Increased Plasma High-density Lipoprotein Research Articles

Obicetrapib Alone and in Combination with Ezetimibe Reduces Atherosclerotic Lesion Prevalence, Size and Severity in ApoE*3-Leiden.CETP Mice

Background and Aims: Obicetrapib is a selective, potent, cholesteryl ester transfer protein (CETP) inhibitor in clinical development for the treatment of hypercholesterolemia and reduction of cardiovascular risk. It strongly reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and increases plasma high-density lipoprotein cholesterol (HDL-C). Ezetimibe is a potent, selective inhibitor of biliary and dietary cholesterol absorption from the small intestine, also reducing LDL-C levels. The current study evaluated the effect of obicetrapib monotherapy and in combination with ezetimibe on atherosclerosis development in a mouse model for hyperlipidemia and atherosclerosis.Methods: Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib alone (2 mg/kg/day), ezetimibe alone (on average 0.6 mg/kg/day), or the combination of obicetrapib and ezetimibe. After 28 weeks of treatment, atherosclerosis development was measured in the aortic roots.Results: Obicetrapib, ezetimibe, and the combination reduced total plasma cholesterol levels (-31%, -19% and -53%), mainly attributed to a decrease in non-HDL-C levels (-53%, -19% and -75%). Obicetrapib and combination treatment nearly completely blocked CETP activity (-98% and -98%). Obicetrapib, ezetimibe, and the combination reduced atherosclerotic lesion size (-90%, -50% and -98%) and reduced severe lesions (-82%, -31% and -98%). The percentage of unaffected segments was increased by obicetrapib and the combination treatment (+347%, +442%).Conclusions: Obicetrapib alone and the combination with ezetimibe robustly lowers non-HDL-C levels and impedes atherosclerosis development through a large decrease in atherosclerotic lesion size and severity.

Reduction of lauric acid content in virgin coconut oil improved plasma lipid profile in high-fat diet-induced hypercholesterolemic mice.

Virgin coconut oil (VCO) is claimed to have various health benefits, but favorable effects of its major component (∼50%), lauric acid, are controversial. Therefore, we aimed to reduce lauric acid content (∼30%) in VCO and evaluate its effect compared to VCO and medium-chain triglycerides (MCT), on food intake, bodyweight (BW), lipid profiles, and hepatic histology. Female C57BL/6 mice were treated with different diets for 3 months: control (normal diet), high-fat diet (HF), HF+VCO, HF+MCT, HF+low lauric acid VCO (LLA), and normal diet+LLA (C+LLA). LLA was prepared by enzymatic interesterification of VCO with methyl octanoate (methyl caprylate) and methyl decanoate (methyl caprate). Plasma and liver lipids, including total cholesterol (TC), high-density lipoprotein (HDL), and triglyceride, were measured by colorimetric assay, and hepatic fat accumulation was examined by oil-red-O staining. HF mice exhibited high plasma and liver TC and low-density lipoprotein (LDL). VCO or MCT treatment lowered liver TC and LDL, whereas LLA increased plasma HDL and markedly improved TC:HDL ratio. The HF-induced hepatic fat accumulation was attenuated by all treatments, of which VCO was the most effective. Control mice administered with LLA demonstrated lower liver TC and LDL, but higher plasma TC and HDL compared to controls. Lowest BW gain and food intake were found in mice treated with LLA. In conclusion, VCO, MCT, and LLA ameliorated hepatic histopathology caused by HF. VCO and MCT improved liver lipid profiles, whereas LLA has more beneficial effect on plasma lipids via a better TC:HDL ratio and showed promise for BW control.

Protective Impact of Vanillic Acid on Lipid Profile and Lipid Metabolic Enzymes in Diabetic Hypertensive Rat Model Generated by a High-Fat Diet.

