Rosanne M Crooke

Boston Children's Hospital, Boston, Massachusetts, United States

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Publications (77)487.47 Total impact

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    ABSTRACT: Proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds the low-density lipoprotein receptor and targets it for degradation, has emerged as an important regulator of serum cholesterol levels and cardiovascular disease risk. Although much work is currently focused on developing therapies for inhibiting PCSK9, the endogenous regulation of PCSK9, particularly by insulin, remains unclear. The objective of these studies was to determine the effects of insulin on PCSK9 in vitro and in vivo. Using rat hepatoma cells and primary rat hepatocytes, we found that insulin increased PCSK9 expression and increased low-density lipoprotein receptor degradation in a PCSK9-dependent manner. In parallel, hepatic Pcsk9 mRNA and plasma PCSK9 protein levels were reduced by 55% to 75% in mice with liver-specific knockout of the insulin receptor; 75% to 88% in mice made insulin-deficient with streptozotocin; and 65% in ob/ob mice treated with antisense oligonucleotides against the insulin receptor. However, antisense oligonucleotide-mediated knockdown of insulin receptor in lean, wild-type mice had little effect. In addition, we found that fasting was able to reduce PCSK9 expression by 80% even in mice that lack hepatic insulin signaling. Taken together, these data indicate that although insulin induces PCSK9 expression, it is not the sole or even dominant regulator of PCSK9 under all conditions. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2015; DOI:10.1161/ATVBAHA.115.305688 · 5.53 Impact Factor
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    ABSTRACT: Insulin resistance and β-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and β-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of β-cell cytoplasmic free Ca(2+) concentration ([Ca(2+)]i) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca(2+)]i response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of β-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.
    Proceedings of the National Academy of Sciences 05/2015; DOI:10.1073/pnas.1423849112 · 9.81 Impact Factor
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    ABSTRACT: Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction.
    Nature Communications 04/2015; 6. DOI:10.1038/ncomms7498 · 10.74 Impact Factor
  • Clinical Lipidology 04/2015; 10(2):191-203. DOI:10.2217/clp.15.7 · 0.86 Impact Factor
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    ABSTRACT: Atherosclerosis and associated cardiovascular disease (CVD) remain the largest causes of mortality in developed countries (Go et al., 2013). Despite widespread use of statins, CVD-associated mortality and morbidity have been reduced by only ∼30% (Go et al., 2013), demonstrating a clear need for better therapeutic strategies. Elevation of high-density lipoprotein (HDL) function is thought to be an attractive therapeutic strategy (Rader and Tall, 2012). However, recent clinical trials (Boden et al., 2011 and Schwartz et al., 2012) and Mendelian randomization studies (Voight et al., 2012) have failed to show clinical benefits of HDL cholesterol elevation, calling into question the role of HDL cholesterol as a surrogate marker of protection from atherosclerosis (Rader and Tall, 2012). Both proponents and critics alike of the “HDL hypothesis” agree on one thing: further studies are needed to understand the mechanism regulating the fundamental process of HDL-driven reverse cholesterol transport (RCT). The prevailing model for RCT is that cholesterol from the artery wall is delivered to the liver via HDL, from where it is then secreted into bile before leaving the body through the feces (Dietschy and Turley, 2002, Rader et al., 2009 and Rosenson et al., 2012). However, we and others have recently demonstrated that RCT can also proceed through a nonbiliary pathway known as transintestinal cholesterol excretion (TICE), which persists in both the surgical or genetic absence of biliary cholesterol secretion (Temel et al., 2010, Temel and Brown, 2012, Brown et al., 2008, Le May et al., 2013, van der Velde et al., 2007 and van der Veen et al., 2009). Under normal physiologic conditions the hepatobiliary route predominates and TICE is a minor pathway, only contributing ∼30% of the total cholesterol lost through the feces in mice (Temel and Brown, 2012). However, pharmacologic activation of liver X receptor (LXR) can preferentially stimulate the nonbiliary pathway to where TICE contributes greater than 60% of the total cholesterol lost through the feces (van der Veen et al., 2009). Although mechanisms regulating the classic hepatobiliary pathway of RCT have been well defined (Yu et al., 2002, Graf et al., 2003, Groen et al., 2008, Wiersma et al., 2009 and Temel et al., 2007), almost no mechanistic information exists for the nonbiliary TICE pathway (Temel and Brown, 2012 and Brufau et al., 2011).
