Increased Plasma Lipid Research Articles

The cross-sectional study of hepatic lipase SNPs and plasma lipid levels.

By the combination of meta‐analysis, the data of the 1,000 Genomes Project Phase 3, and the promoter sequence of hepatic lipase (LIPC), we performed the cross‐sectional study to explore the associations of four variants (rs1077835; rs1077834; rs1800588 [C‐514T], and rs2070895 [G‐250A]) in LIPC promoter with plasma lipid levels. Our results indicate that the first and the next three of the four SNPs are, respectively, reported to be associated with the decreased and increased HDL‐c level. Meta‐analysis of 87 studies with 101,988 participants indicates that HDL‐c level in rs1800588 (C‐514T) (pooled mean difference = 0.03, 95%CI (0.03, 0.04), p < .001) and rs2070895 (G‐250A) (pooled mean difference = 0.07, 95%CI (0.05, 0.09), p < .001) is higher in allele T or A carriers. Similarly, LDL‐c, TC, TG, and BMI levels are generally increased in T or A alleles carriers. We failed to conduct the meta‐analysis of rs1077835 and rs1077834 due to the limited previous reports. Data from the 1,000 Genomes indicate that the allele frequencies of the four SNPs in total or subpopulations are almost equal to each other. The paired value r 2 and D' of the four SNPs are larger than 0.8, which indicate the linkage disequilibrium of the four variants. The analysis of LIPC promoter indicate that C‐514T and G‐250A are, respectively, located in transcriptional factor binding sites of USF1and Pbx1b, which may partly explain the effect of the two SNPs on the decreased LIPC activity in the alleles carriers and the corresponding increased plasma lipids hydrolyzed by LIPC. These results may help us to better understand the different effects of the four SNPs on the plasma lipid levels among subpopulations and offer clues for future clinical treatment of dyslipidemia‐related diseases.

Maternal folic acid supplementation does not counteract the deleterious impact of prenatal exposure to environmental pollutants on lipid homeostasis in male rat descendants.

Prenatal exposure to persistent organic pollutants (POPs) has been associated with the development of metabolic syndrome-related diseases in offspring. According to epidemiological studies, father's transmission of environmental effects in addition to mother's can influence offspring health. Moreover, maternal prenatal dietary folic acid (FA) may beneficially impact offspring health. The objective is to investigate whether prenatal FA supplementation can overcome the deleterious effects of prenatal exposure to POPs on lipid homeostasis and inflammation in three generations of male rat descendants through the paternal lineage. Female Sprague-Dawley rats (F0) were exposed to a POPs mixture (or corn oil) +/- FA supplementation for 9 weeks before and during gestation. F1 and F2 males were mated with untreated females. Plasma and hepatic lipids were measured in F1, F2, and F3 males after 12-h fast. Gene expression of inflammatory cytokines was determined by qPCR in epididymal adipose tissue. In F1 males, prenatal POPs exposure increased plasma lipids at 14 weeks old and hepatic lipids at 28 weeks old and prenatal FA supplementation decreased plasma total cholesterol at 14 weeks old. Prenatal POPs exposure decreased plasma triglycerides at 14 weeks old in F2 males. No change was observed in inflammatory markers. Our results show an impact of the paternal lineage on lipid homeostasis in rats up to the F2 male generation. FA supplementation of the F0 diet, regardless of POPs exposure, lowered plasma cholesterol in F1 males but failed to attenuate the deleterious effects of prenatal POPs exposure on plasma and hepatic lipids in F1 males.

Metformin inhibited Nod-like receptor protein 3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE−/− mice

