Medicine and Health Sciences Commons^™

Dementia Risk Reduction: Why Haven't The Pharmacological Risk Reduction Trials Worked? An In-Depth Exploration Of Seven Established Risk Factors, Ruth Peters, John Breitner, Sarah James, Gregory A. Jicha, Pierre-Francois Meyer, Marcus Richards, A. David Smith, Hussein N. Yassine, Erin L. Abner, Atticus H. Hainsworth, Patrick G. Kehoe, Nigel Beckett, Christopher Weber, Craig Anderson, Kaarin J. Anstey, Hiroko H. Dodge

Neurology Faculty Publications

Identifying the leading health and lifestyle factors for the risk of incident dementia and Alzheimer's disease has yet to translate to risk reduction. To understand why, we examined the discrepancies between observational and clinical trial evidence for seven modifiable risk factors: type 2 diabetes, dyslipidemia, hypertension, estrogens, inflammation, omega-3 fatty acids, and hyperhomocysteinemia. Sample heterogeneity and paucity of intervention details (dose, timing, formulation) were common themes. Epidemiological evidence is more mature for some interventions (eg, non-steroidal anti-inflammatory drugs [NSAIDs]) than others. Trial data are promising for anti-hypertensives and B vitamin supplementation. Taken together, these risk factors highlight a future need …

Associations Of Circulating Dimethylarginines With The Metabolic Syndrome In The Framingham Offspring Study, Ibrahim Musa Yola, Carlee Moser, Meredith S. Duncan, Edzard Schwedhelm, Dorothee Atzler, Renke Maas, Juliane Hannemann, Rainer H. Böger, Ramachandran S. Vasan, Vanessa Xanthakis

Biostatistics Faculty Publications

BACKGROUND: Circulating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively.

METHODS: We related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study …

Mechanisms Of Smoothened Regulation In Hedgehog Signaling, Jie Zhang, Zulong Liu, Jianhang Jia

Markey Cancer Center Faculty Publications

The seven-transmembrane protein, Smoothened (SMO), has shown to be critical for the hedgehog (HH) signal transduction on the cell membrane (and the cilium in vertebrates). SMO is subjected to multiple types of post-translational regulations, including phosphorylation, ubiquitination, and sumoylation, which alter SMO intracellular trafficking and cell surface accumulation. Recently, SMO is also shown to be regulated by small molecules, such as oxysterol, cholesterol, and phospholipid. The activity of SMO must be very well balanced by these different mechanisms in vivo because the malfunction of SMO will not only cause developmental defects in early stages, but also induce cancers in late …

Sitosterolemia: Twenty Years Of Discovery Of The Function Of Abcg5abcg8, Kori Williams, Allison Segard, Gregory A. Graf

Pharmaceutical Sciences Faculty Publications

Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty …

Microrna-148a Regulates Low-Density Lipoprotein Metabolism By Repressing The (Pro)Renin Receptor, Na Wang, Lishu He, Hui Lin, Lunbo Tan, Yuan Sun, Xiaoying Zhang, A. H. Jan Danser, Hong S. Lu, Yongcheng He, Xifeng Lu

Saha Cardiovascular Research Center Faculty Publications

High plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDL receptor (LDLR) regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we have identified the (pro)renin receptor [(P)RR] as a novel regulator of LDL metabolism, which regulates LDLR degradation and hence its protein abundance and activity. In silico analysis suggests that the (P)RR is a target of miR-148a. In this study we determined whether miR-148a could regulate LDL metabolism by regulating (P)RR expression in HepG2 and Huh7 cells. We found that miR-148a suppressed (P)RR expression by binding to the 3’-untranslated regions (3’-UTR) of the (P)RR …

Non-Fasting High-Density Lipoprotein Is Associated With White Matter Microstructure In Healthy Older Adults, Nathan F. Johnson, Brian T. Gold, Dorothy Ross, Alison L. Bailey, Jody L. Clasey, Vedant Gupta, Steve W. Leung, David K. Powell

