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===PCSK9 Inhibition===
===PCSK9 Inhibition===
Increased low-density lipoprotein cholesterol (LDL-C) levels in the plasma is associated with the development and progression of [[atherosclerosis]] and associated diseases such as [[myocardial infarction]] and [[stroke]].  LDL receptors, which are responsible for clearing LDL-C from the circulation, get recycled back into the plasma membrane in order to bind more LDL-C. A novel approach to lipid management focuses on inhibiting the serine protease PCSK9 which is involved in the degradation of LDL receptors subsequently preventing the binding of new LDLs to be cleared from the circulation. <ref name=lopez>{{cite journal | author = Lopez D|title = Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia | journal = Drug News Perspect. | volume = 21|issue = 6 | pages = 323–30 | year = 2008 | pmid = 18836590 | doi = 10.1358/dnp.2008.21.6.1246795 }}</ref><ref name=steinberg>{{cite journal|author = Steinberg D, Witztum JL | title = Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels | journal = Proc. Natl. Acad. Sci. U.S.A. |volume = 106 | issue = 24 | pages = 9546–7 | year = 2009 | month = June | pmid = 19506257 | pmc = 2701045|doi = 10.1073/pnas.0904560106 }}</ref><ref name=mayer>{{cite journal | author = Mayer G, Poirier S, Seidah NG | title = Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels | journal = J. Biol. Chem. | volume = 283|issue = 46 | pages = 31791–801 | year = 2008 | month = November | pmid = 18799458| doi = 10.1074/jbc.M805971200 }}</ref><ref name=bms>{{cite web | url = http://www.fiercebiotech.com/press-releases/bristol-myers-squibb-selects-isis-drug-targeting-pcsk9-development-candidate-preventi| title = Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease | author = | authorlink = | coauthors = | date = 2008-04-08  | format = | work = Press Release | publisher = FierceBiotech| pages =| language = | archiveurl = | archivedate = | quote = | accessdate = 2010-09-18 }}</ref>
PCSK9 has a major role in the metabolism of hepatic cholesterol.  It is a serine protease which binds to the epidermal growth factor-like repeat A (EGF-A) domain of the [[low-density lipoprotein]] receptor (LDLR), inducing LDLR degradation in the lysosomes.  Reduced LDL receptor levels result in decreased metabolism of [[low density lipoprotein]] (LDL), which could lead to hypercholesterolemia.<ref name=uendo>*{{cite web | url =http://www.uendocrine.com/presentations/hyperlipidemia/the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol| title = The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol |author = | authorlink = | coauthors = | date = 2012-11-11 }}</ref> The [[Sterol regulatory element binding protein|sterol regulatory element-binding protein-2 (SREBP-2)]], which is activated in the presence of low intracellular levels of cholesterol, also induces the expression of PCSK9, thereby increasing the amount of circulating LDL-cholesterol.<ref name="Maxwell-2003">{{Cite journal | last1 = Maxwell | first1 = KN. | last2 = Soccio | first2 = RE. | last3 = Duncan |first3 = EM. | last4 = Sehayek | first4 = E. | last5 = Breslow | first5 = JL. | title = Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. | journal = J Lipid Res | volume = 44 | issue = 11 | pages = 2109-19 | month = Nov | year = 2003 | doi = 10.1194/jlr.M300203-JLR200 | PMID = 12897189 }}</ref>
====Monoclonal Antibodies====
In addition to the effect on LDL-C, PCSK9 deficiency has also been shown to lower cardiovascular risk factors by reducing postprandial triglyceridemia.<ref name="Le May-2009">{{Cite journal | last1 = Le May | first1 = C. | last2 = Kourimate | first2 = S. | last3 = Langhi | first3 = C. | last4 = Chétiveaux |first4 = M. | last5 = Jarry | first5 = A. | last6 = Comera | first6 = C. | last7 = Collet | first7 = X. | last8 = Kuipers | first8 = F. | last9 = Krempf |first9 = M. | title = Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. | journal = Arterioscler Thromb Vasc Biol | volume = 29 | issue = 5 | pages = 684-90 | month = May | year = 2009 | doi = 10.1161/ATVBAHA.108.181586 | PMID = 19265033 }}</ref> In another study, PCSK9-deficient mice were also demonstrated to have a reduced lymphatic apoB secretion,<ref name="Sun-2012">{{Cite journal  | last1 = Sun | first1 = H.| last2 = Samarghandi | first2 = A. | last3 = Zhang | first3 = N. | last4 = Yao | first4 = Z. | last5 = Xiong | first5 = M. | last6 = Teng | first6 = BB. |title = Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. | journal = Arterioscler Thromb Vasc Biol|volume = 32 | issue = 7 | pages = 1585-95 | month = Jul | year = 2012 | doi = 10.1161/ATVBAHA.112.250043 | PMID = 22580899 }}</ref> as well as an increased ability to clear [[chylomicrons]].
====Antisense Oligonucleotides (ASO)====
 
