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Hypertriglyceridemia: HELP
Articles from Alabama
Based on 20 articles published since 2010
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These are the 20 published articles about Hypertriglyceridemia that originated from Alabama during 2010-2020.
 
+ Citations + Abstracts
1 Review Implications for REDUCE IT in clinical practice. 2019

Bittner, Vera. ·Division of Cardiovascular Disease, University of Alabama at Birmingham, United States of America. Electronic address: vbittner@uab.edu. ·Prog Cardiovasc Dis · Pubmed #31715195.

ABSTRACT: Statin therapy is effective in primary and secondary prevention, but substantial residual risk remains on statin treatment, especially among high risk and very high risk patients. Add-on therapy with ezetimibe and proprotein convertase subtilisin /kexin type 9 (PCSK9) inhibitors provides additional risk reduction through further reduction in low density lipoprotein cholesterol. Elevated triglycerides/triglyceride rich lipoproteins contribute to atherogenesis and to the residual risk on statin therapy. Addition of icosapent ethyl to statins has recently been shown to markedly lower risk of ASCVD events in patients with established atherosclerotic CVD (ASCVD) and high risk patients with type II diabetes mellitus. These data are discussed in the context of current guidelines and synthesized in a decision pathway to guide combination lipid-lowering therapy in patients at high ASCVD risk.

2 Review Hypertriglyceridemia: A review of the evidence. 2018

Elkins, Casey / Friedrich, Debra. ·Casey Elkins is an assistant professor at the University of South Alabama, Mobile, Ala. Debra Friedrich is an assistant professor at the University of South Florida, Tampa, Fla. ·Nurse Pract · Pubmed #30153192.

ABSTRACT: Elevated triglycerides are independently associated with increased atherosclerotic cardiovascular disease risk. Hypertriglyceridemia is often a polygenic condition that can be affected by numerous interventions. Primary care NPs are well positioned to appropriately evaluate and manage hypertriglyceridemia, improving overall health outcomes.

3 Review Hospital Management of Severe Hypertriglyceridemia in Children. 2017

Valaiyapathi, Badhma / Ashraf, Ambika P. ·Department of Epidemiology, School of Public Health, The University of Alabama at Birmingham, Alabama, United States. · Department of Pediatrics/Division of Pediatric Endocrinology and Metabolism, Children's of Alabama, University of Alabama at Birmingham, Alabama, United States. ·Curr Pediatr Rev · Pubmed #29345595.

ABSTRACT: BACKGROUND: Severe Hypertriglyceridemia (HTG), i.e., plasma triglyceride levels exceeding 1000 mg/dL, is one of the established causes of acute pancreatitis and severe abdominal pain. There are no established pediatric guidelines regarding treatment of children and adolescents with severe HTG. OBJECTIVE: To review the pathophysiology and etiology of severe HTG in the pediatric age group, and to discuss management options. METHOD AND RESULTS: Severe HTG is usually due to deficient or absent Lipoprotein Lipase (LPL) activity, which can be due to primary genetic etiology or secondary causes triggering HTG in those with underlying genetic susceptibility. Hospitalization is indicated for patients with severe HTG who are symptomatic with abdominal pain or pancreatitis, in those with uncontrolled diabetes requiring insulin, or, in those with substantial elevations of plasma TG. Fasting followed by fat free diet until plasma TG declines to <1000mg/dL is essential. Subsequently, stringent fat restriction followed by slowly increasing the dietary fat while maintaining the plasma TG concentration at a targeted level is recommended. Insulin infusions are helpful in patients who have some LPL activity, especially in those with diabetes. Plasmapheresis may be considered in those with severe pancreatitis, shock or multi-organ failure. Medications such as fibrates and omega-3 fatty acids are not effective if LPL activity is absent or when plasma TG is >1800 mg/dL. Medications only have an adjunct role in the management. Low fat diet, lifestyle changes, weight loss, control of secondary causes, and patient education form the mainstay of management once the patient is discharged.

4 Review Approach to Hypertriglyceridemia in the Pediatric Population. 2017

Valaiyapathi, Badhma / Sunil, Bhuvana / Ashraf, Ambika P. ·Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL. · Department of Pediatrics, Harlem Hospital Center, New York, NY. · Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, Children's of Alabama, University of Alabama at Birmingham, Birmingham, AL. ·Pediatr Rev · Pubmed #28864733.

