A5046009433- Cholesterol and Lipid Metabolism
- Lipoproteins and Cardiovascular Health
- Lipid metabolism and disorders
- Peroxisome Proliferator-Activated Receptors
- Cancer, Lipids, and Metabolism
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Lipid metabolism and biosynthesis
- Bioactive Compounds in Plants
- Adipokines, Inflammation, and Metabolic Diseases
- Atherosclerosis and Cardiovascular Diseases
- Fatty Acid Research and Health
- Phytochemicals and Antioxidant Activities
- Adipose Tissue and Metabolism
- Drug Transport and Resistance Mechanisms
- Liver Disease Diagnosis and Treatment
- Metabolism and Genetic Disorders
- Plant biochemistry and biosynthesis
- Bioactive natural compounds
- Antioxidant Activity and Oxidative Stress
- Muscle metabolism and nutrition
- Natural Antidiabetic Agents Studies
- Estrogen and related hormone effects
- Diet and metabolism studies
- Metabolism, Diabetes, and Cancer
- Nuclear Structure and Function
Western University
2012-2021
Robarts Clinical Trials
2008-2019
GTx (United States)
2012-2018
Esperion Therapeutics (United States)
2017
Montreal Heart Institute
2016
Université de Montréal
2016
University of Toronto
1994-2014
University of Victoria
2014
University of Washington
1997-2011
Cedars-Sinai Medical Center
2011
OBJECTIVE The global epidemic of metabolic syndrome and its complications demands rapid evaluation new accessible interventions. Insulin resistance is the central biochemical disturbance in syndrome. citrus-derived flavonoid, naringenin, has lipid-lowering properties inhibits VLDL secretion from cultured hepatocytes a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production insulin sensitivity context vivo. RESEARCH DESIGN AND METHODS LDL receptor–null...
Objective— Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision prevalence estimates and attribution polygenic effects. Here, we examined the contributions monogenic factors in patients with severe hypercholesterolemia referred to a specialty clinic. Approach Results— We applied targeted next-generation custom annotation, coupled evaluation large-scale copy number variation scores for raised low-density...
The citrus flavonoids, naringenin and hesperetin, lower plasma cholesterol in vivo. However, the underlying mechanisms are not fully understood. ability of these flavonoids to modulate apolipoprotein B (apoB) secretion cellular homeostasis was determined human hepatoma cell line, HepG2. apoB accumulation media decreased a dose-dependent manner following 24-h incubations with (up 82%, P < 0.00001) or hesperetin 74%, 0.002). Decreased associated reduced cholesteryl ester mass. Cholesterol...
Rabbits fed a low fat, cholesterol-free, semipurified diet containing casein became hypercholesterolemic (=300 mg/dl) after 5 weeks on diet.Rabbits similar soy protein isolate had plasma cholesterols comparable to those commercial feed (40- 60 mg/dl).Cholesterol turnover, which conformed twopool model, was determined by analysis of the decay cholesterol specific activity single intravenous injection [26-14C]cholesterol.Rabbits or showed much faster rate turnover and reduced size pool A...
Increased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim current study was to evaluate effect polymethoxylated flavonoid nobiletin on lipoprotein secretion cultured human hepatoma cells (HepG2) a mouse model atherosclerosis.Lipoprotein determined HepG2 incubated or insulin. mRNA...
Objective— Naringenin is a citrus flavonoid that potently inhibits the assembly and secretion of apolipoprotein B100–containing lipoproteins in cultured hepatocytes improves dyslipidemia insulin resistance mouse model metabolic syndrome. In present study, we used low-density lipoprotein receptor–null mice fed high-fat diet (Western, TD96125) to test hypothesis naringenin prevents atherosclerosis. Methods Results— Three groups (chow, Western, Western plus naringenin) were ad libitum for 6...
Obesity-associated chronic inflammation contributes to metabolic dysfunction and propagates atherosclerosis. Recent evidence suggests that increased dietary cholesterol exacerbates in adipose tissue liver, contributing the proatherogenic milieu. The ability of citrus flavonoid naringenin prevent these cholesterol-induced perturbations is unknown. To assess amplified inflammatory response atherosclerosis induced by cholesterol, male Ldlr−/− mice were fed either a cholesterol-enriched high-fat...
