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Hypertriglyceridemia: HELP
Articles from University of California San Diego
Based on 16 articles published since 2008
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These are the 16 published articles about Hypertriglyceridemia that originated from University of California San Diego during 2008-2019.
 
+ Citations + Abstracts
1 Review Hepatic heparan sulfate proteoglycans and endocytic clearance of triglyceride-rich lipoproteins. 2010

Foley, Erin M / Esko, Jeffrey D. ·Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA. ·Prog Mol Biol Transl Sci · Pubmed #20807647.

ABSTRACT: Hypertriglyceridemia, characterized by the accumulation of triglyceride-rich lipoproteins in the blood, affects 10-20% of the population in western countries and increases the risk of atherosclerosis, coronary artery disease, and pancreatitis. The etiology of hypertriglyceridemia is complex, and much interest exists in identifying and characterizing the biological and environmental factors that affect the synthesis and turnover of plasma triglycerides. Genetic studies in mice have recently identified that heparan sulfate proteoglycans are a class of receptors that mediate the clearance of triglyceride-rich lipoproteins in the liver. Heparan sulfate proteoglycans are expressed by endothelial cells that line the hepatic sinusoids and the underlying hepatocytes, and are present in the perisinusoidal space (space of Disse). This chapter discusses the dependence of lipoprotein binding on heparan sulfate structure and the identification of hepatocyte syndecan-1 as the primary proteoglycan that mediates triglyceride-rich lipoprotein clearance.

2 Review Which comes first: atypical antipsychotic treatment or cardiometabolic risk? 2009

Stahl, S M / Mignon, L / Meyer, J M. ·Department of Psychiatry, University of California, San Diego School of Medicine, San Diego, CA 92008, USA. smstahl@neiglobal.com ·Acta Psychiatr Scand · Pubmed #19178394.

ABSTRACT: OBJECTIVE: To provide an overview for practicing clinicians on the pharmacological basis of cardiometabolic risk induced by antipsychotic drugs in patients with serious mental illness, to propose hypotheses to explain these risks and to give tips for managing cardiometabolic risk during antipsychotic treatment. METHOD: A MEDLINE search using terms for atypical antipsychotics (including individual drug names), metabolic, cardiovascular, weight gain and insulin resistance, cross-referenced with schizophrenia was performed on articles published between 1990 and May 2008. RESULTS: Strong evidence exists for significant cardiometabolic risk differences among several antipsychotic agents. Histamine H1 and serotonin 5HT2C antagonism are associated with risk of weight gain, but receptor targets for dyslipidemia and insulin resistance have not yet been identified. Convincing data indicate that hypertriglyceridemia and insulin resistance may occur in the absence of weight gain with certain antipsychotics. CONCLUSION: Although lifestyle and genetics may contribute independent risks of cardiometabolic dysfunction in schizophrenia and other serious mental illness, antipsychotic treatment also represents an important contributor to risk of cardiometabolic dysfunction, particularly for certain drugs and for vulnerable patients. Mental health professionals must learn to recognize the clinical signposts indicating antipsychotic-related cardiometabolic problems to forestall progression to type II diabetes, cardiovascular events and premature death.

3 Clinical Trial Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidaemia at high cardiovascular risk. 2017

Müller-Wieland, Dirk / Leiter, Lawrence A / Cariou, Bertrand / Letierce, Alexia / Colhoun, Helen M / Del Prato, Stefano / Henry, Robert R / Tinahones, Francisco J / Aurand, Lisa / Maroni, Jaman / Ray, Kausik K / Bujas-Bobanovic, Maja. ·Department of Internal Medicine I, University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany. dirmueller@ukaachen.de. · Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. · Institut du Thorax, CHU Nantes, Nantes, France. · Biostatistics and Programming Department, Sanofi, Chilly-Mazarin, France. · University of Edinburgh, Edinburgh, Scotland, UK. · Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. · University of California San Diego School of Medicine, Center for Metabolic Research, Veterans Affairs, San Diego Healthcare System, San Diego, CA, USA. · CIBERobn, Hospital Virgen de la Victoria, Málaga University, Málaga, Spain. · Sanofi, Bridgewater, NJ, USA. · Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. · Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK. · Sanofi, Paris, France. ·Cardiovasc Diabetol · Pubmed #28545518.

