Elevated Plasma Total Cholesterol Research Articles

Subtherapeutic Kitasamycin Promoted Fat Accumulation in the Longissimus Dorsi Muscle in Growing-Finishing Pigs.

Kitasamycin (KM), a broad-spectrum macrolide antibiotic, has implications for growth performance and residue in animals and humans. This study aimed to explore the effects of different KM doses on intramuscular fat accumulation, cecal microflora, and short-chain fatty acids (SCFAs) using a growing-finishing pig model. Forty-two pigs were divided into three groups: control, subtherapeutic KM (50 mg/kg, KM50), and therapeutic KM (200 mg/kg, KM200) diets over 8 weeks. KM50 led to increased back fat thickness, fat content in the longissimus dorsi muscle (LM), and elevated plasma total cholesterol (TC) levels (p < 0.05), supported by upregulated lipid synthesis gene expression (Acc1, Fas, Scd1) (p < 0.05) in the LM. KM50 altered cecal microflora, reducing Lactobacillus spp. and Bifidobacterium spp. abundance, while increasing SCFA concentrations (acetic acid, propionic acid, total SCFAs) (p < 0.05). KM200 had minimal effects on intestinal weight and density, with increased apparent digestibility of nutrients. These findings highlight the dose-dependent impact of KM on intramuscular fat deposition. Subtherapeutic KM induced ectopic fat deposition, emphasizing potential risks in disease treatment for humans and animals.

Diet and Lipid-Lowering Nutraceuticals in Pediatric Patients with Familial Hypercholesterolemia.

Familial hypercholesterolemia is a genetically determined disease characterized by elevated plasma total and LDL cholesterol levels from the very first years of life, leading to early atherosclerosis. Nutritional intervention is the first-line treatment, complemented with nutraceuticals and drug therapy when necessary. Nutraceuticals with a lipid-lowering effect have been extensively studied in the past few decades, and have been recently included in international guidelines as a complement to nutritional and pharmacological treatment in subjects with dyslipidemia. In this review, we explore current nutritional interventions for dyslipidemia in childhood, with a specific focus on the main nutraceuticals studied for treating severe dyslipidemia in pediatric patients. Additionally, we briefly describe their primary mechanisms of action and highlight the advantages and risks associated with the use of lipid-lowering nutraceuticals in childhood.

Effects of Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination on inflammatory responses in atherosclerotic mice

The study aims to observe the effects and explore the mechanisms of Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination in the treatment of the inflammatory response of mice with atherosclerosis(AS) via the Toll-like receptor 4(TLR4)/myeloid differentiation primary response protein 88(MyD88)/nuclear factor-κB(NF-κB) signaling pathway. Male ApoE~(-/-) mice were randomly assigned into a model group, a Buyang Huanwu Decoction group, an Astragali Radix-Angelicae Sinensis Radix combination group, and an atorvastatin group, and male C57BL/6J mice of the same weeks old were used as the control group. Other groups except the control group were given high-fat diets for 12 weeks to establish the AS model, and drugs were administrated by gavage. Aortic intimal hyperplasia thickness, blood lipid level, plasma inflammatory cytokine levels, M1/M2 macrophage markers, and expression levels of proteins in TLR4/MyD88/NF-κB pathway in the vessel wall were measured to evaluate the effects of drugs on AS lesions and inflammatory responses. The results showed that the AS model was successfully established with the ApoE~(-/-) mice fed with high-fat diets. Compared with the control group, the model group showed elevated plasma total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c) levels(P&lt;0.05), thickened intima(P&lt;0.01), and increased plasma tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) levels(P&lt;0.01). Moreover, the model group showed increased expression of vascular cell adhesion molecule-1(VCAM-1) and inducible nitric oxide synthase(iNOS)(P&lt;0.01), inhibited expression of endothelial nitric oxide synthase(eNOS) and cluster of differentiation 206(CD206)(P&lt;0.01), and up-regulated mRNA and protein levels of TLR4, MyD88, NF-κB inhibitor alpha(IκBα), and NF-κB in the vessel wall(P&lt;0.05). Compared with the model group, Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination lowered the plasma TC and LDL-c levels(P&lt;0.01), alleviated the intimal hyperplasia(P&lt;0.01), and reduced the plasma TNF-α and IL-6 levels(P&lt;0.05). Moreover, the two interventions promoted the expression of eNOS and CD206(P&lt;0.05), inhibited the expression of VCAM-1 and iNOS(P&lt;0.01), and down-regulated the mRNA and protein levels of TLR4, MyD88, IκBα, and NF-κB(P&lt;0.05) in the vessel wall. This study indicated that Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination could delay the progression of AS, inhibit the polarization of vascular wall macrophages toward M1 type, and attenuate vascular inflammatory response by inhibiting the activation of TLR4/MyD88/NF-κB signaling pathway in the vascular wall. Astragali Radix and Angelicae Sinensis Radix were the main pharmacological substances in Buyang Huanwu Decoction for alleviating the AS vascular inflammatory response.