AimsThe present study aimed to investigate the effect of metformin on diabetes-accelerated atherosclerosis and whether Nod-like receptor protein 3 (NLRP3) inflammasome is a target for metformin. Materials and methodsApoE−/− male mice were divided randomly into control, streptozocin-induced diabetes mellitus and metformin groups. Metabolic parameters, atherosclerotic lesion, activation of NLRP3 inflammasomes and related signaling pathways were detected. THP-1-differentiated macrophages were used in in vitro experiments. ResultsCompared with control mice, increased plasma lipids and proinflammatory interleukin-1β, aggravated macrophage infiltration into the atherosclerotic lesion, and accelerated development of atherosclerosis were observed in diabetic mice, which were associated with the activation of NLRP3 inflammasomes and dysregulation of thioredoxin-1 and thioredoxin-interacting protein. Treatment with metformin alleviated diabetes-induced metabolic disorders and atherosclerosis, as well as NLRP3 inflammasomes activation and dysregulation of thioredoxin-1/thioredoxin-interacting protein. In vitro experiments showed that high glucose induced the accumulation of reactive oxygen species and activated NLRP3 inflammasomes, which was significantly suppressed by treatment with metformin or antioxidant N-acetyl-L-cysteine. Moreover, Compound C, an inhibitor of adenosine 5′-monophosphate-activated protein kinase (AMPK), blocked the anti-inflammatory effect of metformin, indicating that metformin inhibited high glucose-induced NLRP3 inflammasomes activation through AMPK activation. Moreover, high glucose decreased thioredoxin-1 expression and increased thioredoxin-interacting protein expression, which was also reversed by metformin. ConclusionsMetformin inhibited NLRP3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE−/− mice, which at least partially through activation of AMPK and regulation of thioredoxin-1/thioredoxin-interacting protein.

Phospholipids as Indicators of Docetaxel‐Resistant Castration‐Resistant Prostate Cancer

The association of circulating lipids with clinical outcomes of drug‐resistant castration‐resistant prostate cancer (CRPC) is not fully understood. While it is known that increases in plasma lipids correlates to decreased survival, neither the mechanisms mediating alterations in these lipids nor the correlation of resistance to treatment are well characterized. We addressed this gap‐in‐knowledge using in vitro models of non‐cancerous, hormone sensitive, CRPC and drug‐resistant cell lines combined with quantitative HPLC‐ESI‐Orbitrap‐MS lipidomic analysis. HPLC‐MS based metabolomic analysis identified 83 features that were significantly altered in the drug‐resistant cell lines as compared to non‐resistant control group. Within the 83 species, two were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer from previous studies. Principal component analysis (PCA) demonstrated that drug‐resistant and control cell‐lines were visually separated by these identified lipid biomarkers. Two out of the 83 lipid classes were identified as phosphatidylcholine (PC) 18:0/18:1 and PC 18:0/18:2), both of which had high level of abundance in Docetaxel‐resistant CRPC. An untargeted approach indicated that lipids corresponding to PC, phosphatidylglycerol (PG), phosphatidic acid (PA) and phosphatidylserine (PS) all had higher relative abundance in DR‐CRPC cells (DU145‐DR) compared to parent control (DU145). These data suggest that the lipidomic profiles of prostate cancer cells lines recapitulate lipidomic profiles in the plasma of prostate cancer patients. As such, these metastatic dependent and drug‐resistant cell lines may prove useful for understanding the molecular mechanisms mediating lipid changes in prostate cancer patients.Support or Funding InformationNational Institute of Biomedical Imaging and Bioengineering NIBIB (EB0160100) Department of Defense Prostate Cancer Research Program Idea Development Award (PC150431 GRANT11996600)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Leptin Replacement Therapy Improves Endothelial Function and Vascular Inflammation in a Mouse Model of Acquired Lipodystrophy Associated with Antiretroviral Treatment by Regulating Nox1‐Derived ROS and C‐C Chemokine Receptor Type 5