Diabetes is the most common component of metabolic syndrome, including abdominal obesity, insulin resistance, hypertension, and dyslipoproteinemia. This study aims to determine whether vanillic acid has antihyperlipidemic properties in diabetic hypertensive rats. For this study healthy male albino Wister rats (180-220 gm) were selected. A 20-week highfat diet (HFD) was given to produce diabetic hypertension in Wister rats. Control and diabetic hypertensive rats were treated with vanillic acid. Vanillic acid effects on lipid profiles (cholesterol, triglycerides, phospholipids, free fatty acids, high-density lipoproteins (HDL)) and lipid metabolizing enzymes LPL, LCAT, and HMG CoA reductase studied by a conventional method. To understand the effect of vanillic acid control, experimental rat lipid and metabolic enzymes were studied and treated and controlled animal liver tissues were observed using the different histology staining agents. Vanillic acid caused considerable lipid profile reductions except for HDL and increased plasma HDL levels. After eight weeks of vanillic acid administration also boosts lipid marker enzyme activity (HMG CoA reductase, LPL, and LCAT). In addition, vanillic acid reduces the accumulation of collagen in liver tissues. These research studies suggest that vanillic acid has antihyperlipidemic effects in diabetic hypertensive rats fed an HFD.

8(R)-hydroxy-eicosapentaenoic acid (8R-HEPE) induces transcription of cholesterol efflux receptors via activation of liver X receptor in macrophages.

Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease. 8-HEPE from North Pacific krill (Euphausia pacifica) is known to reduce plasma LDL cholesterol levels and increase plasma HDL cholesterol levels in LDL receptor knock-out mice fed a western diet. Moreover, 8-HEPE also reduces the area of aortic atherosclerosis in apoE knock-out mice fed the same diet. In this study, we examined the stereochemical specific activity of 8-HEPE for inducing expression of cholesterol efflux receptors (Abca1 and Abcg1) in J774.1 cells. Our findings show 8R-HEPE induces the expression of Abca1 and Abcg1 via activation of liver X receptor, whereas 8S-HEPE elicits no such activity. These results suggest that 8R-HEPE derived from North Pacific krill may have beneficial effects against dyslipidemia.

Sichuan dark tea improves lipid metabolism and prevents aortic lipid deposition in diet-induced atherosclerosis model rats.

Sichuan dark tea (ST), Zangcha, is a traditional fermented Chinese tea found in Sichuan and Tibet and claimed for beneficial effects against lifestyle-related metabolic disorders. We examined the effects of ST on lipid metabolism and atherosclerosis. Sichuan dark tea was given to fat-rich diet-induced atherosclerosis model rats in comparison with dark-fermented Chinese Pu-erh tea (PT) and Japanese green tea (GT). After 8 weeks of feeding, ST and PT induced an increase in high-density lipoprotein (HDL)-cholesterol and a decrease in glucose, and ST decreased triglyceride in plasma. ST also induced low pH in the cecum. There was no significant change in their body weight among the fat-feeding groups but a decrease was found in the visceral fat and liver weight in the ST group. Accordingly, ST reduced lipid deposition in the aorta in comparison with PT and GT. ST increased mRNA of LXRα, PPARα, PPARγ, and ABCA1 in the rat liver. The extract of ST stimulated the AMPK pathway to increase the expression of ABCA1 in J774 cells and increased expression of lipoprotein lipase and hormone-sensitive lipase in 3T3L1 cells, consistent with its anti-atherogenic effects in rats. High-performance liquid chromatography analysis showed unique spectra of original specific compounds of caffeine and catechins in each tea extract, but none of them was likely responsible for these effects. Sichuan dark tea increases plasma HDL and reduces plasma triglyceride to decrease atherosclerosis through AMPK activation. Further study is required to identify specific components for the effects of this tea preparation.

Probiotics and Synbiotics Addition to Bama Mini-Pigs' Diet Improve Carcass Traits and Meat Quality by Altering Plasma Metabolites and Related Gene Expression of Offspring.