ABSTRACT: BACKGROUND: Type 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-high-density lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non-HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterol-lowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator. METHODS: DM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-C ≥100 mg/dl [≥2.59 mmol/l], and triglycerides ≥150 and <500 mg/dl [≥1.70 and <5.65 mmol/l]) with documented atherosclerotic cardiovascular disease or ≥1 additional cardiovascular risk factor. Participants were randomised (2:1) to alirocumab 75 mg every 2 weeks (Q2W) or lipid-lowering usual care on top of maximally tolerated statin (or no statin if intolerant). If randomised to usual care, investigators were able to add their pre-specified choice of one of the following to the patient's current statin regimen: ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid, in accordance with local standard-of-care. Alirocumab-treated individuals with non-HDL-C ≥100 mg/dl at week 8 will undergo a blinded dose increase to 150 mg Q2W at week 12. The primary efficacy endpoint is non-HDL-C change from baseline to week 24 with alirocumab versus usual care; other lipid levels (including LDL-C), glycaemia-related measures, safety and tolerability will also be assessed. Alirocumab will be compared to fenofibrate in a secondary analysis. RESULTS: Recruitment completed with 413 individuals randomised in 14 countries worldwide. Results of this trial are expected in the second quarter of 2017. CONCLUSIONS: ODYSSEY DM-DYSLIPIDEMIA will provide information on the efficacy and safety of alirocumab versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk using non-HDL-C as the primary efficacy endpoint. Trial registration NCT02642159 (registered December 24, 2015).

4 Clinical Trial AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes. 2016

Katz, L / Manamley, N / Snyder, W J / Dodds, M / Agafonova, N / Sierra-Johnson, J / Cruz, M / Kaur, P / Mudaliar, S / Raskin, P / Kewalramani, R / Pellacani, A. ·Amgen Inc., Thousand Oaks, CA, USA. · Amgen Ltd, Cambridge, UK. · Amgen Inc., Seattle, WA, USA. · Center for Metabolic Research, Veterans Administration San Diego Healthcare System, San Diego, CA, USA. · University of Texas Southwestern Medical Center, Dallas, TX, USA. ·Diabetes Obes Metab · Pubmed #26434934.

ABSTRACT: Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.

5 Clinical Trial Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. 2015

Gaudet, Daniel / Alexander, Veronica J / Baker, Brenda F / Brisson, Diane / Tremblay, Karine / Singleton, Walter / Geary, Richard S / Hughes, Steven G / Viney, Nicholas J / Graham, Mark J / Crooke, Rosanne M / Witztum, Joseph L / Brunzell, John D / Kastelein, John J P. ·From the Department of Medicine, Université de Montréal and Ecogene-21 Clinical Research Centre, Chicoutimi, QC, Canada (D.G., D.B., K.T.) · Isis Pharmaceuticals, Carlsbad (V.J.A., B.F.B., W.S., R.S.G., S.G.H., N.J.V., M.J.G., R.M.C.), and the Department of Medicine, University of California, San Diego, La Jolla (J.L.W.) - both in California · the Department of Medicine, University of Washington, Seattle (J.D.B.) · and the Department of Vascular Medicine, Academic Medical Center, Amsterdam (J.J.P.K.). ·N Engl J Med · Pubmed #26222559.

ABSTRACT: BACKGROUND: Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline. RESULTS: A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study. CONCLUSIONS: We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).

6 Article Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease. 2018

Harlow, Kathryn E / Africa, Jonathan A / Wells, Alan / Belt, Patricia H / Behling, Cynthia A / Jain, Ajay K / Molleston, Jean P / Newton, Kimberly P / Rosenthal, Philip / Vos, Miriam B / Xanthakos, Stavra A / Lavine, Joel E / Schwimmer, Jeffrey B / Anonymous1621131. ·Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, CA; Department of Pediatrics, Division of Gastroenterology, Rady Children's Hospital, San Diego, CA. · Department of Pediatrics, Division of Dysmorphology and Teratology, University of California, San Diego, CA. · Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. · Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, CA; Department of Pathology, Sharp Medical Center, San Diego, CA. · Department of Pediatrics, St. Louis University, St. Louis, MO. · Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, IN. · Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA. · Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA. · Steatohepatitis Center, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. · Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University, New York, NY. · Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, CA; Department of Pediatrics, Division of Gastroenterology, Rady Children's Hospital, San Diego, CA. Electronic address: jschwimmer@ucsd.edu. ·J Pediatr · Pubmed #29661561.

ABSTRACT: OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management.