Highly active antiretroviral therapy (HAART) has been used at suppressing HIV replication, as a side effect HAART promotes lipodystrophy, which is a metabolic disorder characterized by an abnormal adipose tissue distribution, reduced leptin plasma levels and vascular complications. Leptin replacement therapy (LRT) is currently used to treat metabolic dysfunctions in patients diagnosed with congenital lipodystrophy. Here, we sought to investigate whether LRT restores vascular function and reduces inflammation in mice treated with the antiretroviral agent, ritonavir. Four weeks of ritonavir reduced body weight [control (C): 28.4±0.5 vs. Rit: 24.4 ± 0.2g*, *P&lt;0.05], fat mass (C: 10 ± 0.4 vs. Rit: 4.5 ± 0.9 %*, *P&lt;0.05) and leptin plasma levels (C: 4.7 ± 0.05 vs. Rit: 2.0 ± 0.36 ng/mL*, *P&lt;0.05) confirming that it induces acquired lipodystrophy. Acquired lipodystrophy impaired endothelial function, increased plasma lipid peroxidation and vascular H2O2, and ROS producing enzymes (Nox1 and NoxA1). Furthermore, acquired lipodystrophy was associated with vascular inflammation characterized by elevation of NLRP3, Caspase‐1, IL‐1β, MCP‐1, F4/80, CCR5 and CCL5 gene expression. ROS scavenging via tempol (SOD mimetic, 100 μmol/l) or GKT771 (Nox1 inhibitor, 10 μmol/l) restored endothelial function. LRT (10μg/day/7 days, osmotic mini‐pump), at the end of the 3‐week ritonavir, restored endothelial function, reduced vascular oxidative stress and Nox1 and NOXA1 gene expression and vascular inflammation. Nox1 deficiency (Nox1−/−) protected mice from acquired lipodystrophy‐induced endothelial dysfunction and reduced inflammatory markers including CCR5 and CCL5. In order to analyze whether vascular inflammation is occurring via CCR5/CCL5, we induced lipodystrophy in CCR5 deficient mice (CCR5−/−). These mice were protected from acquired lipodystrophy‐induced endothelial dysfunction and vascular inflammation. Moreover, deleting endothelial leptin signaling via specific deletion of leptin receptor (LepR) in endothelial cells (LepR−/−EC mice) promoted endothelial dysfunction, which was reverted by pre‐incubating aortic rings with Nox1 inhibitor (GKT771) in vitro and increased inflammatory markers. Furthermore, LepR−/−EC mice were resistant to the vascular protective effects of LRT. Taken all together, LRT restores endothelial function and reduces vascular inflammation in acquired lipodystrophy associated with HAART via endothelium dependent reduction in Nox1‐derived ROS and CCR5/CCL5. Taken together these data support a key role for endothelial leptin signaling in the control of vascular tone and inflammation and suggest that LRT could represent a potential new avenue for the treatment of vascular diseases associated with acquired lipodystrophy.Support or Funding InformationWork supported by 17POST33410363 and 1K99HL140139‐01A1 to TBN and 1R01HL13030101 to EJ.BdC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of bile acids feeding on atherosclerosis in ApoE−/− mice

Bile acids (BAs) account for lipids absorption in the small intestine and are key regulators of cholesterol homeostasis as they clear cholesterol excess in the liver. Therefore, we hypothesize that long term BAs feeding could prevent the development of atherosclerosis.To prove this, we took ApoE−/− mice and fed them for 8 weeks with a western diet (WD) or a WD containing 0.1% cholic acid (CA) (WD‐CA) or 0.1% chenodeoxycholic acid (CDCA) (WD‐CDCA) and assessed their plasma lipoprotein and hepatic lipid content, intestinal cholesterol absorption and atherosclerosis.WD‐CA increased plasma LDL‐C by ~75%, HDL‐C by ~30%, hepatic cholesterol by ~40% and cholesterol ester by ~300%. WD‐CA additionally increased cholesterol absorption by 25%. All these changes led to a 100% increase of the atherosclerotic lesions. In contrary, WD‐CDCA had no effect on plasma lipoproteins and hepatic cholesterol but massively increased hepatic cholesterol ester. WD‐CDCA additionally decreased cholesterol absorption by 25%, but atherosclerotic lesions were of the same magnitude as in ApoE−/− mice fed with WD.Long term administration of CA and CDCA enhanced cholesterol accumulation in the liver and had no benefit towards atherosclerosis development in ApoE−/− mice. Even more, CA was atherogenic, mainly because of increased plasma lipids and intestinal cholesterol absorption. Despite improved intestinal cholesterol elimination, CDCA treatment did not reduce atherosclerosis. Other strategies are required to reduce atherosclerosis without causing liver damage in mice.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

One-Year Treatment with Olanzapine Depot in Female Rats: Metabolic Effects.

BackgroundAntipsychotic drugs can negatively affect the metabolic status of patients, with olanzapine as one of the most potent drugs. While patients are often medicated for long time periods, experiments in rats typically run for 1 to 12 weeks, showing olanzapine-related weight gain and increased plasma lipid levels, with transcriptional upregulation of lipogenic genes in liver and adipose tissue. It remains unknown whether metabolic status will deteriorate with time.MethodsTo examine long-term metabolic effects, we administered intramuscular long-acting injections of olanzapine (100 mg/kg BW) or control substance to female rats for up to 13 months.ResultsExposure to olanzapine long-acting injections led to rapid weight gain, which was sustained throughout the experiment. At 1, 6, and 13 months, plasma lipid levels were measured in separate cohorts of rats, displaying no increase. Hepatic transcription of lipid-related genes was transiently upregulated at 1 month. Glucose and insulin tolerance tests indicated insulin resistance in olanzapine-treated rats after 12 months.ConclusionOur data show that the continuous increase in body weight in response to long-term olanzapine exposure was accompanied by surprisingly few concomitant changes in plasma lipids and lipogenic gene expression, suggesting that adaptive mechanisms are involved to reduce long-term metabolic adverse effects of this antipsychotic agent in rats.