Physical Therapy Faculty Publications

A growing body of evidence indicates that biomarkers of cardiovascular risk may be related to cerebral health. However, little is known about the role that non-fasting lipoproteins play in assessing age-related declines in a cerebral biomarker sensitive to vascular compromise, white matter (WM) microstructure. High-density lipoprotein cholesterol (HDL-C) is atheroprotective and low-density lipoprotein cholesterol (LDL-C) is a major atherogenic lipoprotein. This study explored the relationships between non-fasting levels of cholesterol and WM microstructure in healthy older adults. A voxelwise and region of interest approach was used to determine the relationship between cholesterol and fractional anisotropy (FA). Participants included 87 older …

Rationale And Methods For A Multicenter Clinical Trial Assessing Exercise And Intensive Vascular Risk Reduction In Preventing Dementia (Rrad Study), Amanda N. Szabo-Reed, Eric Vidoni, Ellen F. Binder, Jeffrey Burns, C. Munro Cullum, William P. Gahan, Aditi Gupta, Linda S. Hynan, Diana R. Kerwin, Heidi Rossetti, Ann M. Stowe, Wanpen Vongpatanasin, David C. Zhu, Rong Zhang, Jeffrey N. Keller

Neurology Faculty Publications

Alzheimer's Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer's Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of …

An Exome-Wide Sequencing Study Of The Goldn Cohort Reveals Novel Associations Of Coding Variants And Fasting Plasma Lipids, Xin Geng, Marguerite R. Irvin, Bertha Hidalgo, Stella Aslibekyan, Vinodh Srinivasasainagendra, Ping An, Alexis C. Frazier-Wood, Hemant K. Tiwari, Tushar Dave, Kathleen Ryan, Jose M. Ordovas, Robert J. Straka, Mary F. Feitosa, Paul N. Hopkins, Ingrid Borecki, Michael A. Province, Braxton D. Mitchell, Donna K. Arnett, Degui Zhi

Epidemiology and Environmental Health Faculty Publications

Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants.

Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7) was associated with fasting triglyceride levels (P = 7.66E-08), …

Hdl In Endocrine Carcinomas: Biomarker, Drug Carrier, And Potential Therapeutic, Emily E. Morin, Xiang-An Li, Anna Schwendeman

Physiology Faculty Publications

High-density lipoprotein (HDL) have long been studied for their protective role against cardiovascular diseases, however recently relationship between HDL and cancer came into focus. Several epidemiological studies have shown an inverse correlation between HDL-cholesterol (HDL-C) and cancer risk, and some have even implied that HDL-C can be used as a predictive measure for survival prognosis in for specific sub-population of certain types of cancer. HDL itself is an endogenous nanoparticle capable of removing excess cholesterol from the periphery and returning it to the liver for excretion. One of the main receptors for HDL, scavenger receptor type B-I (SR-BI), is highly …

Abcg5 And Abcg8: More Than A Defense Against Xenosterols, Shailendra B. Patel, Gregory A. Graf, Ryan E. Temel

Pharmaceutical Sciences Faculty Publications

The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The sitosterolemia locus has been genetically associated with lipid levels and downstream atherosclerotic disease, as well as …

Metabolic And Inflammatory Biomarkers Are Associated With Epigenetic Aging Acceleration Estimates In The Goldn Study, Marguerite R. Irvin, Stella Aslibekyan, Anh Do, Degui Zhi, Bertha Hidalgo, Steven A. Claas, Vinodh Srinivasasainagendra, Steve Horvath, Hemant K. Tiwari, Devin M. Absher, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background: Recently, epigenetic age acceleration-or older epigenetic age in comparison to chronological age-has been robustly associated with mortality and various morbidities. However, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids.