7 Article The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study. 2017

Davidson, Michael / Stevenson, Michael / Hsieh, Andrew / Ahmad, Zahid / Crowson, Caroline / Witztum, Joseph L. ·a Department of Medicine , University of Chicago , Chicago , IL , USA. · b Akcea Therapeutics , Cambridge , MA , USA. · c Division of Nutrition and Metabolic Disease, Department of Internal Medicine , University of Texas Southwestern Medical Center , Dallas , TX , USA. · d Trinity Partners , Waltham , MA , USA. · e Department of Medicine, Division of Endocrinology and Metabolism , University of California San Diego , La Jolla , CA , USA. ·Expert Rev Cardiovasc Ther · Pubmed #28338353.

ABSTRACT: BACKGROUND: Familial Chylomicronemia Syndrome (FCS) is a rare genetic disorder that is caused by a decrease or an absence of lipoprotein lipase activity. FCS is characterized by marked accumulation of chylomicrons and extreme hypertriglyceridemia, which have major effects on both physical and mental health. To date, there have been no systematic efforts to characterize the impact of chylomicronemia on FCS patients' lives. In particular, the impact of FCS on the burden of illness (BoI) and quality of life (QoL) has not been fully described in the literature. METHODS: IN-FOCUS was a comprehensive web-based research survey of patients with FCS focused on capturing the BoI and impact on QoL associated with FCS. Sixty patients from the US diagnosed with FCS participated. Patients described multiple symptoms spanning across physical, emotional and cognitive domains. RESULTS: Patients on average cycled through 5 physicians of varying specialty before being diagnosed with FCS, reflecting a lengthy journey to diagnosis Nearly all respondents indicated that FCS had a major impact on BoI and QoL and significantly influenced their career choice and employment status, and caused significant work loss due to their disease. CONCLUSION: FCS imparts a considerable burden across multiple domains with reported impairment on activities of daily living and QoL.

8 Article A randomized, placebo-controlled, double-blind study on the effects of (-)-epicatechin on the triglyceride/HDLc ratio and cardiometabolic profile of subjects with hypertriglyceridemia: Unique in vitro effects. 2016

Gutiérrez-Salmeán, Gabriela / Meaney, Eduardo / Lanaspa, Miguel A / Cicerchi, Christina / Johnson, Richard J / Dugar, Sundeep / Taub, Pam / Ramírez-Sánchez, Israel / Villarreal, Francisco / Schreiner, George / Ceballos, Guillermo. ·Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico. · University of Colorado at Denver, United States. · Cardero Therapeutics, Inc., United States. · Department of Medicine, University of California San Diego, United States. · Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico; Department of Medicine, University of California San Diego, United States. · Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico. Electronic address: gceballosr@ipn.mx. ·Int J Cardiol · Pubmed #27552564.

ABSTRACT: BACKGROUND: Cardiometabolic disruptions such as insulin resistance, obesity, high blood pressure, hyperglycemia, and dyslipidemias, are known to increase the risk for cardiovascular and metabolic diseases such as type 2 diabetes mellitus and atherosclerosis. Several screening tools for assessing cardiometabolic risk have been developed including the TG/HDLc ratio, which has been, demonstrated to possess a strong association with insulin resistance and coronary disease. Dietary modifications, together with regular moderate exercise have proven to be effective in attenuating cardiometabolic disruptions. However, they often exhibit poor long-term patient compliance. Nutraceutics, including (-)-epicatechin (EPI), have gained increasing interest as coadjuvant effective and safe therapies that are able to attenuate hypertension, hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hypoalphalipoproteinemia. METHODS: The aims of this study were: 1) to compare the in vitro effect of EPI vs. (+)-catechin on fructose induced triglyceride accumulation and mitochondrial function in Hep2 cells in culture, 2) to evaluate the efficacy of EPI treatment in reducing fasting blood triglycerides and improving the TG/HDLc ratio in hypertriglyceridemic patients with a total daily dose of 100mg of EPI. Secondary clinical variables included total cholesterol, LDLc, fructosamine, glucose, insulin, and high sensitivity C-reactive protein blood levels. RESULTS AND CONCLUSION: Our results provide preliminary evidence as to favorable effects of EPI on glycemia homeostasis, lipid profile and systemic inflammation such bioactive actions are not class-effects (i.e. limited to their antioxidant potential) but instead, may result from the specific activation of associated downstream signaling pathways since catechin has no effects.

9 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.

10 Article Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance. 2012

Deng, Yiping / Foley, Erin M / Gonzales, Jon C / Gordts, Philip L / Li, Yulin / Esko, Jeffrey D. ·Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0687, USA. ·Hepatology · Pubmed #21898481.