Spermidine and Voluntary Activity Exert Differential Effects on Sucrose- Compared with Fat-Induced Systemic Changes in Male Mice

Excess dietary fat and sugar are linked to obesity and metabolic syndrome. Polyamines such as spermidine are implicated in fat accumulation and may support activity-induced weight loss. This study tested interventional spermidine supplementation and voluntary activity against fat- and sucrose-induced systemic and gut microbiota changes. A 3-factorial study design (3×2×2) was used to test the factors diet, activity, and spermidine. Male 6-wk-old C57BL/6N mice were fed a control diet (CD; carbohydrate:protein:fat, 70%:20%:10% of energy; 7% sucrose), a high-fat diet (HFD; carbohydrate:protein:fat, 20%:20%:60% of energy; 7% sucrose), or a high-sucrose diet (HSD; carbohydrate:protein:fat, 70%:20%:10% of energy; 35% sucrose). Diet groups were left untreated (+0) or had unlimited access to running wheels (+A) or were supplemented with 3 mM spermidine via drinking water (+S) or a combination of both (+A+S) for 30 wk (n=7-10). In comparison to the CD, the HFD enhanced body weights (by 36%, P<0.001), plasma lipids (cholesterol by 24%, P<0.001; triglycerides by 27%, P=0.004), and glucose concentrations (by 18%, P<0.001), whereas the HSD increased weight by 13% (P<0.001) and fasting glucose by 17% (P<0.001) but did not increase plasma lipids. Microbiota taxonomic composition changed upon the HFD and HSD (both P<0.001); however, only the HSD increased microbial diversity (P<0.001) compared with the CD. Activity influenced microbiota composition (P<0.01) and reduced glucose concentrations in HSD-fed (P=0.021) and HFD-fed (P<0.001) mice compared with nonactive mice. The combination of activity and spermidine affected energy intake (P-interaction=0.037) and reduced body weights of HSD+A+S mice compared with HSD+0 mice (P=0.024). In male C57BL/6N mice, dietary sucrose and fat caused diverse metabolic and microbiota changes that were differentially susceptible to physical exercise. Spermidine has the potential to augment activity-induced beneficial effects, particularly for sucrose-induced obesity.

Novel aspects of PCSK9 and lipoprotein receptors in renal disease-related dyslipidemia

Chronic kidney disease (CKD) is a global health problem with a profound impact on quality of life. Cardiovascular disease is established as a major cause of morbidity and mortality in patients with CKD. Dyslipidemia is frequently observed in CKD patients, suggesting a causal relation between dyslipidemia and cardiovascular disease in CKD patients. Currently, lipid-lowering drugs such as statins, are the primary choice for lipid lowering therapy in high-risk populations. Despite many studies showing CVD risk reduction with statins, CVD still remains the leading cause of the death in CKD. This underscores the need for new therapeutic approaches to reduce cardiovascular risk in CKD patients. Reduced lipoprotein lipase activity, increased very low-density lipoprotein production, increased proprotein convertase subtilisin kexin type 9 (PCSK9) expression and loss of hepatic heparan sulfate proteoglycans (HSPG) syndecan-1 have been associated with CKD-related dyslipidemia. Low-density lipoprotein receptor (LDLR), low-density lipoprotein receptor-related protein 1 (LRP-1) and syndecan-1, are the most important hepatic receptors for lipoprotein clearance. However, their contributions to the pathogenesis of dyslipidemia and cardiovascular disease in CKD remain unclear. Interestingly, in CKD, increased plasma lipid levels are associated with elevated levels of PCSK9. This promotes the proteolysis of LDLR, suggesting a role for PCSK9 in CKD-associated dyslipidemia. Fully humanized monoclonal antibodies targeting PCSK9 have been approved by the US Food and Drug Administration and the European Medicines Agency as lipid lowering treatment for patients with hypercholesterolemia. In CKD sub-group analysis, ODYSSEY COMBO I and ODYSSEY COMBO II studies demonstrated strong reduction in LDL-C by alirocumab compared to placebo and ezetimibe and when added to statins. However, their efficacy in reducing plasma TG is controversial. Therefore, further research work is need for a detailed analysis on efficacy and safety of PCSK9 antibodies in CKD groups. Interestingly, novel findings on PCSK9 interaction with HSPG might shed new insight on altered lipid metabolism in CKD. In this review, we discuss various aspects of lipoprotein metabolism and hepatic lipoprotein receptor signaling pathways along with the concept of renal disease-related dyslipidemia. Furthermore, this review highlights the drawbacks of current lipid-lowering therapies and proposes novel approaches for lipid management in CKD.