====Small Interfering RNAs (SiRNAs)====
Click [[PCSK9|here]] for more information regarding this novel approach to lipid management.
 
===Microsomal Triglyceride Transfer Protein (MTP) Inhibition===
===Microsomal Triglyceride Transfer Protein (MTP) Inhibition===
[[Microsomal triglyceride transfer protein]] is an endosomal protein found in the [[hepatocytes]] and intestinal enterocytes. It catalyses the transfer of cholesterol esters and [[triglycerides]] to nascent apo B, leading to the formation of [[chylomicron]] and [[VLDL]] in the intestine and hepatocyte respectively.<ref name="Wetterau-1997">{{Cite journal | last1 = Wetterau | first1 = JR. | last2 = Lin | first2 = MC. | last3 = Jamil | first3 = H. | title = Microsomal triglyceride transfer protein. | journal = Biochim Biophys Acta | volume = 1345 | issue = 2 | pages = 136-50 | month = Apr | year = 1997 | doi = |PMID = 9106493 }}</ref> Chylomicrons and other apo-B48-containing remnant lipoproteins are essential for intestinal fat absorption and its transfer to peripheral tissues. Mutations of the MTTP gene leads to a condition known as [[abetalipoproteinemia]], which causes an absence of apo-B-containing lipoproteins and very low levels of [[LDL-C]] and [[triglycerides]].<ref name="Sharp-1993">{{Cite journal | last1 = Sharp | first1 = D. | last2 = Blinderman |first2 = L. | last3 = Combs | first3 = KA. | last4 = Kienzle | first4 = B. | last5 = Ricci | first5 = B. | last6 = Wager-Smith | first6 = K. | last7 = Gil |first7 = CM. | last8 = Turck | first8 = CW. | last9 = Bouma | first9 = ME. | title = Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. | journal = Nature | volume = 365 | issue = 6441 | pages = 65-9 | month = Sep | year = 1993 | doi = 10.1038/365065a0 |PMID = 8361539 }}</ref><ref name="Rader-1993">{{Cite journal | last1 = Rader | first1 = DJ. | last2 = Brewer | first2 = HB. | title = Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. | journal = JAMA | volume = 270 | issue = 7 | pages = 865-9 |month = Aug | year = 1993 | doi = | PMID = 8340987 }}</ref> Individuals with this recessive condition have severe intestinal malabsorption of fat and fat-soluble vitamins (A, D, E, K) manifesting as [[fatty liver]], [[Nyctalopia|night-blindness]], [[rickets]] or [[osteomalacia]], [[neuropathy]], [[ataxia]], and[[coagulopathy]].
[[Microsomal triglyceride transfer protein]] is an endosomal protein found in the [[hepatocytes]] and intestinal enterocytes. It catalyses the transfer of cholesterol esters and [[triglycerides]] to nascent apo B, leading to the formation of [[chylomicron]] and [[VLDL]] in the intestine and hepatocyte respectively.<ref name="Wetterau-1997">{{Cite journal | last1 = Wetterau | first1 = JR. | last2 = Lin | first2 = MC. | last3 = Jamil | first3 = H. | title = Microsomal triglyceride transfer protein. | journal = Biochim Biophys Acta | volume = 1345 | issue = 2 | pages = 136-50 | month = Apr | year = 1997 | doi = |PMID = 9106493 }}</ref> Chylomicrons and other apo-B48-containing remnant lipoproteins are essential for intestinal fat absorption and its transfer to peripheral tissues. Mutations of the MTTP gene leads to a condition known as [[abetalipoproteinemia]], which causes an absence of apo-B-containing lipoproteins and very low levels of [[LDL-C]] and [[triglycerides]].<ref name="Sharp-1993">{{Cite journal | last1 = Sharp | first1 = D. | last2 = Blinderman |first2 = L. | last3 = Combs | first3 = KA. | last4 = Kienzle | first4 = B. | last5 = Ricci | first5 = B. | last6 = Wager-Smith | first6 = K. | last7 = Gil |first7 = CM. | last8 = Turck | first8 = CW. | last9 = Bouma | first9 = ME. | title = Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. | journal = Nature | volume = 365 | issue = 6441 | pages = 65-9 | month = Sep | year = 1993 | doi = 10.1038/365065a0 |PMID = 8361539 }}</ref><ref name="Rader-1993">{{Cite journal | last1 = Rader | first1 = DJ. | last2 = Brewer | first2 = HB. | title = Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. | journal = JAMA | volume = 270 | issue = 7 | pages = 865-9 |month = Aug | year = 1993 | doi = | PMID = 8340987 }}</ref> Individuals with this recessive condition have severe intestinal malabsorption of fat and fat-soluble vitamins (A, D, E, K) manifesting as [[fatty liver]], [[Nyctalopia|night-blindness]], [[rickets]] or [[osteomalacia]], [[neuropathy]], [[ataxia]], and[[coagulopathy]].

