Increased Plasma High-density Lipoprotein Research Articles

Acute Toxicity Study and Comparative effect of Kigelia Pinnata (Cucumber Tree) Ethanolic leaf extract on Serum Lipid profile of Albino Wistarrats treated fat diet.

The aim of this study was designed to evaluate the activity of the Kigelia Pinnata ethanolic leaf extract on the serum lipid profile of male albino Wistar rats exposed to a fat diet. Kigelia Pinnata leaves were obtained, air dried, powdered and extracted in a Soxhlet apparatusin 400ml ethanol solution. Hypolipidaemic activity studies on rat models fed with palm oil and coconut milk was conducted. The acute toxicity test of the extract was carried out by the lorke's method. Results showed that Kigelia Pinnata ethanolic leaf extract significantly lowered (P<0.05) plasma Total Cholesterol (TC), Low Density Lipoprotein (LDL)-Cholesterol and Triacylglycerol (TG) and significantly (P<0.05) increased plasma High Density Lipoprotein (HDL)-Cholesterol. Toxicity studies suggested that, the extract was safe at the doze 2000mg/kg. Overall findings from this study showed that the ethanolic extract exhibited hypolipidaemic activity and may possess cardio-protective properties.

Apolipoprotein A-I enhances insulin-dependent and insulin-independent glucose uptake by skeletal muscle

Therapeutic interventions that increase plasma high density lipoprotein (HDL) and apolipoprotein (apo) A-I levels have been reported to reduce plasma glucose levels and attenuate insulin resistance. The present study asks if this is a direct effect of increased glucose uptake by skeletal muscle. Incubation of primary human skeletal muscle cells (HSKMCs) with apoA-I increased insulin-dependent and insulin–independent glucose uptake in a time- and concentration-dependent manner. The increased glucose uptake was accompanied by enhanced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), the serine/threonine kinase Akt and Akt substrate of 160 kDa (AS160). Cell surface levels of the glucose transporter type 4, GLUT4, were also increased. The apoA-I-mediated increase in glucose uptake by HSKMCs was dependent on phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt, the ATP binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-B1). Taken together, these results establish that apoA-I increases glucose disposal in skeletal muscle by activating the IR/IRS-1/PI3K/Akt/AS160 signal transduction pathway. The findings suggest that therapeutic agents that increase apoA-I levels may improve glycemic control in people with type 2 diabetes.

Statins: Adverse reactions, oxidative stress and metabolic interactions.

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are currently the most effective lipid-lowering drugs, effectively reducing the plasma total cholesterol and low-density lipoprotein, while also decreasing three triacylglycerols and increasing plasma high-density lipoprotein to a certain extent. However, the excessive or long-term use of statins can cause in vitro cytotoxicity, in vivo liver injury, liver necrosis, kidney damage, and myopathy in both human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with statins, and various antioxidants have been evaluated to investigate their protective roles against statin-induced liver, kidney, and muscle toxicities. Widespread attention has been given to statin-induced oxidative stress, with and without the use of other drugs. Much of the information about the mechanism for this reduction comes from cell culture and in experimental animal studies. The primary focus of this article is to summarize the research progress associated with oxidative stress as a plausible mechanism for statin-induced toxicity, as well as its metabolic interactions. This review summarizes the research conducted over the past five years into the production of reactive oxygen species, oxidative stress as a result of statin treatments, and their correlation with statin-induced toxicity and metabolism. Statin-induced metabolism involves various CYP450 enzymes, which provide potential sites for statin-induced oxidative stress, and these metabolic factors are also reviewed. The therapeutics of a variety of compounds against statin-induced organ damage based on their anti-oxidative effects is also discussed to further understand the role of oxidative stress in statin-induced toxicity. This review sheds new light on the critical roles of oxidative stress in statin-induced toxicity and prevention of this oxidative damage, as well as on the contradictions and unknowns that still exist regarding statin toxicity and the cellular effects in terms of organ injury and cell signaling pathways.

Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition.