Lipoprotein markers associated with disability from multiple sclerosis

Altered lipid metabolism is a feature of chronic inflammatory disorders. Increased plasma lipids and lipoproteins have been associated with multiple sclerosis (MS) disease activity. Our objective was to characterise the specific lipids and associated plasma lipoproteins increased in MS and to test for an association with disability. Plasma samples were collected from 27 RRMS patients (median EDSS, 1.5, range 1–7) and 31 healthy controls. Concentrations of lipids within lipoprotein sub-classes were determined from NMR spectra. Plasma cytokines were measured using the MesoScale Discovery V-PLEX kit. Associations were tested using multivariate linear regression. Differences between the patient and volunteer groups were found for lipids within VLDL and HDL lipoprotein sub-fractions (p < 0.05). Multivariate regression demonstrated a high correlation between lipids within VLDL sub-classes and the Expanded Disability Status Scale (EDSS) (p < 0.05). An optimal model for EDSS included free cholesterol carried by VLDL-2, gender and age (R2 = 0.38, p < 0.05). Free cholesterol carried by VLDL-2 was highly correlated with plasma cytokines CCL-17 and IL-7 (R2 = 0.78, p < 0.0001). These results highlight relationships between disability, inflammatory responses and systemic lipid metabolism in RRMS. Altered lipid metabolism with systemic inflammation may contribute to immune activation.

Coiled-coil domain-containing 80 accelerates atherosclerosis development through decreasing lipoprotein lipase expression via ERK1/2 phosphorylation and TET2 expression

Recent studies showed that coiled-coil domain-containing 80 (CCDC80) has a positive link with atherosclerosis and that plasma CCDC80 levels are positively correlated with the levels of fasting plasma triglycerides (TG) in obese individuals. The underlying mechanisms, however, are unclear. Using Hematoxylin-eosin (H&E) and Oil Red O staining, we found that CCDC80 overexpression in vivo significantly increased plasma lipid contents, decreased the expression and activity of lipoprotein lipase (LPL), and accelerated the development of atherosclerosis. Conversely, knockdown of CCDC80 decreased plaque lesions area. In vitro, qRT-PCR and western blot results showed that CCDC80 overexpression significantly decreased, while CCDC80 knockdown increased, LPL expression in cultured vascular smooth muscle cells (VSMCs). Further, we found that CCDC80 reduced LPL expression via inhibiting the phosphorylation of extracellular regulated protein kinase 1/2 (ERK1/2) and also increased the methylation of LPL promoter via down-regulating Tet methylcytosine dioxygenase 2 (TET2). Our results also revealed that CCDC80 significantly down-regulated TET2 expression through decreasing the phosphorylation of ERK1/2. In addition, we found that CCDC80 decreased binding of TET2 to forkhead box O3 (FOXO3a) but had no effect on FOXO3a expression. On the other hand, and that FOXO3a was partially involved in TET2-regulated LPL expression. CCDC80 down-regulated ERK1/2 phosphorylation and decreased expression of TET2 and its interaction with FOXO3a, leading to a reduction of LPL expression and acceleration of atherosclerosis.

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy.

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.

Hypolipidemic activities of partially deacetylated α-chitin nanofibers/nanowhiskers in mice.

Partially deacetylated α-chitin nanofibers/nanowhiskers mixtures (DEChNs) were prepared by 35% sodium hydroxide (NaOH) treatment followed by disintegration in water at pH 3–4. The aim of this study was to investigate the hypolipidemic effects of DEChNs at different dosage levels in male Kunming mice. The male mice were randomly separated into five groups, that is, a normal diet group, a high-fat diet group, and three DEChN groups that were treated with different doses of DEChN dispersions (L: low dose, M: medium dose, H: high dose). Primarily, the DEChNs significantly decreased body weight (BW) gain and adipose tissue weight (ATW) gain of mice. Meanwhile, the decreasing extent of weight ratios between ATW and BW was dependent on the dose of DEChNs. Moreover, the DEChNs prevented an increase in plasma lipids (cholesterol and triacylglycerol) in mice when they were fed a high-fat diet. Histopathological examination of hepatocytes revealed that the DEChNs were effective in decreasing the accumulation of lipids in the liver and preventing the development of a fatty liver. The results suggested that the DEChNs reduced the absorption of dietary fat and cholesterol in vivo and could effectively reduce hypercholesterolemia in mice.