Methods: We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations based on differing sets of 5′-Cytosine-phosphate-guanine-3′ genomic site, derived from the Horvath and Hannum DNA methylation age calculators, respectively. GOLDN participants underwent a standardized high-fat meal challenge after fasting for at least …

An Exome-Wide Sequencing Study Of Lipid Response To High-Fat Meal And Fenofibrate In Caucasians From The Goldn Cohort, Xin Geng, Marguerite R. Irvin, Bertha Hidalgo, Stella Aslibekyan, Vinodh Srinivasasainagendra, Ping An, Alexis C. Frazier-Wood, Hemant K. Tiwari, Tushar Dave, Kathleen Ryan, Jose M. Ordovas, Robert J. Straka, Mary F. Feitosa, Paul N. Hopkins, Ingrid Borecki, Michael A. Province, Braxton D. Mitchell, Donna K. Arnett, Degui Zhi

Epidemiology and Environmental Health Faculty Publications

Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in ITGA7, SIPA1L2, and CEP72 are significantly associated with fasting LDL cholesterol response to FFB (P = 1.24E-07), triglyceride postprandial area under the increase (AUI) (P = 2.31E-06), and triglyceride postprandial …

Adropin: An Endocrine Link Between The Biological Clock And Cholesterol Homeostasis, Sarbani Ghoshal, Joseph R. Stevens, Cyrielle Billon, Clemence Girardet, Sadichha Sitaula, Arthur S. Leon, D.C. Rao, James S. Skinner, Tuomo Rankinen, Claude Bouchard, Marinelle V. Nuñez, Kimber L. Stanhope, Deborah A. Howatt, Alan Daugherty, Jinsong Zhang, Matthew Schuelke, Edward P. Weiss, Alisha R. Coffey, Brian J. Bennett, Praveen Sethupathy, Thomas P. Burris, Peter J. Havel, Andrew A. Butler

Physiology Faculty Publications

Objective

Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function.

Methods

Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models.

Results

In humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = …

Prevention Of Renal Apob Retention Is Protective Against Diabetic Nephropathy: Role Of Tgf-Β Inhibition, Patricia G. Wilson, Joel C. Thompson, Meghan S. Yoder, Richard Charnigo, Lisa R. Tannock

Internal Medicine Faculty Publications

Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr^−/− mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-β (TGF-β), in some experiments mice were injected with either the TGF-β-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect …

Epigenetics Of Lipid Phenotypes, Sergi Sayols-Baixeras, Marguerite R. Irvin, Donna K. Arnett, Roberto Elosua, Stella W. Aslibekyan

Epidemiology and Environmental Health Faculty Publications

Dyslipidemia is a well-established risk factor for cardiovascular disease, the main cause of death worldwide. Blood lipid profiles are patterned by both genetic and environmental factors. In recent years, epigenetics has emerged as a paradigm that unifies these influences. In this review, we have summarized the latest evidence implicating epigenetic mechanisms—DNA methylation, histone modification, and regulation by RNAs—in lipid homeostasis. Key findings have emerged in a number of novel epigenetic loci located in biologically plausible genes (eg, CPT1A, ABCG1, SREBF1, and others), as well as microRNA-33a/b. Evidence from animal and cell culture models suggests a complex interplay …

Serum Amyloid A Impairs The Antiinflammatory Properties Of Hdl, Chang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O'Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. De Beer, Frederick C. De Beer, William R. Osborne, Keith B. Elkon, Alan Chait

Physiology Faculty Publications

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO₃ fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO₃-injected mice lacking Saa1.1 …

Infusion Of Reconstituted High-Density Lipoprotein, Csl112, In Patients With Atherosclerosis: Safety And Pharmacokinetic Results From A Phase 2a Randomized Clinical Trial, Pierluigi Tricoci, Denise M. D'Andrea, Paul A. Gurbel, Zhenling Yao, Marina Cuchel, Brion Winston, Robert Schott, Robert Weiss, Michael A. Blazing, Louis Cannon, Alison L. Bailey, Dominick J. Angiolillo, Andreas Gille, Charles L. Shear, Samuel D. Wright, John H. Alexander

Gill Heart & Vascular Institute Faculty Publications

Background CSL112 is a new formulation of human apolipoprotein A‐I (apoA‐I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double‐blind, multicenter, dose‐ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.