Angioplasty and stent implantation, the most common treatment for atherosclerotic lesions, have a significant failure rate because of restenosis. This study asks whether increasing plasma high-density lipoprotein (HDL) levels by inhibiting cholesteryl ester transfer protein activity with the anacetrapib analog, des-fluoro-anacetrapib, prevents stent-induced neointimal hyperplasia. New Zealand White rabbits received normal chow or chow supplemented with 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Iliac artery endothelial denudation and bare metal steel stent deployment were performed after 2 weeks of des-fluoro-anacetrapib treatment. The animals were euthanized 4 weeks poststent deployment. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma cholesteryl ester transfer protein activity and increased plasma apolipoprotein A-I and HDL cholesterol levels by 53±6.3% and 120±19%, respectively. Non-HDL cholesterol levels were unaffected. Des-fluoro-anacetrapib treatment reduced the intimal area of the stented arteries by 43±5.6% (P<0.001), the media area was unchanged, and the arterial lumen area increased by 12±2.4% (P<0.05). Des-fluoro-anacetrapib treatment inhibited vascular smooth muscle cell proliferation by 41±4.5% (P<0.001). Incubation of isolated HDLs from des-fluoro-anacetrapib-treated animals with human aortic smooth muscle cells at apolipoprotein A-I concentrations comparable to their plasma levels inhibited cell proliferation and migration. These effects were dependent on scavenger receptor-B1, the adaptor protein PDZ domain-containing protein 1, and phosphatidylinositol-3-kinase/Akt activation. HDLs from des-fluoro-anacetrapib-treated animals also inhibited proinflammatory cytokine-induced human aortic smooth muscle cell proliferation and stent-induced vascular inflammation. Inhibiting cholesteryl ester transfer protein activity in New Zealand White rabbits with iliac artery balloon injury and stent deployment increases HDL levels, inhibits vascular smooth muscle cell proliferation, and reduces neointimal hyperplasia in an scavenger receptor-B1, PDZ domain-containing protein 1- and phosphatidylinositol-3-kinase/Akt-dependent manner.

HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner.

Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+ mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tg mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.

Myeloid-specific genetic ablation of ATP-binding cassette transporter ABCA1 is protective against cancer.

Increased circulating levels of apolipoprotein A-I (apoA-I), the major protein of high-density lipoprotein (HDL), by genetic manipulation or infusion, protects against melanoma growth and metastasis. Herein, we explored potential roles in melanoma tumorigenesis for host scavenger receptor class B, type 1 (SR-B1), and ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), all mediators of apoA-I and HDL sterol and lipid transport function. In a syngeneic murine melanoma tumor model, B16F10, mice with global deletion of SR-B1 expression exhibited increased plasma HDL cholesterol (HDLc) levels and decreased tumor volume, indicating host SR-B1 does not directly contribute to HDL-associated anti-tumor activity. In mice with myeloid-specific loss of ABCA1 (Abca1−M/−M; A1−M/−M), tumor growth was inhibited by ∼4.8-fold relative to wild type (WT) animals. Abcg1−M/−M (G1−M/−M) animals were also protected by 2.5-fold relative to WT, with no further inhibition of tumor growth in Abca1/Abcg1 myeloid-specific double knockout animals (DKO). Analyses of tumor-infiltrating immune cells revealed a correlation between tumor protection and decreased presence of the immune suppressive myeloid-derived suppressor cell (MDSC) subsets, Ly-6G+Ly-6CLo and Ly-6GnegLy-6CHi cells. The growth of the syngeneic MB49 murine bladder cancer cells was also inhibited in A1−M/−M mice. Collectively, our studies provide further evidence for an immune modulatory role for cholesterol homeostasis pathways in cancer.