Trib1 Deficiency Promotes Hyperlipidemia, Inflammation, and Atherosclerosis in LDL Receptor Knockout Mice.

Genetic variants at the TRIB1 gene locus are strongly associated with plasma lipid traits and the risk of coronary artery disease in humans. Here, we analyzed the consequences of Trib1 deficiency on lipid metabolism and atherosclerotic lesion formation in atherosclerosis-susceptible Ldlr-/- mice. Trib1-/- mice were crossed onto the Ldlr-/- background to generate double-knockout mice (Trib1-/-Ldlr-/-) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol and 4.3% fat) until 20 weeks of age. Trib1-/-Ldlr-/- mice had profoundly larger (5.8-fold) and more advanced atherosclerotic lesions at the aortic root as compared with Trib1+/+Ldlr-/- controls. Further, we observed significantly elevated plasma total cholesterol and triglyceride levels in Trib1-/-Ldlr-/- mice, resulting from higher VLDL (very-low-density lipoprotein) secretion. Lipidomics analysis revealed that loss of Trib1 altered hepatic lipid composition, including the accumulation of cholesterol and proinflammatory ceramide species, which was accompanied by signs of hepatic inflammation and injury. Concomitantly, we detected higher plasma levels of IL (interleukin)-6 and LCN2 (lipocalin 2), suggesting increased systemic inflammation in Trib1-/-Ldlr-/- mice. Hepatic transcriptome analysis demonstrated significant upregulation of key genes controlling lipid metabolism and inflammation in Trib1-/-Ldlr-/- mice. Further experiments suggested that these effects may be mediated through pathways involving a C/EPB (CCAAT/enhancer binding protein)-PPARγ (peroxisome proliferator-activated receptor γ) axis and JNK (c-Jun N-terminal kinase) signaling. We provide experimental evidence that Trib1 deficiency promotes atherosclerotic lesion formation in a complex manner that includes the modulation of lipid metabolism and inflammation.

Plasma Total and Lipoprotein Cholesterol, Liver Cholesterol and Fecal Cholesterol Excretion in Hamsters Fed Fiber Diets

The effect of dietary fibers on plasma lipids, liver cholesterol and fecal cholesterol excretion was investigated in hamsters. Male 9- to 11-wk-old Golden-Syrian hamsters (n = 155) were fed a purified hypercholesterolemic diet (0.1% cholesterol, 10% fat) for 5 wk to elevate plasma lipid concentrations. Sixteen animals with elevated plasma total cholesterol were randomly assigned to each treatment group: control, oat bran, guar gum, cellulose, xylan and terminal groups. After 4 wk of fiber diet consumption, the plasma total cholesterol concentrations were significantly decreased in the oat bran, guar gum and xylan groups (16, 12 and 15%, respectively) (P < 0.05). Plasma HDL cholesterol concentration was significantly decreased only in the guar gum group (12%) (P < 0.05). The combined plasma VLDL+LDL cholesterol concentrations were significantly lowered by the oat bran, xylan and cellulose diets (38, 34 and 40%, respectively) (P < 0.05). After 4 wk of control diet consumption, the liver cholesterol concentration quadrupled to 10.6 mumol cholesterol/g liver (P < 0.05). After 4 wk of consumption of the treatment diets, liver cholesterol was further increased (P < 0.05) only in the cellulose group, to 14.5 mumol cholesterol/g liver. The total fecal cholesterol excretion was the highest (P < 0.05) in the oat bran group. In the present study, oat bran, guar gum and xylan were effective hypocholesterolemic agents in hamsters.