Revision as of 18:14, 24 November 2013

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

The Unmet Need Driving Research Into Lowering LDL

Investigational Therapies

Inhibition of Apolipoprotein B Production

Apolipoprotein B (apo B) is a large protein that is present in all atherogenic lipoproteins i.e., VLDL, LDL, IDL. There is a single copy of apo B-100 in all these lipoproteins, therefore plasma levels of apo B-100 is proportionate to the concentration of circulating atherogenic lipoproteins and a predictor of cardiovascular risk.[1] From the apoB gene, the liver synthesizes apo B-100; and the intestine synthesizes apo B-48 which is required for chylomicron assemly and fat absorption. The apo B-100 serves two functions - provides structural stability to the circulating lipoproteins as well as acts as a ligand for LDL receptors (LDLR). The removal of LDL from the plasma involves the binding of apo B to LDLR, then, the resulting apo B-100-LDLR complex gets internalized into the liver for processing.[2] Mutations that lower the affinity of apo B-100 for LDLR result in decreased clearance of LDLs, a condition known as familial defective apo B with an increased risk of atherosclerotic cardiovascular diseases.[3][4] In contrast, mutations in apo B that decrease its translation or secretion, or increase its breakdown have been demonstrated to reduce the circulating LDL-C and improve cardiovascular risk.[5]

The DNA contains two strands - 'sense' and 'antisense' which run complementary to each other. The antisense strand encodes a sequence of events that initiates protein synthesis and production of messenger RNA (mRNA) which later serves as a template for protein synthesis through a process called translation. Antisense oligoneucleotides (ASOs) are short, deoxyribonucleotide strands which bind to the targeted mRNAs to inhibit gene expression. They can inhibit mRNA translation and mRNA splicing leading to its enzymatic degradation by ribonuclease (RNAse H or argonaute 2); inhibit translation or prevent the maturation of mRNA.[6]

ISIS 301012 or mipomersen, by ISIS Pharmaceuticals, is a second-generation 20 nucleotide ASO which selectively inhibits apo B gene expression via RNAse H activation.[7] Phases I and II clinical trials have demonstrated a dose-dependent reduction of plasma apo B levels by 40% and up to 50% reduction in LDL-C of a subcutaneously administered ISIS-301012 or mipomersen, even with a defective LDLR.[8][9][10] Furthermore, a phase III randomized clinical trial involving homozygous FH revealed a 15% elevation in HDL-C.[11] Despite its efficacy in lowering LDL-C, its approval have been hampered with the development of adverse effects - injection site reactions (80-100% of patients), flu-like illness, and 3-fold elevation in liver transaminases (15%).