Pectin penta-oligogalacturonide reduces cholesterol accumulation by promoting bile acid biosynthesis and excretion in high-cholesterol-fed mice

Haw pectin penta-oligogalacturonide (HPPS) has important role in improving cholesterol metabolism and promoting the conversion of cholesterol to bile acids (BA) in mice fed high-cholesterol diet (HCD). However, the mechanism is not clear. This study aims to investigate the effects of HPPS on cholesterol accumulation and the regulation of hepatic BA synthesis and transport in HCD-fed mice. Results showed that HPPS significantly decreased plasma and hepatic TC levels but increased plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, compared to HCD. BA analysis showed that HPPS markedly decreased hepatic and small intestine BA levels but increased the gallbladder BA levels, and finally decreased the total BA pool size, compared to HCD. Studies of molecular mechanism revealed that HPPS promoted hepatic ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor BI (SR-BI) expression but did not affect ATB binding cassette transporter G5/G8 (ABCG5/8) expression. HPPS inactivated hepatic farnesoid X receptor (FXR) and target genes expression, which resulted in significant increase of cholesterol 7α-hydroxylase 1 (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) expression, with up-regulations of 204.2% and 33.5% for mRNA levels, respectively, compared with HCD. In addition, HPPS markedly enhanced bile salt export pump (BSEP) expression but didn't affect the sodium/taurocholate co-transporting polypeptide (NTCP) expression. In conclusion, the study revealed that HPPS reduced cholesterol accumulation by promoting BA synthesis in the liver and excretion in the feces, and might promote macrophage-to-liver reverse cholesterol transport (RCT) but did not liver-to-fecal RCT.

Short-term cooling increases serum triglycerides and small high-density lipoprotein levels in humans

Cold exposure and β3-adrenergic receptor agonism, which both activate brown adipose tissue, markedly influence lipoprotein metabolism by enhancing lipoprotein lipase-mediated catabolism of triglyceride-rich lipoproteins and increasing plasma high-density lipoprotein (HDL) levels and functionality in mice. However, the effect of short-term cooling on human lipid and lipoprotein metabolism remained largely elusive. The objective was to assess the effect of short-term cooling on the serum lipoprotein profile and HDL functionality in men. Body mass index-matched young, lean men were exposed to a personalized cooling protocol for 2hours. Before and after cooling, serum samples were collected for analysis of lipids and lipoprotein composition by 1H-nuclear magnetic resonance. Adenosine triphosphate-binding cassette A1 (ABCA1)-mediated cholesterol efflux capacity of HDL was measured using [3H]cholesterol-loaded ABCA1-transfected Chinese hamster ovary cells. Short-term cooling increased serum levels of free fatty acids, triglycerides, and cholesterol. Cooling increased the concentration of large very low-density lipoprotein (VLDL) particles accompanied by increased mean size of VLDL particles. In addition, cooling enhanced the concentration of small LDL and small HDL particles as well as the cholesterol levels within these particles. The increase in small HDL was accompanied by increased ABCA1-dependent cholesterol efflux invitro. Our data show that short-term cooling increases the concentration of large VLDL particles and increases the generation of small LDL and HDL particles. We interpret that cooling increases VLDL production and turnover, which results in formation of surface remnants that form small HDL particles that attract cellular cholesterol.

Revisit on the value of increasing plasma high-density lipoprotein cholesterol levels

Revisit on the value of increasing plasma high-density lipoprotein cholesterol levels

Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice

Peroxisome proliferator-activated receptor α (PPARα) is a well-known therapeutic target for treating hyperlipidemia. K-877 is a novel selective PPARα modulator (SPPARMα) that enhances PPARα transcriptional activity with high selectivity and potency, resulting in reduced plasma lipid levels. This study aimed to evaluate the effects of K-877 on hyperlipidemia in low-density lipoprotein receptor knockout (Ldlr−/−) mice, a mouse model of atherosclerosis. We revealed that K-877 administration significantly decreased plasma triglyceride (TG) and total cholesterol (TC) levels and increased plasma high-density lipoprotein cholesterol (HDL-C) levels in Ldlr−/− mice. K-877 administration to Ldlr−/− mice efficiently increased the gene expression of PPARα and its target genes related to fatty acid oxidation in the liver and small intestine. The same treatment significantly increased ATP-binding cassette a1 gene expression in the liver and small intestine and reduced Niemann Pick C1-like 1 gene expression in the small intestine, suggesting that K-877 administration induced HDL-C production in the liver and small intestine and reduced cholesterol absorption in the small intestine. In conclusion, K-877 administration had pronounced effects on the liver and small intestine in Ldlr−/− mice. K-877 is an attractive PPARα-modulating drug for treating hyperlipidemia that works equally well in both the liver and small intestine.