    Cell Reports 01/2015; 66(3). DOI:10.1016/j.celrep.2014.12.036 · 7.21 Impact Factor
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    ABSTRACT: The familial chylomicronemia syndrome is a genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis due to a deficiency in lipoprotein lipase (LPL). Currently, there are no effective therapies except for extreme restriction in the consumption of dietary fat. Apolipoprotein C-III (APOC3) is known to inhibit LPL, although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. We administered an inhibitor of APOC3 messenger RNA (mRNA), called ISIS 304801, to treat three patients with the familial chylomicronemia syndrome and triglyceride levels ranging from 1406 to 2083 mg per deciliter (15.9 to 23.5 mmol per liter). After 13 weeks of study-drug administration, plasma APOC3 levels were reduced by 71 to 90% and triglyceride levels by 56 to 86%. During the study, all patients had a triglyceride level of less than 500 mg per deciliter (5.7 mmol per liter) with treatment. These data support the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.
    New England Journal of Medicine 12/2014; 371(23):2200-6. DOI:10.1056/NEJMoa1400284 · 54.42 Impact Factor
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    ABSTRACT: Background-C-reactive protein (CRP) binds to damaged cells, activates the classical complement pathway, is elevated in multiple inflammatory conditions, and provides prognostic information on risk of future atherosclerotic events. It is controversial, however, as to whether inhibiting CRP synthesis would have any direct anti-inflammatory effects in humans. Methods and Results-A placebo-controlled study was used to evaluate the effects of ISIS 329993 (ISIS-CRPRx) on the acute-phase response after endotoxin challenge in 30 evaluable subjects. Healthy adult males were randomly allocated to receive 6 injections over a 22-day period of placebo or active therapy with ISIS 329993 at 400- or 600-mg doses. Eligible subjects were subsequently challenged with a bolus of endotoxin (2 ng/kg). Inflammatory and hematological biomarkers were measured before and serially after the challenge. ISIS-CRPRx was well tolerated with no serious adverse events. Median CRP levels increased more than 50-fold from baseline 24 hours after endotoxin challenge in the placebo group. In contrast, the median increase in CRP levels was attenuated by 37% (400 mg) and 69% (600 mg) in subjects pretreated with ISIS-CRPRx (P<0.05 vs. placebo). All other aspects of the acute inflammatory response were similar between treatment groups. Conclusion-Pretreatment of subjects with ISIS-CRPRx selectively reduced the endotoxin-induced increase in CRP levels in a dose-dependent manner, without affecting other components of the acute-phase response. These data demonstrate the specificity of antisense oligonucleotides and provide an investigative tool to further define the role of CRP in human pathological conditions.
    Journal of the American Heart Association 06/2014; 3(4). DOI:10.1161/JAHA.114.001084 · 2.88 Impact Factor
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    ABSTRACT: The primary risk factor for atherosclerotic cardiovascular disease is LDL cholesterol, which can be reduced by increasing cholesterol excretion from the body. Fecal cholesterol excretion can be driven by a hepatobiliary as well as a non-biliary pathway known as transintestinal cholesterol efflux (TICE). We previously showed that chronic knockdown of the hepatic cholesterol esterifying enzyme sterol O-acyltransferase 2 (SOAT2) increased fecal cholesterol loss via TICE. To elucidate the initial events that stimulate TICE, C57Bl/6 mice were fed a high cholesterol diet to induce hepatic cholesterol accumulation and were then treated for 1 or 2 weeks with an antisense oligonucleotide targeting SOAT2. Within 2 weeks of hepatic SOAT2 knockdown (SOAT2HKD), the concentration of cholesteryl ester in the liver was reduced by 70% without a reciprocal increase in hepatic free cholesterol. The rapid mobilization of hepatic cholesterol stores resulted in a ∼2-fold increase in fecal neutral sterol loss but no change in biliary cholesterol concentration. Acute SOAT2HKD increased plasma cholesterol carried primarily in lipoproteins enriched in apoB and apoE. Collectively, our data suggest that acutely reducing SOAT2 causes hepatic cholesterol to be swiftly mobilized and packaged onto nascent lipoproteins that feed cholesterol into the TICE pathway for fecal excretion.