ABSTRACT: Hypertriglyceridemia is increasingly identified in children and adolescents, owing to improved screening and higher prevalence of childhood obesity. Hypertriglyceridemia can result from either increased triglyceride (TG) production or reduced TG clearance. The etiologic origin can be primary (genetic) or secondary, but it is often multifactorial. Management is challenging because of the interplay of genetic and secondary causes and lack of evidence-based guidelines. Lifestyle changes and dietary interventions are most important, especially in hypertriglyceridemia associated with obesity. Dietary restriction of fat remains the mainstay of management in primary hypertriglyceridemia. When fasting TG concentration is increased above 500 mg/dL (5.65 mmol/L), fibrates may be used to prevent pancreatitis. Omega-3 fatty acids are often used as an adjunctive therapy. When the fasting TG concentration is less than 500 mg/dL (5.65 mmol/L) and if the non-high-density lipoprotein cholesterol level is above 145 mg/dL (3.76 mmol/L), statin treatment can be considered.

5 Review The proteinuria-hypertriglyceridemia connection as a basis for novel therapeutics for nephrotic syndrome. 2015

Clement, Lionel C / Macé, Camille / Del Nogal Avila, Maria / Marshall, Caroline B / Chugh, Sumant S. ·Glomerular Disease Therapeutics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama. · Glomerular Disease Therapeutics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: chugh@uab.edu. ·Transl Res · Pubmed #25005737.

ABSTRACT: The development of new and specific treatment options for kidney disease in general and glomerular diseases in specific has lagged behind other fields like heart disease and cancer. As a result, nephrologists have had to test and adapt therapeutics developed for other indications to treat glomerular diseases. One of the major factors contributing to this inertia has been the poor understanding of disease mechanisms. One way to elucidate these disease mechanisms is to study the association between the cardinal manifestations of glomerular diseases. Because many of these patients develop nephrotic syndrome, understanding the relationship of proteinuria, the primary driver in this syndrome, with hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, edema, and lipiduria could provide valuable insight. The recent unraveling of the relationship between proteinuria and hypertriglyceridemia mediated by free fatty acids, albumin, and the secreted glycoprotein angiopoietin-like 4 (Angptl4) offers a unique opportunity to develop novel therapeutics for glomerular diseases. In this review, the therapeutic potential of mutant forms of Angptl4 in reducing proteinuria and, as a consequence, alleviating the other manifestations of nephrotic syndrome is discussed.

6 Review Controversies in the etiologies of acute pancreatitis. 2010

Khan, Ali Safdar / Latif, Sahibzada Usman / Eloubeidi, Mohamad A. ·Department of Medicine, the University of Alabama in Birmingham, Birmingham, AL 35294-0007, USA. ·JOP · Pubmed #21068485.

ABSTRACT: -- No abstract --

7 Clinical Trial Apolipoprotein B genetic variants modify the response to fenofibrate: a GOLDN study. 2010

Wojczynski, Mary K / Gao, Guimin / Borecki, Ingrid / Hopkins, Paul N / Parnell, Laurence / Lai, Chao-Qiang / Ordovas, Jose M / Chung, B Hong / Arnett, Donna K. ·Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA. ·J Lipid Res · Pubmed #20724655.

ABSTRACT: Hypertriglyceridemia, defined as a triglyceride measurement > 150 mg/dl, occurs in up to 34% of adults. Fenofibrate is a commonly used drug to treat hypertriglyceridemia, but response to fenofibrate varies considerably among individuals. We sought to determine if genetic variation in apolipoprotein B (APOB), an essential core of triglyceride-rich lipoprotein formation, may account for some of the inter-individual differences observed in triglyceride (TG) response to fenofibrate treatment. Participants (N = 958) from the Genetics of Lipid Lowering Drugs and Diet Network study completed a three-week intervention with fenofibrate 160 mg/day. Associations of four APOB gene single nucleotide polymorphisms (SNP) (rs934197, rs693, rs676210, and rs1042031) were tested for association with the TG response to fenofibrate using a mixed growth curve model where the familial structure was modeled as a random effect and cardiovascular risk factors were included as covariates. Three of these four SNPs changed the amino acid sequence of APOB, and the fourth was in the promoter region. TG response to fenofibrate treatment was associated with one APOB SNP, rs676210 (Pro2739Leu), such that participants with the TT genotype of rs676210 had greater TG lowering than those with the CC genotype (additive model, P = 0.0017). We conclude the rs676210 variant may identify individuals who respond best to fenofibrate for TG reduction.