High-fat-diet-induced remission of diabetes in a subset of KATP -GOF insulin-secretory-deficient mice.

To examine the effects of a high-fat-diet (HFD) on monogenic neonatal diabetes, without the confounding effects of compensatory hyperinsulinaemia. Mice expressing KATP channel gain-of-function (KATP -GOF) mutations, which models human neonatal diabetes, were fed an HFD. Surprisingly, KATP -GOF mice exhibited resistance to HFD-induced obesity, accompanied by markedly divergent blood glucose control, with some KATP -GOF mice showing persistent diabetes (KATP -GOF-non-remitter [NR] mice) and others showing remission of diabetes (KATP -GOF-remitter [R] mice). Compared with the severely diabetic and insulin-resistant KATP -GOF-NR mice, HFD-fed KATP -GOF-R mice had lower blood glucose, improved insulin sensitivity, and increased circulating plasma insulin and glucagon-like peptide-1 concentrations. Strikingly, while HFD-fed KATP -GOF-NR mice showed increased food intake and decreased physical activity, reduced whole body fat mass and increased plasma lipids, KATP -GOF-R mice showed similar features to those of control littermates. Importantly, KATP -GOF-R mice had restored insulin content and β-cell mass compared with the marked loss observed in both HFD-fed KATP -GOF-NR and chow-fed KATP -GOF mice. Together, our results suggest that restriction of dietary carbohydrates and caloric replacement by fat can induce metabolic changes that are beneficial in reducing glucotoxicity and secondary consequences of diabetes in a mouse model of insulin-secretory deficiency.

Evidence of extensive atherosclerosis, coronary artery disease and myocardial infarction in the ApoE−/−:Ins2+/Akita mouse fed a western diet

Background and aimsDiabetic patients with no history of cardiac infarction have a prevalence of coronary atherosclerosis and a risk of heart attack equivalent to euglycemic patients who have coronary atherosclerosis and have suffered a prior myocardial infarction. Although several murine models of diabetes have been established, none of these show indications of cardiac events. In an attempt to establish a diabetic mouse model with coronary atherosclerosis and myocardial injury, we have fed hyperglycemic ApoE−/−:Ins2+/Akita mice a western diet to enhance the dyslipidemic phenotype. MethodsFive-week-old ApoE−/−:Ins2+/Akita mice and ApoE−/− controls were fed a diet, 0.15% cholesterol and 21% anhydrous milk lipids, until 25 weeks of age. Changes in lifespan, clinical and metabolic parameters were evaluated as well as atherosclerosis and heart injury. ResultsIn comparison to male ApoE−/−, male ApoE−/−:Ins2+/Akita mice presented with chronic hyperglycemia (30.8 ± 1.2 mM vs. 9.3 ± 0.5 mM) accompanied by extremely high levels of total plasma cholesterol (49.3 ± 6.3 mM vs. 30.1 ± 1.5 mM) and triglycerides (11.6 ± 1.7 mM vs. 2.36 ± 0.18 mM). These mice have atherosclerosis at multiple vascular sites, including aortic sinus, ascending and descending aorta, brachiocephalic artery and coronary arteries. In addition, myocardial infarcts and a significant reduction of the lifespan (close to 20% of survival vs. other groups) were observed. Distinctively, both strains of female mice presented a parallel increase in plasma lipids, atherosclerosis, and no effects on mortality. ConclusionsWe have established a diabetic mouse model, the western-diet-fed male ApoE−/−:Ins2+/Akita mouse, with profound cardiovascular disease involving extensive atherosclerosis, coronary artery disease and myocardial infarct resulting in shortened lifespan.

A cynomolgus monkey model of carotid atherosclerosis induced by puncturing and scratching of the carotid artery combined with a high-fat diet.