151-LB: Impact of Concurrent Use of Selective Serotonin Reuptake Inhibitors and Second-Generation Antipsychotic Medications on Cardiometabolic Health in Children

Around 20% of Canadian children are diagnosed with a mental health disorder. Selective serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotics (SGAs) are common treatments. Treatment with SSRIs or SGAs is associated with increased cardiometabolic complications, and risk for type 2 diabetes in children. Little is known about the metabolic effects of concurrent use of SSRIs with SGAs. Our aim was to determine if the combination of SSRI and SGA treatment was associated with cardiometabolic complications in children. Cross-sectional data were collected from children with mental health disorders (aged 5-18 years), recruited from Child and Adolescent Psychiatry at BC Children’s Hospital. Children were classified as naïve (n=242), SSRI-treated (n=123), SGA-treated (n=112), or SSRI+SGA treated (n=98). Anthropometric data and a fasting blood sample were collected. Relationships between treatment groups and cardiometabolic risk factors were determined by adjusted linear and logistic regression models. SSRI+SGA-treated children had higher waist circumference z-scores (0.91 ± 0.89 vs. 0.48 ± 0.95; P&amp;lt;0.05) and a greater odds of waist circumference ≥90th percentile (OR=2.63, 95% CI: 1.34, 5.18; P&amp;lt;0.05) compared to SSRI-treated children. SSRI+SGA-treated children had higher plasma total cholesterol (4.63 ± 0.93 vs. 4.34 ± 0.84 mmol/L; P&amp;lt;0.05, adjusted by age, sex, and BMI z-scores) and a greater odds of plasma total cholesterol ≥5.18 mmol/L (OR=2.36, 95% CI: 1.05, 5.30; P&amp;lt;0.05, adjusted by age, sex, and BMI z-scores) than SGA-treated children. No differences in plasma fasting glucose, insulin, or insulin resistance (HOMA-IR) were observed between the treatment groups. Concurrent SSRI+SGA treatment is associated with elevated waist circumference and plasma total cholesterol in children. Our findings suggest greater cardiometabolic complications in children concurrently treated with SSRIs and SGAs. Disclosure R. Thandi: None. A. M. Wiedeman: None. A. M. Devlin: None. C. Panagiotopoulos: Advisory Panel; Self; Dexcom, Inc., Speaker’s Bureau; Self; Eli Lilly and Company. Funding BC Mental Health and Substance Use Services

A spontaneously hypertensive diet-induced atherosclerosis-prone mouse model of metabolic syndrome

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.

URIC ACID-ASSOCIATED CARDIAC TISSUE DAMAGE CAUSED BY HIGH FAT DIET IS REVERSED BY SODIUM BUTYRATE

Objective: Increased global consumption of high-fat/high-calorie diet has led to higher incidence of the multifactorial cardiometabolic syndrome especially among women. The links between glucose deregulation and eventual mortal cardiac diseases are still being investigated. However, several reports have implicated elevated uric acid (UA) in the progression of metabolic disorders especially during high-fructose diet. Also, butyrate (BUT) a short-chain fatty acid is being identified with intriguing therapeutic potentials in metabolic disorders. We therefore hypothesized that high-fat diet-induced glucose deregulation and cardiac tissue damage are associated with elevated UA and attenuated by BUT in female rats. Design and method: Twenty-four 10-week-old female Wistar rats with weights ranging from 135 to 150 g were treated with normal rat chow and distilled water (po) or sodium butyrate (200 mg/kg; po) or high-fat diet and distilled water (po) or high-fat diet and sodium butyrate. Treatments lasted for 6 weeks. Results: Results showed that high-fat diet caused glucose dysmetabolism, elevated plasma triglyceride (TG), total cholesterol (TC), corticosterone, malondialdehyde (MDA), plasma and cardiac UA, and lactate dehydrogenase (LDH). High-fat diet also led to depressed reduced glutathione (GSH). Histological analysis of cardiac tissue showed cellular infarction, infiltration, and fibrosis in high-fat diet-fed rats. However, all these effects were ameliorated by BUT treatment. Conclusions: The findings here showed that high-fat diet resulted in glucose dysmetabolism and cardiac tissue damage through a uric acid (UA) - dependent mechanism and that butyrate (BUT) can protect against high-fat diet-induced cardiometabolic disorders through UA suppression and augmentation of glutathione antioxidant defenses. This study therefore demonstrates that UA is involved in high fat diet-induced cardiometabolic syndrome. However, data here shows that the UA - associated events in high fat diet will chronically engender cardiac tissue damage. Interestingly, with UA suppression, BUT treatment showed plausible beneficial glucoregulatory, anti-inflammatory and antioxidant properties which were potent enough to confer protection on the cardiac tissue preventing overt damage in high fat diet-fed rats. Therefore, BUT may be considered for the development of suitable therapeutic candidate in the treatment of metabolic syndrome and cardiac derangements associated with heightened UA.

Sildenafil augments fetal weight and placental adiponectin in gestational testosterone-induced glucose intolerant rats.