ABSTRACT: CONCLUSION: These findings suggest that syndecan-1 mediates hepatic VLDL turnover in humans as well as in mice and that shedding might contribute to hypertriglyceridemia in patients with sepsis.

11 Article Insulin infusion to treat severe hypertriglyceridemia associated with pegaspargase therapy: a case report. 2011

Lawson, Eileen B / Gottschalk, Michael / Schiff, Deborah E. ·UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, San Diego, CA, USA. ebrigid@ucsd.edu ·J Pediatr Hematol Oncol · Pubmed #21343748.

ABSTRACT: We describe a pediatric patient with acute leukemia who developed an uncommon but significant metabolic consequence of pegaspargase therapy-severe hypertriglyceridemia (hyperTG). We also relate our experience with continuous insulin infusion treatment for pegaspargase-induced hyperTG. This treatment approach led to a decrease in triglycerides from 4640 mg/dL on admission to 522 mg/dL at discharge 9 days later. Genetic testing revealed that our patient was an apolipoprotein E 3/4 heterozygote. Our review of the literature suggests that apolipoprotein E polymorphism may influence the development of hyperlipidemia in acute lymphoblastic leukemia patients receiving asparaginase therapy and may identify patients at high risk for developing asparaginase-induced hyperTG.

12 Article Hypertriglyceridemia in combination antiretroviral-treated HIV-positive individuals: potential impact on HIV sensory polyneuropathy. 2011

Banerjee, Sugato / McCutchan, J Allen / Ances, Beau M / Deutsch, Reena / Riggs, Patricia K / Way, Lauren / Ellis, Ronald J. ·Department of Neurosciences, USA bDepartment of Medicine, University of California, San Diego, California 92103-8231, USA. ·AIDS · Pubmed #21150557.

ABSTRACT: OBJECTIVE: in HIV populations that are aging due to improved longevity with combination antiretroviral therapy (CART), both hypertriglyceridemia (hTRG) and sensory neuropathy have become increasingly common. Sensory neuropathy is associated with substantial long-term disability and frequently requires management with analgesics. Elevated serum triglycerides (TRGs) are associated with an increased risk for sensory neuropathy in diabetes mellitus. However, the contribution of hTRG to sensory neuropathy in HIV has not been carefully evaluated. DESIGN: prospective, comparative, single-center, cross-sectional cohort study. METHODS: clinical correlates of sensory neuropathy were assessed in HIV-positive and HIV-negative participants. HIV-sensory neuropathy was defined as one or more clinical signs of reduced distal sensation or ankle reflexes; symptoms were distal leg and foot pain, parasthesias or numbness. TRG levels were assessed along with concomitant metabolic and other risk factors including glucose, lipids, age, height, current and nadir CD4, and past or current use of protease inhibitors, dideoxynucleoside antiretrovirals (d-drugs), and statins in univariable and multivariable logistic regression. RESULTS: of 436 HIV patients (median age 52 years; 75% on CART), 27% had sensory neuropathy; 48% were symptomatic. TRG levels were significantly higher in HIV-positive than HIV-negative individuals (mean ± SD, 245 ± 242 versus 160 ± 97 mg/dl; P < 0.001). Among HIV-positive patients, those with TRG levels in the highest tertile (≥ 244 mg/dl) were more likely to have sensory neuropathy than those in the lowest tertile (reference, ≤ 142 mg/dl) after adjusting for concurrent predictors (adjusted odds ratio 2.7, 95% confidence interval 1.4-5.5). CONCLUSIONS: elevated triglyceride levels increased the risk for HIV-sensory neuropathy in HIV-positive individuals independently of other known risk factors.

13 Article Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans. 2010

Bishop, Joseph R / Passos-Bueno, Maria Rita / Fong, Loren / Stanford, Kristin I / Gonzales, Jon C / Yeh, Erika / Young, Stephen G / Bensadoun, Andre / Witztum, Joseph L / Esko, Jeffrey D / Moulton, Karen S. ·Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America. ·PLoS One · Pubmed #21085708.

ABSTRACT: BACKGROUND: Lipoprotein lipase (Lpl) acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism. METHODS AND FINDINGS: We examined mutant mice defective in collagen XVIII (Col18), a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia. CONCLUSIONS: This is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.

14 Article Insulin-dependent diabetes mellitus in mice does not alter liver heparan sulfate. 2010

Bishop, Joseph R / Foley, Erin / Lawrence, Roger / Esko, Jeffrey D. ·Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, USA. ·J Biol Chem · Pubmed #20236939.