Cardio-cerebrovascular disease is one of the three major causes of mortality in humans and constitutes a major socioeconomic burden. Carotid atherosclerosis (CAS) is a very common lesion of the arterial walls, which leads to narrowing of the arteries, in some cases occluding them entirely, increasing the risk of cardiovascular events. The aim of the present study was to evaluate a cynomolgus monkey model of carotid atherosclerosis (CAS) induced by puncturing and scratching combined with a high-fat diet. A total of 12 cynomolgus monkeys were randomly divided into four groups: A, puncturing and scratching carotid artery intimas + high-fat diet (n=3); B, puncturing and scratching carotid artery intimas + regular diet (n=3); C, high-fat diet only (n=3); and D, regular diet only (n=3). Blood was harvested at weeks 4, 6 and 8 and plasma lipid levels were assessed. At week 8, monkeys were sacrificed and carotid arteries were harvested for hematoxylin and eosin (H&E) staining to observe pathological changes. The results revealed that a high-fat diet led to increased plasma lipid levels and accelerated plaque formation. Carotid color Doppler ultrasonography was performed and, along with H&E staining, revealed plaque formation in group A. In summary, the results of the present study suggest that a cynomolgus monkey model of CAS model may be successfully constructed by puncturing and scratching of the carotid artery intimas in combination with a high-fat diet.

Effects Of High-fat Diet And Exercise On Total Plasma Macronutrient Contents By Fourier-transform Infrared Spectroscopy

High fat-low carbohydrate (HFLC) diets are increasingly considered by endurance athletes to enhance their performances and overall health. Total macronutrient contents in plasma may be affected by diets and exercise. PURPOSE: To examine the effects of HFLC diet and an acute bout of exercise on total plasma macronutrient contents in trained males. METHODS: Eight trained distance runners (age = 39.5±9.9 years and VO2max = 47.9±7.6 mL/kg/min) that were on high-carbohydrate (HC) diets adopted the HFLC diet for 3 weeks, which consisted of 70% of overall caloric intake from fats and no more than 50g of carbohydrates. At the end of each diet trial, participants performed an indoor treadmill exercise for 50 minutes at varying race paces followed by an outdoor 5-km time trial. Overnight fasting blood samples were collected at pre- (baseline) and post-exercise (24-hours) to analyze changes in total plasma lipids, proteins, and carbohydrates using attenuated total reflectance Fourier-transform infrared spectroscopy (ATR FT-IR). The O-H stretch vibrational band of water was used to normalize the IR spectra and the protein content was quantified by measuring the amide I peak intensity at 1600 - 1700 cm-1. To quantify the lipids and carbohydrates, the samples were lyophilized and measured by the intensities at 2800 - 3000 cm-1 and 800 - 1200 cm-1, respectively. RESULTS: The ATR FT-IR analysis showed that total plasma proteins remained unchanged (HC baseline = 135.20±4.20 and HFLC baseline = 135.24±3.91AU). However, the HC diet at baseline showed a significant accumulation of lipids (30.06±7.75 AU, 95% CI = 6.93) and carbohydrates (42.92±11.62 AU, 95% CI = 10.39). Additionally, total lipids in the HC diet significantly decreased at 24-hours post-exercise (from 30.06±7.75 to 28.51±7.91 AU, p=0.016). CONCLUSION: A short-term high-fat diet does not significantly alter any macronutrient contents in plasma, whereas a high-carbohydrate diet increases an accumulation of lipids and carbohydrates. Elevated plasma lipids and carbohydrates with a high-carbohydrate diet may be due to decreased insulin sensitivity, which consequently led to increased plasma lipid contents. Notably, decreased total plasma lipid content following an acute bout of exercise suggests that lipids were the primary energy substrate.

Increased plasma and adipose tissue levels of ANGPTL8/Betatrophin and ANGPTL4 in people with hypertension