8 Article A Rare Cause of Acute Pancreatitis in a Transgender Female. 2020

Shipley, Lindsey C / Steele, David T / Wilcox, Charles M / Burski, Chad M. ·University of Alabama at Birmingham, AL, USA. ·J Investig Med High Impact Case Rep · Pubmed #32406257.

ABSTRACT: Acute pancreatitis is defined as an acute inflammation of the pancreas and is most commonly caused by gallstones and alcohol followed by elevated triglycerides and medications. Estrogen as a cause of secondary hypertriglyceridemic pancreatitis is a rare but known phenomenon in females on hormonal therapy; however, it is not well described in the transgender female population. In this article, we present a case of a 31-year-old transgender female who developed acute, severe pancreatitis after a few months of using estrogen as transition therapy. To our knowledge, this is the third case report of a transgender female presenting with acute pancreatitis secondary to estrogen. Long-term supraphysiologic doses of sex hormones are required to maintain secondary sex characteristics placing this population at a higher risk of developing acute pancreatitis. Further research is needed to determine risk and screening methods to prevent this side effect.

9 Article Predictability and efficacy of therapeutic plasma exchange for hypertriglyceridemia induced acute pancreatitis. 2019

Fei, Fei / Boshell, Nick / Williams, Lance A. ·Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States. · Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States. Electronic address: lawrencewilliams@uabmc.edu. ·Transfus Apher Sci · Pubmed #32085931.

ABSTRACT: BACKGROUND: Hypertriglyceridemia induced acute pancreatitis is associated with more severe clinical course than acute pancreatitis caused by other etiologies. Therapeutic plasma exchange (TPE) is a potential treatment for patients with severe hypertriglyceridemia induced acute pancreatitis due to its rapid effect in lowering triglycerides (TG) levels and reducing inflammatory cytokines. However, clinical data regarding the effectiveness and safety of TPE is limited. METHODS: We retrospectively reviewed eight cases of hypertriglyceridemia induced acute pancreatitis and treated with TPE. Patients' demographic data, personal history, clinical course, laboratory results, apheresis data and clinical outcome were collected and analyzed. RESULTS: At initial presentation, the average TG levels for the eight patients was 3381.6 mg/dl (SD: 1491.6 mg/dl). Twelve procedures were performed on the eight patients in the study, and TG levels decreased by an average of 2673.2 mg/dl (SD: 2306.3 mg/dl) with a corresponding average reduction rate of 60.3 % (SD:21.1 %), ranging from 14.6%-84.9%. A 60 % or greater reduction was achieved in 66.7 % of all the procedures; however, the degree of reduction for each procedure was not predictable, even among repeat procedures on the same patient. CONCLUSIONS: Our study indicates that TPE is an effective and safe treatment option for patients with hypertriglyceridemia induced acute pancreatitis. However, due to the unpredictability of TG removal, repeat procedures may be necessary for some patients.

10 Article Characterization of lipoprotein profiles in patients with hypertriglyceridemic Fredrickson-Levy and Lees dyslipidemia phenotypes: the Very Large Database of Lipids Studies 6 and 7. 2019

Quispe, Renato / Hendrani, Aditya D / Baradaran-Noveiry, Behnoud / Martin, Seth S / Brown, Emily / Kulkarni, Krishnaji R / Banach, Maciej / Toth, Peter P / Brinton, Eliot A / Jones, Steven R / Joshi, Parag H. ·Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA. · Department of Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY, USA. · Louisiana State University Health Science Center-Shreveport, LA, USA. · Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD, USA. · Center for Inherited Heart Disease, Johns Hopkins Hospital, Baltimore, MD, USA. · VAP Diagnostics Laboratory, Birmingham, AL, USA. · Department of Hypertension, Medical University of Lodz, Lodz, Poland. · Department of Preventive Cardiology, CGH Medical Center, Sterling, IL, USA. · Department of Family and Community Medicine, University of Illinois College of Medicine, Peoria, IL, USA. · Utah Lipid Center, Salt Lake City, UT, USA. · Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. ·Arch Med Sci · Pubmed #31572464.