Methods and Results Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2‐hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug–related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA‐I plasma …

The Tmao-Generating Enzyme Flavin Monooxygenase 3 Is A Central Regulator Of Cholesterol Balance, Manya Warrier, Diana M. Shih, Amy C. Burrows, Daniel Ferguson, Anthony D. Gromovsky, Amanda L. Brown, Stephanie Marshall, Allison Mcdaniel, Rebecca C. Schugar, Zeneng Wang, Jessica Sacks, Xin Rong, Thomas De Aguiar Vallim, Jeff Chou, Pavlina T. Ivanova, David S. Myers, H. Alex Brown, Richard G. Lee, Rosanne M. Crooke, Mark J. Graham, Xiuli Liu, Paolo Parini, Peter Tontonoz, Aldon J. Lusis, Stanley L. Hazen, Ryan E. Temel, J. Mark Brown

Saha Cardiovascular Research Center Faculty Publications

Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here, we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT) and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic endoplasmic reticulum (ER) stress …

A Life Span Approach To The Relationship Between Cholesterol, Late Onset Alzheimer’S Disease, And Cognitive Functioning Among Older Adults, Brian Downer

Theses and Dissertations--Gerontology

There is evidence that cholesterol presents an important risk factor for Alzheimer’s disease (AD), but the direction of this relationship is modified by age. High cholesterol during midlife and low cholesterol during late life are both associated with an increased risk for AD. This dissertation research engaged a life span approach to study the relationship between cholesterol, AD and cognitive functioning among older adults. The purpose of this research was to determine if trajectories of cholesterol from midlife through late life differ according to AD status and if these trajectories are associated with cognitive functioning during old age.

This research …

Physiological And Toxicological Roles Of Abc Transporters In Cellular Efflux Of Substrates, Donna J. Coy

Theses and Dissertations--Toxicology and Cancer Biology

ATP-binding cassette (ABC) transporters are transmembrane proteins that transport a wide variety of substrates across intra and extra-cellular membranes. A few examples of endo and xenobiotic substrates are metabolic products, lipids, sterols, and drugs. An important function of ABC transporters involved in export is to prevent intracellular the buildup of toxic products. Several ABC transporters have also been associated with drug resistance upon treatment with chemotherapeutic agents. P-glycoprotein (P-GP) and the multidrug resistant (MRP) transporters of the ABC C family are examples of transporters that confer chemo-resistance.

We have studied two unique roles of ABC transporters in the liver and …

Evaluation Of The Global Association Between Cholesterol-Associated Polymorphisms And Alzheimer's Disease Suggests A Role For Rs3846662 And Hmgcr Splicing In Disease Risk, Christopher R. Simmons, Fanggeng Zou, Steven G Younkin, Steven Estus

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD.

RESULTS: Seventeen non-APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are …

Inhibition Of Cholesterol Synthesis By Policosanol, Subhashis Banerjee

University of Kentucky Doctoral Dissertations

Cholesterol is an essential component of the cell, but excessive blood levels are a major risk factor for the development of atherosclerotic plaques that can lead to heart disease and stroke, the foremost cause of premature death in Western societies. Policosanol, a mixture of very long chain alcohols derived from sugarcane, has gained considerable attention among the public as safe and effective means to reduce blood cholesterol levels, a belief based on some early clinical studies. My research investigates one possible mechanism by which policosanol might decrease blood cholesterol levels: the inhibition of cholesterol synthesis in the liver. Previous studies …

Regulation Of Acetylated Low Density Lipoprotein Uptake In Macrophages By Pertussis Toxin-Sensitive G Proteins, Stewart C. Whitman, Alan Daugherty, Steven R. Post

Gill Heart & Vascular Institute Faculty Publications

Class A scavenger receptors (SR-A) mediate the uptake of modified low density lipoprotein (LDL) by macrophages. Although not typically associated with the activation of intracellular signaling cascades, results with peritoneal macrophages indicate that the SR-A ligand acetylated LDL (AcLDL) promotes activation of cytosolic kinases and phospholipases. These signaling responses were blocked by the treatment of cells with pertussis toxin (PTX) indicating that SR-A activates G_i/o-linked signaling pathways. The functional significance of SR-A-mediated G_i/o activation is not clear. In this study, we investigated the potential role of G_i/o activation in regulating SR-A-mediated lipoprotein uptake. Treatment of mouse …