Obesity and its associated metabolic dysfunction cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin nobiletin, protect against Ldlr-/- mice fed high-fat cholesterol-containing (HFHC) diet. However, their effects an intervention model are unknown. In this report,...
Abstract The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia improves glucose tolerance were investigated in C57BL6/J wild-type mice fibroblast growth factor 21 (FGF21) null (Fgf21−/−) mice. FGF21 regulates energy homeostasis adaptation to fasting. One avenue of this regulation is through induction peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator hepatic fatty acid oxidation ketogenesis. Because...
The flavonoid naringenin improves hyperlipidemia and hyperglycemia in streptozotocin-treated rats. In HepG2 human hepatoma cells, inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake. Phosphatidylinositol 3-kinase (PI3K) activation insulin increases sterol regulatory element-binding (SREBP)-1 LDLr expression apoB hepatocytes. Thus, we determined whether activates...
Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation in GWA would also be severe hypertriglyceridemia (HTG). studied 132 patients European ancestry HTG (fasting > 10 mmol/l), who had no mutations found by resequencing candidate genes, and 351 matched normolipidemic controls. determined genotypes for: GALNT2 rs4846914,...
The cholesterol biosynthetic pathway produces numerous signaling molecules. Oxysterols through liver X receptor (LXR) activation regulate efflux, whereas the non-sterol mevalonate metabolite, geranylgeranyl pyrophosphate (GGPP), was recently demonstrated to inhibit ABCA1 expression directly, antagonism of LXR and indirectly enhanced RhoA geranylgeranylation. We used HMG-CoA reductase inhibitors (statins) test hypothesis that reduced synthesis metabolites would enhance efflux attenuate foam...
Microsomal triglyceride transfer protein (MTP) is necessary for hepatocyte assembly and secretion of apolipoprotein (apo)B100-containing lipoproteins. The citrus flavonoid naringenin, like insulin, decreased MTP expression in HepG2 cells, resulting inhibition apoB100 secretion; however, the mechanism naringenin independent insulin receptor substrate-1/2. Recently, it was reported that cells via mitogen-activated kinase (MAPK)/extracellular signal–regulated (ERK) (MAPKerk) pathway. We...
The combination of ezetimibe, an inhibitor Niemann-Pick C1-like 1 protein (NPC1L1), and HMG-CoA reductase decreases cholesterol absorption synthesis. In clinical trials, ezetimibe plus simvastatin produces greater LDL-cholesterol reductions than does monotherapy. molecular mechanism for this enhanced efficacy has not been defined. Apolipoprotein B-100 (apoB-100) kinetics were determined in miniature pigs treated with (0.1 mg/kg/day), (10 or placebo (n = 7/group). Ezetimibe decreased (-79%)...
Abstract Background The rs9939609 T>A single-nucleotide polymorphism (SNP) in the FTO gene has previously been found to be associated with obesity European Caucasian samples. objective of this study is examine whether association extends metabolic syndrome (MetS) and applies non-Caucasian Methods SNP was genotyped 2121 subjects from four different geographical ancestries. Subjects were classified for presence or absence MetS according International Diabetes Federation (IDF) National...
Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation normolipidemic subjects. However, since these GWAS did not specifically evaluate patients rare disorders of lipoprotein metabolism--'hyperlipoproteinemia' (HLP)--it remains largely unresolved whether any SNP determinants modest physiological changes TG are necessarily also most HLP phenotypes. To address this...
Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls confirmed spectrum of rare lipid-associated variants this heterogeneity.First, demonstrated determinants plasma lipids lipoproteins, including associated with triglyceride (TG), high-density...
Rare variant accumulation studies can implicate genes in disease susceptibility when a significant burden is observed patients versus control subjects. Such analyses might be particularly useful for candidate that are selected based on experiments other than genome-wide association (GWAS). We sought to determine whether rare variants non-GWAS identified from mouse models and human mendelian syndromes of hypertriglyceridemia (HTG) accumulate with polygenic adult-onset HTG.We resequenced...