ABSTRACT: Introduction: The association between triglycerides (TG) and cardiovascular diseases is complex. The classification of hypertriglyceridemic (HTG) phenotypes proposed by Fredrickson, Levy and Lees (FLL) helps inform treatment strategies. We aimed to describe levels of several lipoprotein variables from individuals with HTG FLL phenotypes from the Very Large Database of Lipids. Material and methods: We included fasting samples from 979,539 individuals from a contemporary large study population of US adults. Lipids were directly measured by density-gradient ultracentrifugation using the Vertical Auto Profile test while TG levels were measured in whole plasma using the Abbott ARCHITECT C-8000 system. Hyperchylomicronemic (Hyper-CM) and non-chylomicronemic (non-CM) phenotypes were defined using computationally derived models. Individuals with FLL type IIa phenotype were excluded. Distributions of lipid variables were compared using medians and Kruskal-Wallis test. Results: A total of 11.9% ( Conclusions: This observational hypothesis-generating study provides insight into the complexity of lipid metabolism in HTG phenotypes, including less traditional lipid measures such as LDL density, HDL subclasses and Lp(a)-C.

11 Article Causal modeling in a multi-omic setting: insights from GAW20. 2018

Auerbach, Jonathan / Howey, Richard / Jiang, Lai / Justice, Anne / Li, Liming / Oualkacha, Karim / Sayols-Baixeras, Sergi / Aslibekyan, Stella W. ·Department of Statistics, Columbia University, 1255 Amsterdam Ave, New York, NY, 10027, USA. · Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ, UK. · Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 1020 Pine Avenue West, Montréal, Quebec, H3A 1A2, Canada. · Biomedical and Translational Informatics, Geisinger Health, 100 North Academy Ave, Danville, PA, 17822, USA. · State Key Laboratory of Genetic Engineering, Institute of Biostatistics, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai, 200438, China. · Département de Mathématiques, Université du Québec à Montréal, 2920 Chemin de la Tour, Montréal, Quebec, H3T 1 J4, Canada. · Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute); Universitat Pompeu Fabra; CIBER Cardiovascular Diseases (CIBERCV), 08003, Barcelona, Catalonia, Spain. · Department of Epidemiology, University of Alabama at Birmingham, 1665 University Blvd, RPHB 230J, Birmingham, AL, 35294, USA. saslibek@uab.edu. ·BMC Genet · Pubmed #30255779.

ABSTRACT: BACKGROUND: Increasingly available multilayered omics data on large populations has opened exciting analytic opportunities and posed unique challenges to robust estimation of causal effects in the setting of complex disease phenotypes. The GAW20 Causal Modeling Working Group has applied complementary approaches (eg, Mendelian randomization, structural equations modeling, Bayesian networks) to discover novel causal effects of genomic and epigenomic variation on lipid phenotypes, as well as to validate prior findings from observational studies. RESULTS: Two Mendelian randomization studies have applied novel approaches to instrumental variable selection in methylation data, identifying bidirectional causal effects of CPT1A and triglycerides, as well as of RNMT and C6orf42, on high-density lipoprotein cholesterol response to fenofibrate. The CPT1A finding also emerged in a Bayesian network study. The Mendelian randomization studies have implemented both existing and novel steps to account for pleiotropic effects, which were independently detected in the GAW20 data via a structural equation modeling approach. Two studies estimated indirect effects of genomic variation (via DNA methylation and/or correlated phenotypes) on lipid outcomes of interest. Finally, a novel weighted R CONCLUSIONS: The GAW20 contributions illustrate the diversity of possible approaches to causal inference in the multi-omic context, highlighting the promises and assumptions of each method and the benefits of integrating both across methods and across omics layers for the most robust and comprehensive insights into disease processes.

