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 …

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 …

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 = …

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 …

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 …