This study evaluated the effects of maternal probiotics and synbiotics addition on several traits and parameters in offspring. A total of 64 Bama mini pigs were randomly allocated into the control (basal diet), antibiotic (50 g/t virginiamycin), probiotics (200 mL/day probiotics), or synbiotics (500 g/t xylo-oligosaccharides and 200 mL/day probiotics) group and fed with experimental diets during pregnancy and lactation. After weaning, two piglets per litter and eight piglets per group were selected and fed with a basal diet. Eight pigs per group were selected for analysis at 65, 95, and 125 days of age. The results showed that the addition of probiotics increased the average daily feed intake of the pigs during the 66- to 95-day-old periods and backfat thickness at 65 and 125 days of age, and that the addition of synbiotics increased backfat thickness and decreased muscle percentage and loin-eye area at 125 days of age. The addition of maternal probiotics increased the cooking yield and pH45min value at 65 and 95 days of age, respectively, the addition of synbiotics increased the meat color at 95 days of age, and the addition of probiotics and synbiotics decreased drip loss and shear force in 65- and 125-day-old pigs, respectively. However, maternal antibiotic addition increased shear force in 125-day-old pigs. Dietary probiotics and synbiotics addition in sows' diets increased several amino acids (AAs), including total AAs, histidine, methionine, asparagine, arginine, and leucine, and decreased glycine, proline, isoleucine, α-aminoadipic acid, α-amino-n-butyric acid, β-alanine, and γ-amino-n-butyric acid in the plasma and longissimus thoracis (LT) muscle of offspring at different stages. In the LT muscle fatty acid (FA) analysis, saturated FA (including C16:0, C17:0, and C20:0) and C18:1n9t contents were lower, and C18:2n6c, C16:1, C20:1, and unsaturated FA contents were higher in the probiotics group. C10:0, C12:0, and C14:0 contents were higher in 65-day-old pigs, and C20:1 and C18:1n9t contents were lower in the synbiotics group in 95- and 125-day-old pigs, respectively. The plasma biochemical analysis revealed that the addition of maternal probiotics and synbiotics decreased plasma cholinesterase, urea nitrogen, and glucose levels in 95-day-old pigs, and that the addition of synbiotics increased plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol concentrations in 65-day-old pigs and triglyceride concentration in 125-day-old pigs. The addition of maternal probiotics and synbiotics regulated muscle fiber type, myogenic regulation, and lipid metabolism-related gene expression of LT muscle in offspring. In conclusion, the addition of maternal probiotics and synbiotics improved the piglet feed intake and altered the meat quality parameters, plasma metabolites, and gene expression related to meat quality.

Combined Effects of High-Intensity Aerobic Exercise Training and Ziziphus jujuba Extract on Tissue Nesfatin-1 in Rats.

Nesfatin-1 is involved in metabolic/feeding regulation and prevention of cardiovascular disease. Previous studies have shown that exercise and herb supplementation can influence nesfatin-1 concentration. The present study investigated the effects of high-intensity training (HIT) and Ziziphus jujuba (ZJ) extract on tissue nesfatin-1 in rats. Twenty-eight female rats were randomly assigned to one of four groups i.e. 1) Saline-Control (SC), 2) Saline-High Intensity Training (ST), 3) Ziziphus jujuba-Control (ZJC), and 4) Ziziphus jujuba-High Intensity Training (ZJT). Rats performed exercise on a treadmill and/or administered supplements intragastrically for 6 weeks, depending on group category. Seventy-two hours after the last training session, rats were anesthetized. Blood, hypothafi 2lamus tissue, heart and gastrocnemius muscles were sent to the laboratory for analyses. Significantly higher nesfatin-1 gene expression and concentration and ATP concentration were found in trained rat. HIT increased plasma High Density Lipoprotein (HDL) and insulin concentration and reduced plasma Triglyceride (TG) and cortisol. ZJ increased tissue nesftain-1 gene expression and concentration while only increasing heart ATP. The combination of exercise and ZJ showed an additive effect compared to each intervention alone on hypothalamus, heart and gastrocnemius NUCB2 gene expression, heart and gastrocnemius nesfatin-1 concentration, plasma HDL and cortisol concentration. The authors recommend both interventions as a means to improve cardiovascular health in rats with further work needed to confirm similar findings in homo sapiens.

Influence of Dietary Chitosan Feeding Duration on Glucose and Lipid Metabolism in a Diabetic Rat Model.

This study was designed to investigate the influence of dietary chitosan feeding-duration on glucose and lipid metabolism in diabetic rats induced by streptozotocin and nicotinamide [a non-insulin-dependent diabetes mellitus (NIDDM) model]. Male Sprague-Dawley rats were used as experimental animals and divided into short-term (6 weeks) and long-term (11 weeks) feeding durations, and each duration contained five groups: (1) control, (2) control + 5% chitosan, (3) diabetes, (4) diabetes + 0.8 mg/kg rosiglitazone (a positive control), and (5) diabetes + 5% chitosan. Whether the chitosan feeding was for 6 or 11 weeks, the chitosan supplementation decreased blood glucose and lipids levels and liver lipid accumulation. However, chitosan supplementation decreased plasma tumor necrosis factor (TNF)-α, insulin levels, alanine aminotransferase (ALT) activity, insulin resistance (HOMA-IR), and adipose tissue lipoprotein lipase activity. Meanwhile, it increased plasma high-density lipoproteins (HDL)-cholesterol level, plasma angiopoietin-like-4 protein expression, and plasma triglyceride levels (at 11-week feeding duration only). Taken together, 11-week (long-term) chitosan feeding may help to ameliorate the glucose and lipid metabolism in a NIDDM diabetic rat model.