12 Article Hypertriglyceridemia in pregnancy. 2017

Simmons, Sierra C / Dorn, David P / Walton, Catherine M / Williams, Lance A / Pham, Huy P. ·Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama. · Infusion and Apheresis Service, University of Alabama at Birmingham Hospital, Birmingham, Alabama. ·Transfusion · Pubmed #29226372.

ABSTRACT: -- No abstract --

13 Article Extreme hypertriglyceridemia, pseudohyponatremia, and pseudoacidosis in a neonate with lipoprotein lipase deficiency due to segmental uniparental disomy. 2017

Ashraf, Ambika P / Hurst, Anna C E / Garg, Abhimanyu. ·Division of Pediatric Endocrinology, Department of Pediatrics, Children's of Alabama, University of Alabama at Birmingham, Birmingham, AL, USA. · Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA. · Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA. Electronic address: abhimanyu.garg@utsouthwestern.edu. ·J Clin Lipidol · Pubmed #28438574.

ABSTRACT: Extreme hypertriglyceridemia is rare in the neonatal period. We report a neonate with lipoprotein lipase (LPL) deficiency who presented with diagnostic and management conundrum. A full-term 36-day-old female was noted to have "Pepto-Bismol like" blood when repeating a newborn screening. The initial plasma triglyceride level was 24,318 mg/dL. The laboratory tests revealed serum bicarbonate level of <5 mmol/L, sodium of 127 mmol/L, and severe anemia. There were no signs of acute distress. The point of care capillary blood testing, however, demonstrated normal serum pH (7.2), bicarbonate (25.4 mmol/L), and sodium (139 mmol/L). The patient had mild elevation of serum lactic acid and no ketonuria. A diagnosis of type I hyperlipoproteinemia was made. Oral feeding was stopped, and the infant received intravenous fluids for the next 7 days resulting in lowering of serum triglyceride levels to 1016 mg/dL. Oral feeding was initiated with an amino acid-rich formula to which medium chain triglycerides were slowly added, while maintaining the total fat content to <15% of total daily energy. Sequencing of the LPL gene revealed a homozygous c.644G>A, p.(Gly215Glu) mutation. Subsequent analysis of the parental samples revealed that only the father, but not the mother, was a heterozygous carrier of the same mutation. Analysis of 18 informative microsatellite markers on chromosome 8 revealed paternal segmental uniparental disomy with partial absence of the maternal chromosome 8p, confirmed by single-nucleotide polymorphism microarray. We conclude that besides pseudohyponatremia, extreme hypertriglyceridemia can rarely present as pseudoacidosis and uniparental disomy can be an underlying mechanism for autosomal recessive diseases such as LPL deficiency.

14 Article A genome-wide study of lipid response to fenofibrate in Caucasians: a combined analysis of the GOLDN and ACCORD studies. 2016

Irvin, Marguerite R / Rotroff, Daniel M / Aslibekyan, Stella / Zhi, Degui / Hidalgo, Bertha / Motsinger-Reif, Alison / Marvel, Skylar / Srinivasasainagendra, Vinodh / Claas, Steven A / Buse, John B / Straka, Robert J / Ordovas, Jose M / Borecki, Ingrid B / Guo, Xiuqing / Chen, Ida Y D / Rotter, Jerome I / Wagner, Michael J / Arnett, Donna K. ·Departments of aEpidemiology bBiostatistics, University of Alabama at Birmingham, Birmingham, Alabama cDepartment of Statistics, North Carolina State University, Raleigh dUAB Biostatistics, Diabetes Center for Research, University of North Carolina at Chapel Hill School of Medicine eUAB Epidemiology, Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina fDepartment of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota gNCState Biostatistics, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts hDepartment of Genetics, Division of Statistical Genomics, Washington University in St Louis, St Louis, Missouri iLaboratory of Statistical and Mathematical Genetics jLaboratory for Biochemistry, Molecular Phenotyping, and Microarray kInstitute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, USA. ·Pharmacogenet Genomics · Pubmed #27002377.