BackgroundHypertension is a risk factor for both cardiovascular diseases (CVDs) and type 2 diabetes (T2D). Angiopoietin-like proteins (ANGPTLs), mainly ANGPTL3, ANGPTL4 and ANGPTL8, are associated with increased plasma lipid content due to their role in regulating the activity of lipoprotein lipase, a key enzyme in metabolism of the lipoprotein in circulation. Dyslipidaemia is a risk factor for hypertension development; however, the roles of ANGPTL3, ANGPTL4 and ANGPTL8 in subjects with hypertension have not yet been established. This study compared the plasma and adipose tissue levels of ANGPTL3, ANGPTL4 and ANGPTL8 in age- and body mass index-matched subjects with and without hypertension.MethodsA total of 119 subjects, including 69 hypertensive and 50 non-hypertensive subjects, were enrolled. ANGPTL3, ANGPTL4 and ANGPTL8 plasma levels were measured by ELISA, whereas their levels in adipose tissue were assessed via real-time PCR.ResultsWe found that ANGPTL4 (202.49 ± 17.44 ng/mL vs. 160.64 ± 10.36 ng/mL, p = 0.04) and ANGPTL8 levels (2310.96 ± 194.88 pg/mL vs. 1583.35 ± 138.27 pg/mL, p = 0.001) were higher in hypertensive subjects than non-hypertensive subjects. However, ANGPTL3 levels were not significantly different between the two populations. Similarly, ANGPTL4 and ANGPTL8 levels were also elevated in subjects with T2D and hypertension than in those with T2D but not hypertension. Additionally, people with highest tertiles of ANGPTL8 had higher odds of having hypertension (odd ratio [OR] = 3.8, 95% confidence interval [CI] = (1.5-9.8), p-Value = 0.005. Similar to its plasma levels, ANGPTL4 and ANGPTL8 were higher in adipose tissue.ConclusionsIn conclusion, our data illustrate that ANGPTL4 and ANGPTL8 levels in both plasma and adipose tissues are increased in subjects with hypertension. The elevated levels of ANGPTL4 and ANGPTL8 in hypertensive subjects highlight their potential involvement, their potential role as biomarkers for hypertension and their therapeutic value in hypertension given their roles in regulating lipid metabolism.

Absence of Nicotinamide Nucleotide Transhydrogenase in C57BL/6J Mice Exacerbates Experimental Atherosclerosis

Background: Mitochondrial reactive oxygen species (ROS) contribute to inflammation and vascular remodeling during atherosclerotic plaque formation. C57BL/6N (6N) and C57BL/6J (6J) mice display distinct mitochondrial redox balance due to the absence of nicotinamide nucleotide transhydrogenase (NNT) in 6J mice. We hypothesize that differential NNT expression between these animals alters plaque development. Methods: 6N and 6J mice were treated with AAV8-PCSK9 (adeno-associated virus serotype 8/proprotein convertase subtilisin/kexin type 9) virus leading to hypercholesterolemia, increased low-density lipoprotein, and atherosclerosis in mice fed a high-fat diet (HFD). Mice were co-treated with the mitochondria-targeted superoxide dismutase mimetic MitoTEMPO to assess the contribution of mitochondrial ROS to atherosclerosis. Results: Baseline and HFD-induced vascular superoxide is increased in 6J compared to 6N mice. MitoTEMPO diminished superoxide in both groups demonstrating differential production of mitochondrial ROS among these strains. PCSK9 treatment and HFD led to similar increases in plasma lipids in both 6N and 6J mice. However, 6J animals displayed significantly higher levels of plaque formation. MitoTEMPO reduced plasma lipids but did not affect plaque formation in 6N mice. In contrast, MitoTEMPO surprisingly increased plaque formation in 6J mice. Conclusion: These data indicate that loss of NNT increases vascular ROS production and exacerbates atherosclerotic plaque development.

Camelina Sativa Oil, but not Fatty Fish or Lean Fish, Improves Serum Lipid Profile in Subjects with Impaired Glucose Metabolism-A Randomized Controlled Trial.

The aim of the study is to examine whether lean fish (LF), fatty fish (FF), and camelina sativa oil (CSO), a plant-based source of alpha-linolenic acid (ALA), differ in their metabolic effects in subjects with impaired glucose metabolism. Altogether 79 volunteers with impaired fasting glucose, BMI 25-36 kg m-2 , age 43-72 years, participated in a 12-week randomized controlled trial with four parallel groups, that is, the FF (four fish meals/week), LF (four fish meals/week), CSO (10 g d-1 ALA), and control (limited intakes of fish and sources of ALA) groups. The proportions of eicosapentaenoic acid and DHA increase in plasma lipids in the FF group, and the proportion of ALA increase in the CSO group (p < 0.0001 for all). In the CSO group, total and LDL-cholesterol (C) concentrations decrease compared with the FF and LF groups; LDL-C/HDL-C and ApoB/ApoA-I ratios decrease compared with the LF group. There are no significant changes in glucose metabolism or markers of low-grade inflammation. A diet enriched in CSO improves serum lipid profile as compared with a diet enriched in FF or LF in subjects with impaired fasting glucose, with no differences in glucose metabolism or concentrations of inflammatory markers.