    PLoS ONE 06/2014; 9(6):e98953. DOI:10.1371/journal.pone.0098953 · 3.53 Impact Factor
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    ABSTRACT: Increased plasma levels of C-reactive protein (CRP) are closely associated with cardiovascular diseases, but whether CRP is directly involved in the pathogenesis of atherosclerosis is still under debate. Many controversial and contradictory results using transgenic mice and rabbits have been published but it is also unclear whether CRP lowering can be used for the treatment of atherosclerosis. In the current study, we examined the effects of the rabbit CRP antisense oligonucleotides (ASO) on the development of atherosclerosis in WHHL rabbits. CRP ASO treatment led to a significant reduction of plasma CRP levels; however, both aortic and coronary atherosclerotic lesions were not significantly changed compared to those of control WHHL rabbits. These results suggest that inhibition of plasma CRP does not affect the development of atherosclerosis in WHHL rabbits.
    Mediators of Inflammation 04/2014; 2014:979132. DOI:10.1155/2014/979132 · 3.24 Impact Factor
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    ABSTRACT: Raised blood C-reactive protein (CRP) level is a predictor of cardiovascular events, but whether blood CRP is causal in the disease process is unknown. The latter would best be defined by pharmacological inhibition of the protein in the context of a randomized case-control study. However, no CRP specific drug is currently available so such a prospective study cannot be performed. Blood CRP is synthesized primarily in the liver and the liver is an organ where antisense oligonucleotide (ASO) drugs accumulate. Taking advantage of this we evaluated the efficacy of CRP specific ASOs in rodents with experimentally induced cardiovascular damage. Treating rats for 4 weeks with a rat CRP-specific ASO achieved >60% reduction of blood CRP. Notably, this effect was associated with improved heart function and pathology following myocardial infarction (induced by ligation of the left anterior descending artery). Likewise in human CRP transgenic mice treated for 2 weeks with a human CRP-specific ASO, blood human CRP was reduced by >70% and carotid artery patency was improved (2 weeks after surgical ligation). CRP specific ASOs might pave the way towards a placebo-controlled trial that could clarify the role of CRP in cardiovascular disease.
    Mediators of Inflammation 04/2014; 2014:353614. DOI:10.1155/2014/353614 · 3.24 Impact Factor
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    ABSTRACT: Previous studies demonstrated that L-Fabp knockout mice are more susceptible to LD induced gallstones because of altered hepatic cholesterol metabolism and increased canalicular cholesterol secretion. Other studies demonstrated that liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) reduced lithogenic diet (LD) induced gallstone formation by increasing biliary phospholipid secretion. Here we show that mice with combined deletion (ie DKO mice) are protected from LD induced gallstone formation. Following two weeks LD feeding, 73% of wild-type (WT) and 100% of L-Fabp knockout mice developed gallstones versus 18% of Mttp-LKO and 23% of DKO mice. This phenotype was recapitulated in both WT and L-Fabp knockout mice treated with an Mttp antisense oligonucleotide (M-ASO). Biliary cholesterol secretion was increased in LD fed L-Fabp knockout mice and decreased in DKO mice. However, phospholipid secretion was unchanged in LD fed Mttp-LKO and DKO mice as well as in M-ASO treated mice. Expression of the canalicular export pump ABCG5/G8 was reduced in LD fed DKO mice and in M-ASO treated L-Fabp knockout mice. We conclude that liver-specific Mttp deletion not only eliminates apical lipoprotein secretion from hepatocytes but also attenuates canalicular cholesterol secretion, which in turn decreases LD induced gallstone susceptibility.