Testosterone induces intra-uterine growth restriction (IUGR) with maternal glucose dysregulation and oxidant release in various tissues. Adiponectin, which modulates the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is expressed in the placenta and affects fetal growth. Sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), used mainly in erectile dysfunction has been widely studied as a plausible pharmacologic candidate in IUGR. Therefore, the present study sought to determine the effect of PDE5i on placental adiponectin/Nrf2 pathway in gestational testosterone-induced impaired glucose tolerance and fetal growth. Fifteen pregnant Wistar rats were allotted into three groups (n = 5/group) receiving vehicles (Ctr; distilled water and olive oil), testosterone propionate (Tes; 3.0 mg/kg; sc) or combination of testosterone propionate (3.0 mg/kg; sc) and sildenafil (50.0 mg/kg; po) from gestational day 14-19. On gestational day 20, plasma and placenta homogenates were obtained for biochemical analysis as well as fetal biometry. Pregnant rats exposed to testosterone had 4-fold increase in circulating testosterone compared with control (20.9 ± 2.8 vs 5.1 ± 1.7 ng/mL; p < 0.05) whereas placenta testosterone levels were similar in testosterone- and vehicle-treated rats. Exposure to gestational testosterone caused reduction in fetal and placental weights, placental Nrf2 and adiponectin. Moreover, impaired glucose tolerance, elevated plasma triglyceride-glucose (TyG) index, placental triglyceride, total cholesterol, lactate, malondialdehyde and alanine aminotransferase were observed in testosterone-exposed rats. Treatment with sildenafil improved glucose tolerance, plasma TyG index, fetal and placental weights and reversed placental adiponectin in testosterone-exposed pregnant rats without any effect on placental Nrf2. Therefore, in testosterone-exposed rats, sildenafil improves impaired glucose tolerance, poor fetal outcome which is accompanied by augmented placental adiponectin regardless of depressed Nrf2.

Chronic consumption of thermally processed palm oil or canola oil modified gut microflora of rats

Dietary oils have critical influences on human health, and thermally cooking or frying modify the components and nutritional functions of oils. Palm oil was the most widely used oil in food processing industry, but its health effects remain debatable. In the current study, we aimed to compare the effects of thermally oxidized palm oil and canola oil on gut microbiota. Palm oil or canola oil were heated at 180 °C for 10 h to prepare high-fat diets. Rats were fed high-fat diets for 3 months, and hematological properties, gut microflora composition and intestinal gene expression were examined. The results indicated that heated canola oil consumption elevated plasma total cholesterol and LDL-c levels compared with unheated canola oil, but heated palm oil do not had these effects; and consumption of heated palm oil significantly elevated the relative abundance of Lactobacillucs and Roseburia in gut, compared with non-heated palm oil or two canola oil groups. Moreover, intestinal expression of IL-22 was increased in heated palm oil fed animal, though ZO-1 and GPR41 were reduced. In conclusion, heating process may enhance the effects of palm oil on proliferation of probiotics Lactobacillucs, and weaken the effects of canola oil on cholesterol transport and metabolism.

Bozulmuş glukoz ve lipid metabolizması ve anormal karaciğer enzim düzeylerinin multipl akrokordonların oluşumundaki rolü: Bir olgu kontrol çalışması

Background Acrochordons, one of skin tumors, are protrusions of the loose fibrous tissue. In various studies, they have found to be associated with abnormal lipid profile, diabetes, cardiovascular disease, obesity, abnormal liver enzymes and genetic factors. In our case-control study, we aimed to determine possible associations of multiple acrochordons with obesity, impaired glucose and lipid metabolism, thyroid disorders, anemia and liver enzymes abnormalities.Methods Sixty-five patients (32 male, 33 female) with at least 8 skin tags and age- and gender-matched 60 controls without skin tags (30 male, 30 female) were enrolled to the study. We noted patients’ and controls’ age, height, weight, body mass index (BMI) and detailed medical history. Locations of acrochordons were recorded for the patient group. We recorded values of fasting plasma glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), total cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), free T3 (fT3), free T4 (fT4), thyroid-stimulating hormone (TSH), hemoglobin, ferritin, vitamin B12, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP).Results Our study has shown a genetic predisposition to the development of multiple skin tags (P=0.0001). The mean BMI was statistically significant between the patients and controls (P&amp;lt;0.0001). In addition, we have found that when fasting plasma glucose, AST and GGT levels increase, the possibility of the forming of multiple acrochordons also increases (P=0.048, P=0.003, P=0.013). We determined that increasing of BMI is a risk factor for both genders (P=0.003, P&amp;lt;0.0001, respectively). We found that elevated fasting plasma glucose, insulin, HOMA-IR, total cholesterol, triglyceride, AST, ALT and GGT levels increase possibility of the forming of multiple acrochordons in females (P=0.037, P=0.022, P=0.013, P=0.03, P=0.007, P&amp;lt;0.0001, P=0.015, P=0.005, respectively).Conclusion Our results show that multiple acrochordons may be the cutaneous signs of abnormal glucose and lipid metabolism and liver enzyme abnormalities. Thus, we suggest that clinicians should see appropriate bloodtests for patients with multiple skin tags and manage them accordingly.

