvastatin enhances HDL antioxidant capacity in a pig model of hypercholesterolemia. Both strategies restore HDL-bound apolipoprotein M content.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apolipoproteínas M , Colesterol/uso terapêutico , HDL-Colesterol , Dieta , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Lipoproteínas HDL/uso terapêutico , Lipoproteínas LDL , Modelos Animais , Rosuvastatina Cálcica/farmacologia , Rosuvastatina Cálcica/uso terapêutico , SuínosRESUMO
There is an increased utilization of wholegrain cereals in food formulations considering their richness in essential nutritional and biological properties. In this study, each component (amaranth, acha and pearl millet) of the multigrain blend was individually pre-fermented. Thereafter, the pre-fermented grain flours were optimized to obtain two unique blends (90:5:5 and 47.98: 26.68:25.34) containing high protein content (~23% and 17%) and low glycemic index (~43). The optimum blends were processed into instant porridges (PR1, PR2) and analyzed for its nutritional composition, blood glucose lowering ability, antioxidant enzyme and tissue/serum biochemical makers modulatory ability in obese-diabetic animals. The porridge showed significant nutritional profile, consumption of formulated multigrain porridge reduced blood glucose level (by 62% and 66%), upregulated the antioxidant defense system to near normal levels likewise, significantly reduced serum biochemical parameters. Thus, suggests that the multigrain blends/porridge is nutrient-dense possessing beneficial effect to maintain antioxidant levels in the diabetic condition with potential to attenuate oxidative damage. PRACTICAL APPLICATIONS: Prolonged feeding with high-fat diet induces hypercholesterolemia in experimental animals. Further interperitoneal injection of streptozotocin induces experimental diabetes with a cascade of oxidative stress related complications in serum and tissue parameters. Porridge is a traditional meal while multigrain porridge is a nutrient dense meal which may exert curative effect. In this work, it was shown that dietary intervention with multigrain porridge product promoted positive weight control, portrayed hepatoprotective effect as shown by the elevated levels of biomarker (ALT, AST, ALP) and antioxidant enzymes (CAT, SOD, GPx) as well as modulation of serum lipid profile (total cholesterol, triglycerides, high density lipoprotein-cholesterol). Thus, the multigrain porridge may be a functional food product to combat hypercholesterolemia and hyperglycemia especially PR1 which appeared to be more efficient than PR2 in modulating oxidative stress, conferring hypoglycemic effect and lowering lipid levels in obese-diabetic rats model studied.
Assuntos
Diabetes Mellitus Experimental , Hipercolesterolemia , Hiperglicemia , Hiperlipidemias , Ratos , Animais , Ratos Wistar , Glicemia , Hipercolesterolemia/etiologia , Antioxidantes/farmacologia , Estresse Oxidativo , Valor Nutritivo , Triglicerídeos , HDL-Colesterol , ObesidadeRESUMO
We have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4+ and CD8+ T cells to ATP depends on their stage of differentiation. Here, we show that CD4+ and CD8+ T cells from B6 mice express different levels of membrane GM1 and P2X7 but similar levels of cholesterol. Thus, in CD4+ T cells, membrane cholesterol content negatively correlated with ATP/P2X7-induced CD62L shedding but positively correlated with pore formation, phosphatidylserine externalization, and cell death. By contrast, in CD8+ T cells, cholesterol, GM1, and P2X7 levels negatively correlated with all these ATP/P2X7-induced cellular responses. The relationship between cholesterol and P2X7-induced cellular responses was confirmed by modulating cholesterol levels either ex vivo or through a high-fat diet. Membrane cholesterol enrichment ex vivo led to a significant reduction in all P2X7-induced cellular responses in T cells. Importantly, diet-induced hypercholesterolemia in B6 mice was also associated with decreased sensitivity to ATP in CD4+ and CD8+ T cells, highlighting the relationship between cholesterol intake and the amplitudes of P2X7-induced cellular responses in T cells.
Assuntos
Linfócitos T CD8-Positivos , Hipercolesterolemia , Trifosfato de Adenosina/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica , Gangliosídeo G(M1)/metabolismo , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Camundongos , Receptores Purinérgicos P2X7/metabolismo , Subpopulações de Linfócitos T/metabolismoRESUMO
Emerging evidence suggests that "leanness" and good metabolic health markers may predict larger increases in LDL cholesterol (LDL-C) in response to carbohydrate restriction. Specifically, a recent cohort study demonstrated an inverse association between BMI and LDL-C change among individuals on carbohydrate-restricted diets and identified a subgroup of "Lean Mass Hyper-Responders" (LMHR) who exhibit exceptional increases in LDL-C, in the context of low triglycerides and high HDL-C. We present the case of one subject, LM, who adopted a ketogenic diet for management of ulcerative colitis. He subsequently experienced an increase in LDL-C from 95 to 545 mg/dl, at peak, in association with HDL-C >100 mg/dl and triglycerides ~40 mg/dl, typical of the emergent LMHR phenotype. Assessments of LM's dietary intake, lipid panels, and BMI are consistent with prior data and suggest that the LMHR phenomenon is not dependent on saturated fat intake but inversely associates with BMI changes. Finally, computed tomography angiography conducted on LM after over 2 years of hypercholesterolemia revealed no evidence of calcified or non-calcified plaque.