    The Journal of Lipid Research 01/2014; 55(3). DOI:10.1194/jlr.M046342 · 4.73 Impact Factor
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    ABSTRACT: An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE) is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL) support TICE, antisense oligonucleotides (ASO) were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP), which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg) mice, which predominantly excrete cholesterol via TICE, and wild type (WT) littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG) and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.
    PLoS ONE 01/2014; 9(1):e84418. DOI:10.1371/journal.pone.0084418 · 3.53 Impact Factor
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    ABSTRACT: The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this, we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues in order to identify in vivo substrates and understand ABHD6's role in energy metabolism. Here, we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches, we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes.
    Cell Reports 10/2013; DOI:10.1016/j.celrep.2013.08.047 · 7.21 Impact Factor
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    ABSTRACT: Antisense oligonucleotides and small interfering RNAs, which suppress the translation of specific mRNA target proteins, are emerging as important therapeutic modalities for the treatment of cardiovascular disease. Over the last 25 years, the advances in all aspects of antisense technology, as well as a detailed understanding of the mechanism of action of antisense drugs, have enabled their use as therapeutic agents. These advancements culminated in the FDA approval of the first chronically administered cardiovascular antisense therapeutic, mipomersen, which targets hepatic apolipoprotein B mRNA. This review provides a brief history of antisense technology, highlights the progression of mipomersen from preclinical studies to multiple Phase III registration trials, and gives an update on the status of other cardiovascular antisense therapeutics currently in the clinic.
    Journal of Cardiovascular Translational Research 07/2013; 6(6). DOI:10.1007/s12265-013-9495-7 · 2.69 Impact Factor
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    ABSTRACT: RNA targeted therapeutics are being developed in a broad array of therapeutic areas, and more recently a growing number of RNA targeted antisense approaches for cardiovascular and metabolic diseases have progressed into clinical development. Cardiovascular and metabolic diseases are growing health issues with significant associated morbidity and mortality. RNA represents a growing and accessible target space that has been shown to be specifically and selectively targeted utilizing short single strand antisense oligonucleotides. Antisense drugs are relatively small synthetic oligonucleotides with predictable safety and pharmacokinetics across a given chemical platform. Once identified, the remaining risk in development as a therapeutic is associated with selection of the right target, sufficient to affect a clinically meaningful change in the course of disease. This review focuses primarily on the translated mRNAs currently being targeted using antisense therapies in cardiovascular and metabolic disease.
    Drug Discovery Today Therapeutic Strategies 07/2013; DOI:10.1016/j.ddstr.2013.06.001
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    ABSTRACT: Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease. In these studies we compared an antisense oligonucleotide (ASO) inhibitor of CETP to the CETP small molecule inhibitor, anacetrapib. In hyperlipidemic CETP transgenic mice, both drugs provided comparable reductions in total plasma cholesterol, decreases in CETP activity and increases in HDL-C. However, only mice treated with the antisense inhibitor showed an enhanced effect on macrophage reverse cholesterol transport, presumably due to differences in HDL apolipoprotein composition and decreases in plasma TG. Additionally, the ASO mediated reductions in CETP mRNA were associated with less accumulation of aortic cholesterol. These preliminary findings suggest that CETP ASOs may represent an alternative means to inhibit that target and further, support their continued development as a treatment for cardiovascular disease in man.