Whole Grain Wheat Consumption Affects Postprandial Inflammatory Response in a Randomized Controlled Trial in Overweight and Obese Adults with Mild Hypercholesterolemia in the Graandioos Study

ABSTRACTBackgroundWhole grain wheat (WGW) consumption is associated with health benefits in observational studies. However, WGW randomized controlled trial (RCT) studies show mixed effects.ObjectivesThe health impact of WGW consumption was investigated by quantification of the body's resilience, which was defined as the “ability to adapt to a standardized challenge.”MethodsA double-blind RCT was performed with overweight and obese (BMI: 25–35 kg/m2) men (n = 19) and postmenopausal women (n = 31) aged 45–70 y, with mildly elevated plasma total cholesterol (>5 mmol/L), who were randomly assigned to either 12-wk WGW (98 g/d) or refined wheat (RW). Before and after the intervention a standardized mixed-meal challenge was performed. Plasma samples were taken after overnight fasting and postprandially (30, 60, 120, and 240 min). Thirty-one biomarkers were quantified focusing on metabolism, liver, cardiovascular health, and inflammation. Linear mixed-models evaluated fasting compared with postprandial intervention effects. Health space models were used to evaluate intervention effects as composite markers representing resilience of inflammation, liver, and metabolism.ResultsPostprandial biomarker changes related to liver showed decreased alanine aminotransferase by WGW (P = 0.03) and increased β-hydroxybutyrate (P = 0.001) response in RW. Postprandial changes related to inflammation showed increased C-reactive protein (P = 0.001), IL-6 (P = 0.02), IL-8 (P = 0.007), and decreased IL-1B (P = 0.0002) in RW and decreased C-reactive protein (P < 0.0001), serum amyloid A (P < 0.0001), IL-8 (P = 0.02), and IL-10 (P < 0.0001) in WGW. Health space visualization demonstrated diminished inflammatory (P < 0.01) and liver resilience (P < 0.01) by RW, whereas liver resilience was rejuvenated by WGW (P < 0.05).ConclusionsTwelve-week 98 g/d WGW consumption can promote liver and inflammatory resilience in overweight and obese subjects with mildly elevated plasma cholesterol. The health space approach appeared appropriate to evaluate intervention effects as composite markers. This trial was registered at www.clinicaltrials.gov as NCT02385149.

Ultrasonographic Evaluation of Fatty Pancreas in Serbian Patients with Non Alcoholic Fatty Liver Disease-A Cross Sectional Study.

Background and Objectives: The aim of the study was to determine the association between presences of fatty pancreas (FP) with the features of metabolic syndrome (MeS) in patients with non–alcoholic fatty liver disease (NAFLD) and to establish a new noninvasive scoring system for the prediction of FP in patients with NAFLD. Material and Methods: 143 patients with NAFLD were classified according to FP severity grade into the two groups and evaluated for diagnostic criteria of MeS. All patients underwent sonographic examination with adiposity measurements and the liver biopsy. Liver fibrosis was evaluated semi-quantitatively according to the METAVIR scoring system and using non-invasive markers of hepatic fibrosis. Results: Waist circumference (WC) was predictive for increased risk of FP in NAFLD patients. Elevated fasting plasma glucose, total cholesterol, serum amylase and lipase levels were associated with presence of severe FP (p value = 0.052, p value = 0.007, p value = 0.014; p value = 0.024, respectively). Presence of increased amounts of mesenteric fat was associated with severe FP (p value = 0.013). The results of this study demonstrated highly significant association between NAFLD and presence of FP. The model for predicting the presence of FP was designed with probability value above 6.5. Conclusion: Pancreatic fat accumulation leads to worsening of pancreatic function which in turns exacerbates severity of metabolic syndrome associated with both, NAFLD and NAFPD.

Sodium butyrate recovers high-fat diet-fed female Wistar rats from glucose dysmetabolism and uric acid-associated cardiac tissue damage.