An octimibate derivative, Oxa17, enhances cholesterol efflux and exerts anti-inflammatory and atheroprotective effects in experimental atherosclerosis

Atherosclerotic cardiovascular diseases (ASCVDs), associated with vascular inflammation and lipid dysregulation, are responsible for high morbidity and mortality rates globally. For ASCVD treatment, cholesterol efflux plays an atheroprotective role in ameliorating inflammation and lipid dysregulation. To develop a multidisciplinary agent for promoting cholesterol efflux, octimibate derivatives were screened and investigated for the expression of ATP-binding cassette transporter A1 (ABCA1). Western blotting and qPCR analysis were conducted to determine the molecular mechanism associated with ABCA1 expression in THP-1 macrophages; results revealed that Oxa17, an octimibate derivative, enhanced ABCA1 expression through liver X receptors alpha (LXRα) activation but not through the microRNA pathway. We also investigated the role of Oxa17 in high-fat diet (HFD)-fed mice used as an in vivo atherosclerosis-prone model. In ldlr−/− mice, Oxa17 increased plasma high-density lipoprotein (HDL) and reduced plaque formation in the aorta. Plaque stability improved via reduction of macrophage accumulation and via narrowing of the necrotic core size under Oxa17 treatment. Our study demonstrates that Oxa17 is a novel and potential agent for ASCVD treatment with atheroprotective and anti-inflammatory properties.

MiR-33 Silencing Reprograms the Immune Cell Landscape in Atherosclerotic Plaques.

[Figure: see text].

Evaluation of the ameliorative effect of Spirulina (Arthrospira platensis) supplementation on parameters relating to lead poisoning and obesity in C57BL/6J mice

• Oral exposure of Spirulina to C57BL/6J mice with lead acetate and high-fat diet. • Lead-related anemia was normalized and hematocrit and ALAD activity were recovered. • Decrease of epididymal white adipose tissue and increase of HDL-C by Spirulina. • Mitigative effects of Spirulina on lead poisoning and obesity were suggested. The current study aimed to validate the possible ameliorative effects of Spirulina ( Arthrospira platensis ) on lead poisoning and obesity using C57BL/6J mice. After a treatment period, we performed metal analyses, as well as hematocrit and plasma biochemical parameter measurements, and assayed oxidative stress markers and erythrocyte δ-aminolevulinic acid dehydratase (ALAD) activity. Our results highlighted the effectiveness of Spirulina in improving anemia status with the normalization of hematocrit levels and ALAD activity ratios, even in mice that exhibited obesity in addition to lead poisoning. Spirulina treatment also decreased epididymal white adipose tissue weight and increased plasma high-density lipoprotein levels, which are normally reduced after lead exposure. However, most of the studied plasma biochemical parameters and oxidative stress markers did not show large changes after treatment, likely because of the short duration of treatment. Further studies with longer-term exposures are required to validate the usefulness of Spirulina suggested in the present study.

The effects of peripheral lipoprotein metabolism on cerebrovascular inflammation in APP/PS1 mice