Functionality of High-Density Lipoprotein as Antiatherosclerotic Therapeutic Target.

A great majority of the morbidity and mortality worldwide can still be attributed to cardiovascular diseases, such as ischemic (coronary) heart disease, angina pectoris, and myocardial and cerebral infarction. Atherosclerosis, narrowing of the arteries because of arterial cholesterol deposition in macrophage foam cells, is the driving force behind the cardiovascular disease pathology. Water-soluble protein/lipid complexes called lipoproteins mediate the transport of cholesterol and other lipoid substances through the blood compartment. Relatively high levels of cholesterol associated with apolipoprotein B–containing low-density lipoprotein (LDL) particles predispose human subjects to the development of atherosclerosis and, thereby, increase the risk for cardiovascular disease.1,2 Apolipoprotein B–containing lipoproteins are, therefore, generally regarded as being proatherogenic factors. Cholesterol ester–rich high-density lipoprotein (HDL) particles use apolipoprotein A1 (apoA1) as their primary protein component. In sharp contrast to LDL, HDL is considered a potent anti-atherogenic agent. This notion is based on the fact that, in the general population, a strong inverse correlation exists between plasma levels of HDL cholesterol and the risk of cardiovascular disease.1 Of note, this inverse association seems to be independent of the level of cholesterol associated with proatherogenic LDL particles. As such, increasing plasma levels of HDL cholesterol has long been regarded a promising alternative therapy to supplement classical statin–based LDL cholesterol–lowering strategies that are able to reduce cardiovascular disease by only ≈30%.3 However, over the last decade, the enthusiasm for HDL as an interesting therapeutic target has been challenged by the HDL hypothesis critics because genetic association studies have excluded HDL cholesterol levels as determinants for cardiovascular disease risk.2,4 Furthermore, several therapeutic HDL-targeting approaches have proven insufficient to secure benefit for cardiovascular disease patients. Niacin is the most effective drug available in the clinic to raise plasma HDL cholesterol levels. Despite the fact that niacin is …

Mendelian randomization analysis in three Japanese populations supports a causal role of alcohol consumption in lowering low-density lipid cholesterol levels and particle numbers

Background and aimsWhile alcohol consumption is known to increase plasma high-density lipoprotein (HDL) cholesterol levels, its relationship with low-density lipoprotein (LDL) cholesterol levels is unclear. Aldehyde dehydrogenase 2 (ALDH2) is a rate-controlling enzyme in alcohol metabolism, but a large number of Japanese people have the inactive allele. Here, we conducted a Mendelian randomization analysis using the ALDH2 genotype to clarify a causal role of alcohol on circulating cholesterol levels and lipoprotein particle numbers. MethodsThis study was conducted in three independent general Japanese populations (men, n = 2289; women, n = 1940; mean age 63.3 ± 11.2 years). Alcohol consumption was assessed using a questionnaire. Lipoprotein particle numbers were determined by nuclear magnetic resonance spectroscopy. ResultsAlcohol consumption increased linearly in proportion to the number of subjects carrying the enzymatically active *1 allele in men (p < 0.001). The *1 allele was also positively associated with HDL cholesterol level (adjusted mean ± standard error, *1*1: 60 ± 0.5, *1*2: 56 ± 0.6, *2*2: 55 ± 1.3 mg/dl, p < 0.001) and inversely associated with LDL cholesterol level (116 ± 0.9, 124 ± 1.1, 130 ± 2.6 mg/dl, p < 0.001). The *1 allele was also positively associated with HDL particle numbers (per-allele: 2.60 ± 0.32 μmol/l, p < 0.001) and inversely associated with LDL particle numbers (−67.8 ± 19.6 nmol/l, p = 0.001). Additional Mendelian randomization analysis failed to clarify the involvement of cholesteryl ester transfer protein in alcohol-related changes in lipoprotein cholesterol levels. No significant association was observed in women, presumably due to their small amount of alcohol intake. ConclusionsAlcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers.