Increased global consumption of high-fat/high-calorie diet has led to higher incidence of the multifactorial cardiometabolic syndrome especially among women. The links between glucose deregulation and eventual mortal cardiac diseases are still being investigated. However, several reports have implicated elevated uric acid (UA) in the progression of metabolic disorders especially during high-fructose diet. Also, butyrate (BUT) a short-chain fatty acid is being identified with intriguing therapeutic potentials in metabolic disorders. We therefore hypothesized that high-fat diet-induced glucose deregulation and cardiac tissue damage are associated with elevated UA and attenuated by BUT in female rats. Twenty-four 10-week-old female Wistar rats with weights ranging from 135 to 150g were treated with normal rat chow and distilled water (po) or sodium butyrate (200mg/kg; po) or high-fat diet and distilled water (po) or high-fat diet and sodium butyrate. Treatments lasted for 6weeks. Results showed that high-fat diet caused glucose dysmetabolism, elevated plasma triglyceride (TG), total cholesterol (TC), corticosterone, malondialdehyde (MDA), plasma and cardiac UA, and lactate dehydrogenase (LDH). High-fat diet also led to depressed reduced glutathione (GSH). Histological analysis of cardiac tissue showed cellular infarction, infiltration, and fibrosis in high-fat diet-fed rats. However, all these effects were ameliorated by BUT treatment. The findings here showed that high-fat diet resulted in glucose dysmetabolism and cardiac tissue damage through a UA-dependent mechanism and that BUT can protect against high-fat diet-induced cardiometabolic disorders through UA suppression and augmentation of glutathione antioxidant defenses.

TRPC6 Inactivation Does Not Protect Against Diabetic Kidney Disease in Streptozotocin (STZ)‐treated Sprague‐Dawley Rats

Glomerular TRPC6 channels are up‐regulated in rodent models of diabetes mellitus, but the role of TRPC6 in driving progression of experimental diabetic nephropathy is controversial. We recently used CRISPR/Cas9 methods to generate Sprague‐Dawley rats with a deletion in exon 2 of the Trpc6 gene that renders the channels non‐functional [1]. In addition, we observed that animals lacking functional TRPC6 were protected in the chronic puromycin aminonucleoside (PAN) model of acquired FSGS [1]. In the present study, 300‐gram adult Trpc6del/del rats and their wild‐type Trpc6wt/wt littermates were examined in the STZ model of type‐1 diabetes using protocols approved by the University of Houston IACUC committee. In our experiments, diabetes was induced by a single intraperitoneal injection of STZ, while controls received vehicle. Animals were not treated with insulin. STZ‐treated rats with severe hyperglycemia (&gt;450 mg/dl) by 5 days after treatment were used for analysis and were monitored for the next 10 weeks. At 4 and 10 weeks after STZ treatment, compared to vehicle‐treated controls, STZ‐treated rats had severe hyperglycemia (745 ± 144 mg/dl, mean ± SD at 10 weeks). They also had elevated plasma triglycerides and total cholesterol, and failed to gain weight. STZ‐treated rats also exhibited markedly increased urine albumin excretion, increased blood urea nitrogen (BUN), and increased plasma creatinine and decreased creatinine clearance, indicating marked declines in renal function in diabetic rats. Two‐way ANOVA analyses of these datasets revealed no differences between Trpc6wt/wt and Trpc6del/del rats in any of these parameters. There was no time in the course of the experiment where we obtained functional data suggesting a protective effect of TRPC6 inactivation on blood glucose, or kidney function in STZ diabetes. Histological analysis carried out 10 weeks after STZ treatment revealed marked glomerular and tubulointerstitial disease in STZ‐treated rats. Mesangial expansion was the prominent feature in glomeruli of STZ‐treated animals, and glomeruli were less disrupted than we previously observed in the chronic PAN model [1]. Blind semi‐quantitative analysis of glomerular histology revealed a significant effect of STZ but no protective effect of TRPC6 inactivation on glomerular pathology. In summary, TRPC6 inactivation does not prevent declines in renal function and appears to have no protective effect in the STZ model of type‐1 diabetes in Sprague‐Dawley rats. This is in marked contrast to our previous work in chronic PAN nephrosis, where TRPC6 inactivation preserves renal function and histology.Support or Funding InformationSupported by NIH grant R01‐DK104708.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Synthesis and &lt;i&gt;in vivo&lt;/i&gt; anti-hyperlipidemic activity of novel n-benzoylphenyl-2-furamide derivatives in Wistar rats