AbstractBackgroundAlthough Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaques and neurofibrillary tangles, most AD patients also exhibit cerebrovascular dysfunction. Therefore, strategies promoting cerebrovascular resilience have potential as therapeutic or preventative interventions against AD. High‐density lipoproteins (HDL) have several known beneficial functions on peripheral vessels. Further, increased plasma HDL concentrations have been associated with reduced dementia risk and HDL supplementation reduces both amyloid pathology and cognitive deficits in AD model mice. We therefore hypothesized that HDL may promote cerebrovascular health to protect against AD. We investigated the effects of HDL specifically on the cerebrovasculature in APP/PS1 mice, an AD model, using two methods.MethodsFirst, we reduced plasma HDL levels by creating APP/PS1 mice genetically deficient for apolipoprotein (apo)A‐I, the primary protein component of HDL. Second, we treated 12‐month old APP/PS1 mice with a non‐brain penetrant liver X receptor (LXR) agonist for seven days to selectively upregulate the HDL biogenesis pathways in peripheral tissues. We measured cognitive deficits using cued and contextual fear conditioning tests. Fluorescent amyloid staining was used to assess vascular amyloid deposition. Immunofluorescent imaging evaluating glial fibrillary acidic protein (GFAP) and intercellular adhesion molecule 1 (ICAM‐1) association with CD31 positive area was used to assess vessel‐associated astrogliosis and endothelial inflammation, respectively.ResultsAt 12 months of age, apoAI‐null mice had increased cognitive deficits in cued and contextual fear conditioning tests, increased vascular amyloid burden, increased vessel‐associated astrogliosis, and increased brain endothelial cell inflammation. Seven days of LXR agonist treatment had no effect on amyloid pathology or astrogliosis. However, LXR agonist‐treated APP/PS1 mice displayed reduced cognitive deficits in cued fear conditioning tests and reduced endothelial cell inflammation.ConclusionsCirculating HDL promotes cerebrovascular health in APP/PS1 mice by limiting both Aβ‐induced vascular inflammation and vascular Aβ deposition resulting in reduced amyloid pathology and cognitive deficits.

Quantile-specific heritability of high-density lipoproteins with implications for precision medicine

We have previously shown that the effect of a high-density lipoprotein (HDL) genetic risk score depends on whether the phenotype (HDL cholesterol) is high or low relative to its distribution (quantile-dependent expressivity). Evidence for quantile-dependent expressivity was sought using a more inclusive genetic measure (quantile-specific heritability, h2) in a larger population (Framingham cohort). Quantile regression was used to test whether the offspring-parent (βOP) and full-sib (βFS) regression slopes increased with the percentiles of the offspring's HDL distribution in 10,650 parent-offspring pairs and 2130 sibships. Quantile-specific heritability was estimated by 2βOP/(1+ rspouse) and [(8βFSrspouse+ 1)0.5-1]/(2rspouse), where rspouse is the spouse correlation. HDL cholesterol heritability estimated from βOP increased significantly (P=4.2×10-5) from the 10th (h2 ± SE: 0.44±0.03), 25th (0.45±0.03), 50th (0.47±0.03), and 75th (0.56±0.04) to the 90th percentiles (0.65±0.06) of the offspring's age- and sex-adjusted HDL cholesterol distribution. Heritability estimated from βFS also increased significantly with the percentiles of the offspring's HDL cholesterol (P=.002), apo A1 (P=.006), HDL2 cholesterol (P=.003), and HDL3 cholesterol distribution (P=.02). Consistent with quantile-dependent expressivity, published pharmacologic and nutritional interventions that raised (eg, statin, fibrates, estrogen replacement therapy, efavirenz, and dietary fat) or lowered HDL cholesterol concentrations (tamoxifen, dietary carbohydrate) correspondingly increased and decreased genetic effects. HDL cholesterol heritability increased with increasing percentile of the offspring's HDL distribution. Whereas precision medicine is based on the premise that genetic markers identify patients most likely to benefit from drugs and diet, quantile-dependent expressivity postulates that the strong signals from these genetic markers simply trace the heritability increase with increasing plasma HDL concentrations. Thus, quantile-dependent expressivity provides an alternative interpretation to these genotype-specific effects.

Consumption of Goat Cheese Naturally Rich in Omega-3 and Conjugated Linoleic Acid Improves the Cardiovascular and Inflammatory Biomarkers of Overweight and Obese Subjects: A Randomized Controlled Trial.

This study examines the value of a goat cheese naturally enriched in polyunsaturated fatty acids (PUFA) (n-3 PUFA and conjugated linolenic acid (CLA)) as means of improving cardiovascular and inflammatory health. Sixty-eight overweight and obese subjects (BMI ≥ 27 and <40 kg/m2), with at least two risk factors for cardiovascular disease (CVD) in a lipid panel blood tests, participated in a randomized, placebo-controlled, double-blind, parallel designed study. The subjects consumed for 12 weeks: (1) 60 g/d control goat cheese and (2) 60 g/d goat cheese naturally enriched in n-3 PUFA and CLA. Diet and physical activity were assessed. Anthropometric and dual-energy X-ray absorptiometry (DXA) tests were performed. Blood samples were collected at the beginning and at the end of the study period. Changes in health status, lifestyle and dietary habits, and daily compliance were recorded. The consumption of a PUFA-enriched goat cheese significantly increased plasma high-density lipoprotein (HDL)-cholesterol, as well as in apolipoprotein B, and it significantly decreased high-sensitivity C-reactive protein concentrations compared to the control goat cheese (p < 0.05). The significant improvement of the plasma lipid profile and inflammatory status of people with risk for CVD due to the consumption of PUFA-enriched cheese suggests a potential role of this dairy product as an alternative to develop high nutritional value food in a balanced diet comprising regular exercise.