    The Journal of Lipid Research 06/2013; 54(10). DOI:10.1194/jlr.M036509 · 4.73 Impact Factor
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    ABSTRACT: Rationale: Elevated plasma triglyceride (TG) levels have been recognized as a risk factor for the development of coronary heart disease (CHD). Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma TG concentrations. Further, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic. Objective: To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and TG levels. Methods and Results: Rodent and human-specific second generation antisense oligonucleotides (ASOs) were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice and non-human primates. We demonstrate the selective reduction of both apoC-III and TG in all preclinical pharmacological evaluations. We also show that inhibition of apoC-III was well tolerated and not associated with increased liver TG deposition or hepatotoxicity. A double-blind, placebo-controlled Phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of TG levels and produced no clinically meaningful signals in the safety evaluations. Conclusions: Antisense inhibition of apoC-III in preclinical models and in a Phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and TG, two known risk factors for CV disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.
    Circulation Research 03/2013; 112(11). DOI:10.1161/CIRCRESAHA.111.300367 · 11.09 Impact Factor
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    ABSTRACT: Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis.
    Cell metabolism 01/2013; 17(1):49-60. DOI:10.1016/j.cmet.2012.12.011 · 16.75 Impact Factor
  • Rosanne M Crooke, Mark J Graham
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    ABSTRACT: Antisense oligonucleotides (ASOs) are a new class of specific therapeutic agents that alter the intermediary metabolism of mRNA, resulting in the suppression of disease-associated gene products. ASOs exert their pharmacological effects after hybridizing, via Watson-Crick base pairing, to a specific target RNA. If appropriately designed, this event results in the recruitment of RNase H, the degradation of targeted mRNA or pre-mRNA, and subsequent inhibition of the synthesis of a specific protein. A key advantage of the technology is the ability to selectively inhibit targets that cannot be modulated by traditional therapeutics such as structural proteins, transcription factors, and, of topical interest, lipoproteins. In this chapter, we will first provide an overview of antisense technology, then more specifically describe the status of lipoprotein-related genes that have been studied using the antisense platform, and finally, outline the general methodology required to design and evaluate the in vitro and in vivo efficacy of those drugs.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 1027:309-24. DOI:10.1007/978-1-60327-369-5_14 · 1.29 Impact Factor
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    ABSTRACT: Inhibitors of apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) are being developed in the clinic to benefit patients who are unable to reach target LDL-C levels with maximally tolerated lipid-lowering agents. In order to compare and contrast the metabolic consequences of inhibiting these targets, murine-specific apoB or MTP antisense oligonucleotides (ASOs) were administered to chow and high fat fed C57BL/6, or chow and western diet fed LDLr -/- mice for periods ranging from two to twelve weeks and detailed analyses of various factors affecting fatty acid metabolism were performed. Administration of these inhibitors significantly reduced both target hepatic mRNA and protein leading to similar inhibition of hepatic VLDL/triglyceride secretion. MTP ASO treatment consistently led to increases in both hepatic triglyceride accumulation and biomarkers of hepatotoxicity relative to apoB ASO due in part to enhanced expression of PPAR gamma target genes and the inability to reduce hepatic fatty acid synthesis.
    The Journal of Lipid Research 12/2012; DOI:10.1194/jlr.M029215 · 4.73 Impact Factor

Publication Stats

2k Citations
487.47 Total Impact Points


  • 2015
    • Boston Children's Hospital
      • Division of Endocrinology
      Boston, Massachusetts, United States
  • 1996–2015
    • Isis Pharmaceuticals, Inc.
      Carlsbad, California, United States
  • 2013
    • University of North Carolina at Chapel Hill
      • Department of Genetics
      North Carolina, United States
  • 2012
    • University of Alabama at Birmingham
      • Division of Clinical Immunology and Rheumatology
      Birmingham, Alabama, United States
  • 2011
    • Seoul National University Hospital
      Sŏul, Seoul, South Korea
  • 2007–2011
    • Columbia University
      • Department of Medicine
      New York City, NY, United States
    • Isis Pharmaceuticals, Inc.
      Carlsbad, California, United States
  • 2010
    • Tufts University
      Georgia, United States
  • 2006
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Vascular Medicine
      Amsterdam, North Holland, Netherlands
    • Tabriz University of Medical Sciences
      Tebriz, East Azarbaijan, Iran