Purpose: To synthesize and evaluate the anti-hyperlipidemic activity of a novel series of N- (benzoylphenyl)-2-furamides ( 3a , 3b , 4a , 4b and 4c ). Methods: Compounds ( 3a , 3b , 4a , 4b and 4c ) were successfully synthesized by reacting activated furan-2-carbonyl-chloride derivatives with aminobenzophenones at 60 °C for 36 h. Hyperlipidemia was induced in overnight fasted rats by intraperitoneal administration of Triton WR-1339 (300 mg/kg). to overnight fasted rats. The rats were divided into six groups: control, hyperlipidemic, hyperlipidemic plus compounds 3b , 4b , 4c , and hyperlipidemic plus bezafibrate-treated. Eighteen hours later, blood samples were collected and plasma lipid profile determined using enzymatic methods. Results: At a dose of 15 mg/kg body weight, the elevated plasma triglyceride (TG) levels, total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were significantly reduced by compounds 4b (p < 0.001) and 4c (p < 0.0001) 18 h later, compared to the hyperlipidemic group. Furthermore, compounds 4b and 4c significantly increased high density lipoprotein cholesterol (HDL-C) levels by 29 and 34 %, respectively. Conclusion: The findings indicate the high potency of N-(benzolphenyl)-2-furamides ( 4b and 4c ) as lipid-lowering agents. Thus, these compounds 4b and 4c may used as lead compounds for the development of new derivatives and agents for targeting dyslipidemia and cardiovascular diseases. Keywords: Triton WR-1339-induced hyperlipidemic rats, N-(benzoylphenyl)-2-furamides, Lipid-lowering activity, Cardiovascular disease, Synthesis

Effects of vitamin d3 on ppar-α and its target gene nfkbia on a rat model of high carbohydrate high fat diet induced non alcoholic steatohepatitis

Accumulating data suggesting that Vitamin D3 could be of a potential therapeutic value for non-alcoholic fatty liver disease (NAFLD) ,but its underlying mechanisms are still under research .Vitamin D3 up regulates PPAR-α and downstream gene nuclear factor-kappa-B inhibitor subunit-alpha (NFKBIA) which may represent a novel strategy for the management of NASH. Therefore, in this study, we investigated the possible protective role of vitamin D3 on high carbohydrate high fat diet (HCHFD) animal model of NASH through PPAR-α and NFKBIA pathway Methods: Thirty male Sprague-Dawley rats were equally divided into three groups; group I: (negative control group) fed standard rat chow diet for 8 weeks. group II: received HCHFD for 8 weeks. group III: fed as group II for 8 weeks and received also, I.P administration of vitamin D3 at a dose of 5 μg/kg twice weekly from the fourth week till the end of the study. At the end of the experiment, serum triglycerides, total cholesterol, liver enzymes, serum albumin, serum bilirubin and liver tissue oxidative stress markers (MDA, SOD and GSH) were measured. Hepatic histopathological alterations were assessed by hematoxylin and eosin, Masson’s trichrome, and Oil Red O staining ; the expressions of NF-κ B p65 (ReIA) was estimated in liver tissues using immunohistochemistry and the expression of hepatic PPAR-α and NFKBIA genes were estimated at the level of mRNA by quantitative real-time PCR. Results: Nonalcoholic steatohepatitis (NASH) model was confirmed by histopathological examination as indicated by elevated NAFLD activity score (NAS) as well as elevation of serum liver enzymes , hyperlipidemia in the form elevated plasma triglycerides and total cholesterol, oxidative stress state (high MDA, low GSH and SOD) and down regulation of PPAR-α and NFKBIA mRNA in liver tissues which was concomitant with up regulation of inflammatory marker NF-κ B-p65(ReIA) . On the other hand, vitamin D3 ameliorated NASH by attenuation of oxidative stress (low MDA, high GSH and SOD) and up regulation of PPAR-α and NFKBIA genes at the level of mRNA in the liver tissues which was accompanied by decrease in hepatocyte nuclear NF-κ B-p65 (ReIA) immunohistochemical brownish staining. Conclusion: Vitamin D3 attenuates NASH in HCHFD rat model by attenuation of redox state and up regulation of PPAR-α and its downstream gene NFKBIA in liver tissues.

Antihyperlipidemic and antioxidant activities of the ethanolic extract of Garcinia cambogia on high fat diet-fed rats.