Fibrinogen and Low-Density Lipoprotein (LDL) Cholesterol Levels with the Occurrence of Acute Myocardial Infarction: Is it Correlated?

Fibrinogen is considered as a risk factor associated with cardiovascular disease, especially acute myocardial infarction (AMI). The role of increasing levels of fibrinogen in the thrombosis shows that there is an effect that causes the pathway to form a thrombosis. Increased plasma high-density lipoprotein (LDL) cholesterol can also induce the development of atherosclerosis and is associated with AMI events. This study was an observational analytic study using a cross-sectional approach, carried out from August-November 2015 in Dr. Soetomo Hospital Surabaya. Samples were 67 subjects who fulfilled inclusion and exclusion criteria. A total of 67 subjects were assessed, 47 (70.15%) were males, and 20 (29.85%) were females. The mean age was 5.07 ± 11.02 years old, ranging from 30 to 85 years. AMI was diagnosed in 49 patients (26.87%). Management of AMI patients consisted of conservative medical therapy (42.86%), thrombolytic therapy (18.37%) and PPCI (38.77%). The statistical analysis revealed significant differences in plasma fibrinogen and LDL cholesterol levels between the AMI patient group and the control group. There was a significant correlation between fibrinogen levels and LDL cholesterol levels. Fibrinogen and LDL cholesterol levels are correlated with AMI risk factors. In subjects with AMI, there were higher fibrinogen and LDL cholesterol levels compared to non-AMI subjects.

The Effect of Subdiaphragmatic Vagotomy on Lipid Profile and Insulin Resistance in Diabetic Obese Rats

The aim of the study was to assess of the effect of subdiaphragmatic vagotomy on lipid profile and insulin resistance in diabetic obese rat model. Fifty Male Albino rats were divided into 5 groups. Subdiaphragmatic vagotomy and sham operations were applied on diabetic obese rat model induced by high fat diet for 5 weeks and low dose of streptozotocin (30mg/kg). Serum samples were collected for confirmation of hyperlipidemia and lee obesity index was measured. At the end of the experiment, oral glucose tolerance test, lee obesity index, lipid profile, fasting insulinemia, fasting glucose, insulin resistance (HOMA-IR) and histopathology of pancreases were assessed. Results revealed that Subdiaphragmatic vagotomy significantly improved hyperlipidemia as it normalized plasma triglyceride level, decreased plasma cholesterol level and increased plasma high density lipoprotein level in diabetic and non-diabetic obese vagotomized rats. Vagotomy significantly decreased lee obesity index and perigonadal fat pads weight, decreased fasting insulinemia, decreased HOMA-IR and improved glucose tolerance in diabetic and non-diabetic obese vagotomized rats. These results were confirmed by regression of degenerative changes and restoration of the size of pancreatic islets of Langerhans. In non-diabetic obese vagotomized group, the results of 120 minutes of oral glucose tolerance test and HOMA-IR were close to normal expected values. However, the same parameters were still away from normal expected values although normal histopathological results of pancreases, in diabetic obese vagotomized group. In Conclusion, subdiaphragmatic vagotomy has a promising role in treating obesity. Nevertheless, its role in treating diabetes needs further long-term studies to be approved.

Targeted Deletion of Hepatocyte Abca1 Increases Plasma HDL (High-Density Lipoprotein) Reverse Cholesterol Transport via the LDL (Low-Density Lipoprotein) Receptor.