The Relationship Among the Level of Serum Amyloid A, High-Density Lipoprotein and Microalbuminuria in Patients With Familial Mediterranean Fever.

Serum amyloid A (SAA), which is produced in the liver, acts as an apoprotein of high-density lipoprotein (HDL) accumulation in extracellular matrix of tissues and organs. SAA elevations play a significant role in the development of amyloidosis. Microalbuminuria (MAU) is the early period of amyloidosis in patients with familial Mediterranean fever (FMF). We assessed the association between SAA as an important factor for the development of amyloidosis in patients with FMF and cytokines, HDL, and MAU. A total of 40 FMF patients diagnosed with Tel-Hashomer criteria and making regular follow-up visits at the tertiary referral center from 2012 to 2013 were included in this study, besides 40 age- and sex-matched individuals as controls. Compared with controls, FMF patients had higher SAA (25.20 ± 45.78 vs. 1.68 ± 0.63 ng/ml; P = 0.002). Also, FMF patients had higher MAU than controls (23.20 ± 39.86 vs. 9.40 ± 5.32 mg/day; P = 0.036). HDL was significantly lower in the patient group than in controls (39.35 ± 10.45 vs. 47.82 ± 15.31 mg/dl; P = 0.023). Interleukin-1 beta (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α) levels were higher in the FMF group than in controls (P < 0.0001, P = 0.009, P = 0.003, respectively). Our results suggest that IL-1, IL-6, TNF-α, SAA, and HDL may serve as markers of subclinical inflammation in FMF patients. Due to increased plasma HDL levels, antiinflammatory and antioxidant effects may elevate in FMF patients.

The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis

BackgroundAtherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation. ObjectiveTo study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice. Approach and resultsPemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice. ConclusionsThese results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.

Effect of Dietary Betaine on Metabolic Syndrome Risk Factors in Asian

Objective: Betaine (trimethylglycine) is a naturally-occurring osmolyte and methyl donor with reported effects on liver metabolism. The aim of this study was to evaluate the safety and the effects of betaine administration to metabolic risk factors in Asian males. Methodology: Twenty Japanese males (30-59 years) with mild fatty liver were enrolled in this blinded, placebocontrolled, randomized, parallel trial to assess the effects of 3 g of daily betaine for 12 weeks on safety and metabolic biomarkers. Selection criteria included fatty liver disease, as assessed by an abdominal ultrasonogram (US), the practice of moderate alcohol consumption, liver performance status and body mass index (≤27). Abdominal computed tomography (CT) as well as blood and urine sampling were performed before and after the intervention period. Results: No differences in the degree of hepatic steatosis or in the occurrence of adverse events were observed between the groups. Compared to the placebo group, the betaine group showed a significant increase in plasma betaine (P<0.0001) and high-density lipoprotein (HDL)-cholesterol (P<0.05) concentrations. Conclusion: Low-dose betaine supplementation to subjects with mild fatty liver disease is safe and well tolerated. Betaine increased plasma HDL which may reflect the favorable effects of betaine on liver function-related metabolic metabolism in Asian population.

Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions.

Obesity is associated with higher incidence of cancer, but the predisposing mechanisms remain poorly understood. The NAD(+)-dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. However, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin resistance. Dbc1 deficiency promoted SirT1-dependent gain of function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids. The metabolic abnormalities in Dbc1(-/-) mice were reversed by ablation of hepatic SirT1 or by inhibition of Scd1 activity. Furthermore, loss of Dbc1 impaired activation of the master tumor suppressor p53 and treatment with an Scd1 inhibitor extended survival of tumor-prone TP53(-/-) mice by decreasing tumor-related death. Together, our findings illustrate a shared mechanism of obesity and tumor progression mediated by hepatic SirT1 and resulting in the activation of a key lipid synthetic enzyme, with potential therapeutic implications.