ABSTRACT: BACKGROUND: Fibrates are commonly prescribed for hypertriglyceridemia, but they also lower LDL cholesterol and increase HDL cholesterol. Large interindividual variations in lipid response suggest that some patients may benefit more than others and genetic studies could help identify such patients. METHODS: We carried out the first genome-wide association study of lipid response to fenofibrate using data from two well-characterized clinical trials: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study. Genome-wide association study data from both studies were imputed to the 1000 Genomes CEU reference panel (phase 1). Lipid response was modeled as the log ratio of the post-treatment lipid level to the pretreatment level. Linear mixed models (GOLDN, N=813 from 173 families) and linear regression models (ACCORD, N=781) adjusted for pretreatment lipid level, demographic variables, clinical covariates, and ancestry were used to evaluate the association of genetic markers with lipid response. Among Caucasians, the results were combined using inverse-variance weighted fixed-effects meta-analyses. The main findings from the meta-analyses were examined in other ethnic groups from the HyperTG study (N=267 Hispanics) and ACCORD (N=83 Hispanics, 138 African Americans). RESULTS: A known lipid locus harboring the pre-B-cell leukemia homeobox 4 (PBX4) gene on chromosome 19 is important for LDL cholesterol response to fenofibrate (smallest P=1.5×10). The main results replicated with nominal statistical significance in Hispanics from ACCORD (P<0.05). CONCLUSION: Future research should evaluate the usefulness of this locus to refine clinical strategies for lipid-lowering treatments.

15 Article Unexplained hemolysis in patients undergoing ECMO: beware of hypertriglyceridemia. 2015

Venado, A / Wille, K / Belott, S C / Diaz-Guzman, E. ·Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Alabama, USA. · Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Alabama, USA. · Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Alabama, USA diaze@uab.edu. ·Perfusion · Pubmed #25361761.

ABSTRACT: Hemolysis is a common complication of extracorporeal membrane oxygenation (ECMO) support and is associated with increased mortality. Frequent monitoring of markers of hemolysis is performed at ECMO centers. We report two cases of spurious hemolysis caused by hypertriglyceridemia in patients undergoing ECMO support. Critically ill patients, including those receiving ECMO, may be at risk of developing medication-induced hypertriglyceridemia. The interference of lipids with the measurement of plasma free hemoglobin, a marker of hemolysis, should be recognized. Our cases highlight the importance of investigating hypertriglyceridemia as part of the assessment of unexplained hemolysis in patients supported with ECMO.

16 Article ABCD2 alters peroxisome proliferator-activated receptor α signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity. 2014

Liu, Xiaoxi / Liu, Jingjing / Liang, Shuang / Schlüter, Agatha / Fourcade, Stephane / Aslibekyan, Stella / Pujol, Aurora / Graf, Gregory A. ·Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.). · Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.) Gregory.Graf@uky.edu. ·Mol Pharmacol · Pubmed #25123288.

ABSTRACT: Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) α ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes.

17 Article Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. 2014

Clement, Lionel C / Macé, Camille / Avila-Casado, Carmen / Joles, Jaap A / Kersten, Sander / Chugh, Sumant S. ·1] Glomerular Disease Therapeutics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, USA. [2]. · 1] Department of Pathology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. [2] Department of Pathology, Instituto Nacional De Cardiologia, Mexico City, Mexico. · Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands. · Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, The Netherlands. · Glomerular Disease Therapeutics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, USA. ·Nat Med · Pubmed #24317117.

ABSTRACT: The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4-β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.

18 Article Comparative effectiveness of fish oil versus fenofibrate, gemfibrozil, and atorvastatin on lowering triglyceride levels among HIV-infected patients in routine clinical care. 2013

Muñoz, Monica A / Liu, Wei / Delaney, Joseph A C / Brown, Elizabeth / Mugavero, Michael J / Mathews, W Chris / Napravnik, Sonia / Willig, James H / Eron, Joseph J / Hunt, Peter W / Kahn, James O / Saag, Michael S / Kitahata, Mari M / Crane, Heidi M. ·*Department of Pharmaceutical Outcome and Policy, University of Florida, Gainesville, FL · †US Food and Drug Administration, Silver Spring, MD · ‡Department of Medicine (HC, MK) and Department of Biostatistics (EB), University of Washington, Seattle, WA · §Department of Medicine, University of Alabama, Birmingham, AL · ‖Department of Medicine, University of California, San Diego, CA · ¶Department of Medicine, University of North Carolina, Chapel Hill, NC · and #Department of Medicine, University of California, San Francisco, CA. ·J Acquir Immune Defic Syndr · Pubmed #23892238.