The role of hepatocyte Abca1 (ATP binding cassette transporter A1) in trafficking hepatic free cholesterol (FC) into plasma versus bile for reverse cholesterol transport (RCT) is poorly understood. We hypothesized that hepatocyte Abca1 recycles plasma HDL-C (high-density lipoprotein cholesterol) taken up by the liver back into plasma, maintaining the plasma HDL-C pool, and decreasing HDL-mediated RCT into feces. Approach and Results: Chow-fed hepatocyte-specific Abca1 knockout (HSKO) and control mice were injected with human HDL radiolabeled with 125I-tyramine cellobiose (125I-TC; protein) and 3H-cholesteryl oleate (3H-CO). 125I-TC and 3H-CO plasma decay, plasma HDL 3H-CO selective clearance (ie, 3H-125I fractional catabolic rate), liver radiolabel uptake, and fecal 3H-sterol were significantly greater in HSKO versus control mice, supporting increased plasma HDL RCT. Twenty-four hours after 3H-CO-HDL injection, HSKO mice had reduced total hepatic 3H-FC (ie, 3H-CO hydrolyzed to 3H-FC in liver) resecretion into plasma, demonstrating Abca1 recycled HDL-derived hepatic 3H-FC back into plasma. Despite similar liver LDLr (low-density lipoprotein receptor) expression between genotypes, HSKO mice treated with LDLr-targeting versus control antisense oligonucleotide had slower plasma 3H-CO-HDL decay, reduced selective 3H-CO clearance, and decreased fecal 3H-sterol excretion that was indistinguishable from control mice. Increased RCT in HSKO mice was selective for 3H-CO-HDL, since macrophage RCT was similar between genotypes. Hepatocyte Abca1 deletion unmasks a novel and selective FC trafficking pathway that requires LDLr expression, accelerating plasma HDL-selective CE uptake by the liver and promoting HDL RCT into feces, consequently reducing HDL-derived hepatic FC recycling into plasma.

Apolipoprotein A-I Protects Against Pregnancy-Induced Insulin Resistance in Rats.

Objective- Insulin resistance and inflammation in pregnancy are risk factors for gestational diabetes mellitus. Increased plasma HDL (high-density lipoprotein) and apo (apolipoprotein) A-I levels have been reported to improve glucose metabolism and inhibit inflammation in animals and humans. This study asks whether increasing plasma apoA-I levels improves insulin sensitivity and reduces inflammation in insulin-resistant pregnant rats. Approach and Results- Insulin-resistant pregnant rats received intravenous infusions of lipid-free apoA-I (8 mg/kg) or saline on days 6, 9, 12, 15, and 18 of pregnancy. The rats were then subjected to a euglycemic-hyperinsulinemic clamp. Glucose uptake was increased in white and brown adipose tissue by 57±13% and 32±10%, respectively ( P<0.05 for both), and in quadriceps and gastrocnemius muscle by 35±9.7% and 47±14%, respectively ( P<0.05 for both), in the apoA-I-treated pregnant rats relative to saline-infused pregnant rats. The pregnant rats that were treated with apoA-I also had reduced plasma TNF-α (tumor necrosis factor-α) levels by 57±8.4%, plasma IL (interleukin)-6 levels by 67±9.5%, and adipose tissue macrophage content by 54±8.2% ( P<0.05 for all) relative to the saline-treated pregnant rats. Conclusions- These studies establish that apoA-I protects against pregnancy-induced insulin resistance in rats by increasing insulin sensitivity in adipose tissue and skeletal muscle and inhibiting inflammation. This identifies apoA-I as a potential target for preventing pregnancy-induced insulin resistance and reducing the incidence of gestational diabetes mellitus.

Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase.

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctrough > 15 fold over mouse plasma EL IC50 over 4 days).

Cyclodextrin Ameliorates the Progression of Atherosclerosis via Increasing High-Density Lipoprotein Cholesterol Plasma Levels and Anti-inflammatory Effects in Rabbits.

To investigate the therapeutic effects of cyclodextrin on the development of atherosclerosis in rabbits, we evaluated the effects of (2-hydroxypropyl)-β-cyclodextrin (HPβCD) therapy on the organ coefficient, lipid profiles, inflammatory cytokines, and atherosclerotic plaques in rabbits fed a high-fat diet. Our results demonstrated that HPβCD therapy reduced plasma triglyceride levels and inflammatory cytokine levels but increased plasma high-density lipoprotein cholesterol levels. HPβCD therapy produced a significant decrease in the atherosclerotic lesion area and reduced macrophage and collagen content in the lesions. The expression levels of inflammatory genes in aortic plaques were significantly reduced by HPβCD treatment, but the expression of ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1 (ABCG1) in aortic plaques and livers increased significantly. HPβCD therapy may produce additional antiatherosclerotic benefits likely via increasing high-density lipoprotein cholesterol levels.