ABSTRACT: Diabetes -associated hyperlipidemia is generally attributed to reduced clearance of plasma lipoproteins, especially remnant lipoproteins enriched in cholesterol and triglycerides. Hepatic clearance of remnants occurs via low density lipoprotein receptors and the heparan sulfate proteoglycan, syndecan-1. Previous studies have suggested alterations in heparan sulfate proteoglycan metabolism in rat and mouse diabetic models, consistent with the idea that diabetic dyslipidemia might be caused by alterations in proteoglycan expression in the liver. In this study we analyzed the content and composition of liver heparan sulfate in streptozotocin-induced insulin-deficient diabetic mice that displayed fasting hypertriglyceridemia and delayed clearance of dietary triglyceride-rich lipoproteins. No differences between normal and diabetic littermates in liver heparan sulfate content, sulfation, syndecan-1 protein levels, or affinity for heparin-binding ligands, such as apolipoprotein E or fibroblast growth factor-2, were noted. Decreased incorporation of [(35)S]sulfate in insulin-deficient mice in vivo was observed, but the decrease was due to increased plasma inorganic sulfate, which reduced the efficiency of labeling of liver heparan sulfate. These results show that hyperlipidemia in insulin-deficient mice is not due to changes in hepatic heparan sulfate composition.

15 Article Heparan sulfate 2-O-sulfotransferase is required for triglyceride-rich lipoprotein clearance. 2010

Stanford, Kristin I / Wang, Lianchun / Castagnola, Jan / Song, Danyin / Bishop, Joseph R / Brown, Jillian R / Lawrence, Roger / Bai, Xaiomei / Habuchi, Hiroko / Tanaka, Masakazu / Cardoso, Wellington V / Kimata, Koji / Esko, Jeffrey D. ·Department of Cellular and Molecular Medicine and the Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687, USA. ·J Biol Chem · Pubmed #19889634.

ABSTRACT: Hepatic clearance of triglyceride-rich lipoproteins depends on heparan sulfate and low density lipoprotein receptors expressed on the basal membrane of hepatocytes. Binding and uptake of the lipoproteins by way of heparan sulfate depends on the degree of sulfation of the chains based on accumulation of plasma triglycerides and delayed clearance of triglyceride-rich lipoproteins in mice bearing a hepatocyte-specific alteration of N-acetylglucosamine (GlcNAc) N-deacetylase-N-sulfotransferase 1 (Ndst1) (MacArthur, J. M., Bishop, J. R., Stanford, K. I., Wang, L., Bensadoun, A., Witztum, J. L., and Esko, J. D. (2007) J. Clin. Invest. 117, 153-164). Inactivation of Ndst1 led to decreased overall sulfation of heparan sulfate due to coupling of uronyl 2-O-sulfation and glucosaminyl 6-O-sulfation to initial N-deacetylation and N-sulfation of GlcNAc residues. To determine whether lipoprotein clearance depends on 2-O-and 6-O-sulfation, we evaluated plasma triglyceride levels in mice containing loxP-flanked conditional alleles of uronyl 2-O-sulfotransferase (Hs2st(f/f)) and glucosaminyl 6-O-sulfotransferase-1 (Hs6st1(f/f)) and the bacterial Cre recombinase expressed in hepatocytes from the rat albumin (Alb) promoter. We show that Hs2st(f/f)AlbCre(+) mice accumulated plasma triglycerides and exhibited delayed clearance of intestinally derived chylomicrons and injected human very low density lipoproteins to the same extent as observed in Ndst1(f/f)AlbCre(+) mice. In contrast, Hs6st1(f/f)AlbCre(+) mice did not exhibit any changes in plasma triglycerides. Chemically modified heparins lacking N-sulfate and 2-O-sulfate groups did not block very low density lipoprotein binding and uptake in isolated hepatocytes, whereas heparin lacking 6-O-sulfate groups was as active as unaltered heparin. Our findings show that plasma lipoprotein clearance depends on specific subclasses of sulfate groups and not on overall charge of the chains.

16 Article Severe hypertriglyceridemia and recurrent pancreatitis in a girl with type Ia glycogen storage disease and type III hyperlipoproteinemia. 2009

Vivatrat, N / Barshop, B A / Jones, K L. ·University of California, San Diego (UCSD), Rady Children's Hospital, San Diego, California, USA. ·Am J Med Genet A · Pubmed #19842193.

ABSTRACT: -- No abstract --