황칠나무 잎 추출물이 고지방·고콜레스테롤 식이를 급여한 마우스의 지질 개선 효과에 미치는 영향

The purpose of this study was to determine the effects of dried Dendropanax morbifera leaf extracts on lipid profiles of mice fed a high-fat and -cholesterol diet (HFCD). ICR mice were divided into six groups based on mice fed AIN-93G diet (Normal), HFCD (Control), HFCD+100 mg/kg/d of D. morbifera leaf aqueous extract (DA-100), HFCD+200 mg/kg/d of D. morbifera leaf aqueous extract (DA-200), HFCD+100 mg/kg/d of D. morbifera leaf ethanol extract (DE-100), or HFCD+200 mg/kg/d of D. morbifera leaf ethanol extract (DE-200) for 7 weeks. The final body weights of mice fed D. morbifera extracts were all lower than those of the control group. Mice treated with D. morbifera extracts showed significantly reduced plasma and hepatic triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol levels, along with increased plasma high-density lipoprotein cholesterol level. Fecal TG level was higher in DE-100 and DE-200 groups and TC level was significantly higher in the DA-200 and DE-200 groups. Relative liver weight, spleen weight, and testicle fat weight in mice treated with D. morbifera were reduced compared to the control group. Plasma insulin, aspartate transaminase, and alanine transaminase levels of experimental groups were also lower than those of the control group. All mice treated with D. morbifera extracts had lower malondialdehyde (MDA) content and higher superoxide dismutase (SOD) activity than the control group. Particularly MDA levels of the DA-200 and DE-200 groups and SOD levels of the DE-200 group were identical to levels of the normal group. These results suggest that D. morbifera extracts have lipid improvement effects in mice fed a HFCD.

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.

Macrophage functions in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arterial wall instigated by the excessive accumulation of lipoproteins; monocyte recruitment and their differentiation into macrophages in the subendothelial space. Repeated failure of innate immune responses to clear subintimal low-density lipoprotein (LDL), results in the deposition of lipid-laden macrophages or foam cells. Foam cells secrete proinflammatory mediators that facilitate lipoprotein retention and maintain vascular inflammation.1 Advancement of lesion is characterized by the apoptosis of these macrophages in the lipid core. Macrophage apoptosis plays a dual role in atherosclerosis. In early fatty streaks lesions, efferocytosis removes apoptotic cells and prevents lesion development, whereas in the advanced lesions, efferocytosis is not efficient to clear the apoptotic debri, leading to the formation of necrotic core which further enhances inflammation and atherogenesis.2 Accumulating indirect evidence suggests that the antiatherogenic role of high density lipoprotein (HDL) could at least in part, be due to its ability to stimulate cholesterol efflux from macrophages by ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1). Complementing this notion, recent studies by Westerterp et al3 show that macrophage deficiency of ABCA1/G1 enhances lipid accumulation in macrophages, atherosclerosis and lesion inflammation. These authors observed that macrophage foam cells in spleen facilitate monocytosis which is inhibited by ABCA1/G1 and high levels of HDL. Studies by Ramirez et al4 demonstrate that activation of liver X receptor (LXR) augments the transcription of microRNA 144 (miR144) and inhibition of miR144 in macrophages upregulates ABCA1 expression and cholesterol efflux. In vivo, supplementation of mice with miR144 suppresses ABCA1 expression in the liver and reduces plasma HDL levels. Silencing of miR144 …

Effects of CP-900691, a novel peroxisome proliferator-activated receptor α, agonist on diabetic nephropathy in the BTBR ob/ob mouse

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF2α, a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF2α excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF2α, possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.