ABSTRACT: OBJECTIVE: The goal of this study was to compare the effectiveness of fish oil, fenofibrate, gemfibrozil, and atorvastatin on reducing triglyceride (TG) levels among a large cohort of HIV-infected patients in clinical care. DESIGN: Retrospective observational cohort study. METHODS: The primary endpoint was absolute change in TG levels measured using the last TG value pretreatment and the first TG value posttreatment. A pre-post quasi-experimental design was used to estimate the change in TG because of initiating fish oil. Linear regression models examined the comparative effectiveness of treatment with fish oil versus gemfibrozil, fenofibrate, or atorvastatin for TG reduction. Models were adjusted for baseline differences in age, sex, race, CD4⁺ cell count, diabetes, body mass index, protease inhibitor use, and time between TG measures. RESULTS: A total of 493 patients (mean age, 46 years; 95% male) were included (46 patients receiving gemfibrozil; 80, fenofibrate; 291, atorvastatin; and 76, fish oil) with a mean baseline TG of 347 mg/dL. New use of fish oil decreased TG [ΔTG, -45 mg/dL; 95% confidence interval (CI): -80 to -11] in the pre-post study. Compared with fish oil (reference), fibrates were more effective (ΔTG, -66; 95% CI: -120 to -12) in reducing TG levels, whereas atorvastatin was not (ΔTG, -39; 95% CI: -86 to 9). CONCLUSIONS: In HIV-infected patients in routine clinical care, fish oil is less effective than fibrates (but not atorvastatin) at lowering TG values. Fish oil may still represent an attractive alternative for patients with moderately elevated TGs, particularly among patients who may not want or tolerate fibrates.

19 Article Variants identified in a GWAS meta-analysis for blood lipids are associated with the lipid response to fenofibrate. 2012

Aslibekyan, Stella / Goodarzi, Mark O / Frazier-Wood, Alexis C / Yan, Xiaofei / Irvin, Marguerite R / Kim, Eric / Tiwari, Hemant K / Guo, Xiuqing / Straka, Robert J / Taylor, Kent D / Tsai, Michael Y / Hopkins, Paul N / Korenman, Stanley G / Borecki, Ingrid B / Chen, Yii-Der I / Ordovas, Jose M / Rotter, Jerome I / Arnett, Donna K. ·Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. saslibek@uab.edu ·PLoS One · Pubmed #23119086.

ABSTRACT: A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 861) we fit linear mixed models with the genetic markers as predictors and high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglyceride concentrations as outcomes. For all four traits, we analyzed both baseline levels and changes in response to treatment with fenofibrate. For the markers that were significantly associated with fenofibrate response, we fit additional models evaluating potential epistatic interactions. All models were adjusted for age, sex, and study center as fixed effects, and pedigree as a random effect. Statistically significant associations were observed between the rs964184 polymorphism near APOA1 (P-value≤0.0001) and fenofibrate response for HDL and triglycerides. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG, n = 267). Suggestive associations with fenofibrate response were observed for markers in or near PDE3A, MOSC1, FLJ36070, CETP, the APOE-APOC1-APOC4-APOC2, and CILP2. Finally, we present strong evidence for epistasis (P-value for interaction =  0.0006 in GOLDN, 0.05 in HyperTG) between rs10401969 near CILP2 and rs4420638 in the APOE-APOC1-APOC4-APOC2 cluster with total cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate pharmacogenetics.

20 Article High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN): an interventional study. 2011

Wojczynski, Mary K / Glasser, Stephen P / Oberman, Albert / Kabagambe, Edmond K / Hopkins, Paul N / Tsai, Michael Y / Straka, Robert J / Ordovas, Jose M / Arnett, Donna K. ·Department of Biostatistics, University of Alabama at Birmingham, Brimingham, AL, USA. ·Lipids Health Dis · Pubmed #22008512.

ABSTRACT: BACKGROUND: Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA. RESULTS: Postprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number. CONCLUSIONS: We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.