The study investigated the antihyperlipidemic and antioxidant activities of the ethanolic extract of Garcinia cambogia on high fat diet-fed rats. The phytochemical constituents, total polyphenol content and ferric reducing antioxidant power (FRAP) were estimated in the G. cambogia extract (GE). Male Wistar rats were fed with either standard rodent diet or 30% high-fat diet and administered with GE at a dose of 400 mg/kg body weight/day for 10 weeks. At the end, lipid profile and oxidative stress parameters were estimated. The analyses revealed the presence of carbohydrates, proteins, sterols, tannins, flavonoids and saponins in GE. The total polyphenol content and FRAP of GE were 82.82±7.64 mg of gallic acid equivalents and 260.49±10.18 µM FRAP per gram of the GE. High-fat feeding elevated plasma total cholesterol (TC), triacylglycerol (TAG), non-high-density lipoprotein-cholesterol (non-HDL-C), malondialdehyde (MDA), reduced HDL-C and blood antioxidants, glutathione (GSH), glutathione peroxidase (GPx), catalase. Increase in total oxidant status (TOS), oxidative stress index (OSI) and decrease in the total antioxidant status (TAS) were observed in plasma, liver and kidney of fat-fed rats. Administration of GE decreased food intake, plasma TC, TAG, non HDL-C, MDA, increased HDL-C and blood antioxidants GSH, GPx, catalase. GE also reduced TOS, OSI and elevated TAS in plasma and liver of fat-fed rats. Renal OSI was significantly reduced upon GE treatment. Our study demonstrated that GE is effective in ameliorating high-fat-diet-induced hyperlipidemia and oxidative stress.

Abstract 127: Effects of miR-33 Antagonism on Glucose and Triglyceride Metabolism in Nonhuman Primates.

Elevated plasma low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL) cholesterol levels increase the risk of cardiovascular disease (CVD). While strategies to lower LDL cholesterol have been successful in reducing CVD-related mortality, there is still an unmet need for developing therapies to reduce the residual risk of atherosclerotic CVD. Plasma HDL cholesterol levels are inversely correlated with CVD risk and thus novel therapies to increase plasma HDL cholesterol levels have garnered much attention in recent years. MicroRNA-33a and b (miR-33a/b) are intronically-encoded microRNAs residing in the sterol response element binding protein genes SREBF2 and SREBF1 and suppress the expression of the genes involved in cholesterol efflux and fatty acid oxidation. Recent studies show that antagonism of miR-33 results in increased ABCA1expression and elevated plasma HDL levels in both mice and nonhuman primates. However, findings in mice suggest that long term miR-33 antagonism may lead to hepatic steatosis and increased production of very low-density lipoprotein (VLDL), the precursor to proatherogenic LDL. In the current study, cynomolgus monkeys were fed a high carbohydrate diet plus Kool Aid prior to administration of antisense oligonucleotides (ASOs) specific for miR-33a/b. As expected, miR-33 antagonism resulted in elevated plasma total cholesterol levels, predominantly due to increased HDL. No differences in plasma LDL or triglycerides were observed between treatment groups. MiR-33a/b antagonism had no effect on VLDL triglyceride secretion rates. Anti-miR-33 treatment did not promote hepatic lipid accumulation or adversely affect liver transaminase levels. Glucose tolerance tests revealed no differences in either plasma glucose or insulin levels in response to miR-33a/b antagonism. These findings suggest that anti-miR-33 therapy raises HDL cholesterol without negatively impacting either triglyceride or glucose homeostasis in nonhuman primates.

Elevated plasma total cholesterol level is associated with the risk of asymptomatic intracranial arterial stenosis.

BackgroundIntracranial arterial stenosis (ICAS) is one of the most common causes of stroke, and dyslipidemia was one of the most common risk factors related to ICAS. However, the correlation between the plasma total cholesterol level (PTC) and ICAS, especially asymptomatic ICAS (AICAS) is not clear.Materials and Methods5,300 participants were enrolled in this study. The diagnosis of AICAS was made by transcranial Doppler ultrasonography. The participants were then divided into 5 essentially equal-sized groups based on their PTC levels. The multivariate logistic regression was used to analyze the correlation between the PTC level and the prevalence of AICAS.Results13.0% of the participants were diagnosed with AICAS. The prevalence of AICAS gradually increased with the increasing PTC level. After adjusted by the possible confounding factors, the Odds Ratios (OR) of the AICAS prevalence between the 1st quintile group and the other 4 groups were 1.13, 1.23, 1.63 and 1.75 with 95% confident intervals (CI) of 0.84–1.52, 0.91–1.66, 1.20–2.22 and 1.23–2.47, respectively. The further subgroup analysis revealed that the PTC level was stronger for males (OR 1.42 95%CI 1.23–1.64), regarding the prevalence of AICAS.ConclusionsIn this large community-based study, the prevalence of AICAS is 13.0%, subjects with higher PTC levels showed a mild increase in the prevalence of AICAS. The PTC level is an independent risk factor of AICAS. Males seem to be significantly more vulnerable to the risk of AICAS.