PCSK9 Inhibition

PCSK9 has a major role in the metabolism of hepatic cholesterol. It is a serine protease which binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation in the lysosomes. Reduced LDL receptor levels result in decreased metabolism of low density lipoprotein (LDL), which could lead to hypercholesterolemia.[12] The sterol regulatory element-binding protein-2 (SREBP-2), which is activated in the presence of low intracellular levels of cholesterol, also induces the expression of PCSK9, thereby increasing the amount of circulating LDL-cholesterol.[13] In addition to the effect on LDL-C, PCSK9 deficiency has also been shown to lower cardiovascular risk factors by reducing postprandial triglyceridemia.[14] In another study, PCSK9-deficient mice were also demonstrated to have a reduced lymphatic apoB secretion,[15] as well as an increased ability to clear chylomicrons.

Click here for more information regarding this novel approach to lipid management.

Microsomal Triglyceride Transfer Protein (MTP) Inhibition

Microsomal triglyceride transfer protein is an endosomal protein found in the hepatocytes and intestinal enterocytes. It catalyses the transfer of cholesterol esters and triglycerides to nascent apo B, leading to the formation of chylomicron and VLDL in the intestine and hepatocyte respectively.[16] Chylomicrons and other apo-B48-containing remnant lipoproteins are essential for intestinal fat absorption and its transfer to peripheral tissues. Mutations of the MTTP gene leads to a condition known as abetalipoproteinemia, which causes an absence of apo-B-containing lipoproteins and very low levels of LDL-C and triglycerides.[17][18] Individuals with this recessive condition have severe intestinal malabsorption of fat and fat-soluble vitamins (A, D, E, K) manifesting as fatty liver, night-blindness, rickets or osteomalacia, neuropathy, ataxia, andcoagulopathy.

Many MTP inhibitors are being investigated, including non-intestinal specific agents such as lomitapide (AEGR-427, previously known as BMS-201038 - Bristol-Myers-Squibb) by Aegerion Pharmaceuticals, implitapide (formerly AEGR-427 or Bayer BAY-13-9952), and CP-34086 by Pfizer; intestinal specific agents such as dirlotapide (by Pfizer), JTT-130, and SLx-4090 by Surface Logix. A clinical trial assessing the efficacy of lometapide in 6 patients with homozygous familial hypercholesterolemia demonstrated a 58%, 51%, and 55% reductions in total cholesterol, LDL-C and apo B respectively.[19] Higher doses were associated with a transient elevation of liver transaminases and hepatic fat. A double-blinded, randomized controlled trial involving 84 subjects further demonstrated a 20%, 30%, and 46% reduction in LDL-C in ezetimide alone, lometapide alone, and lometapide plus ezetimide combination study groups respectively, further emphasizing the beneficial effect of lometapide monotherapy or in combination therapy was associated with significantly greater reductions in LDL-C levels compared with ezetimibe monotherapy.[20] Another MTP inhibitor, CP-34086 by Pfizer, showed a 47% and 72% reduction in total cholesterol and LDL-C in healthy human volunteers respectively.[21] Currently, further developments of CP-34086 and implitapide have been placed on hold due to their hepatic adverse effects.

Intestinal-specific agents such as dirlotapide, JTT-130, and SLx-4090 were developed to prevent the hepatic effects of the non-specific agents. Thus far, they are still early in human clinical trials (except dirlotapide) but there were reports of significant reductions in postprandial triglyceridemia and total cholesterol in preclinical animal studies with dirlotapide.[22] Intestinal-specific MTP inhibitors may be effective in treating hyperchylomicronemia but their efficacy as LDL-C lowering agents is uncertain.

Thyromimetics

Squalene Synthase Inhibition

Inhibition of ACL and Activation of AMPK

ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid), by Esperion Therapeutics, is a small molecule which regulates on lipid and carbohydrate metabolism. It modulates the activity of two distinct molecular targets - hepatic adenosine triphosphate-citrate lyase (ACL) and adenosine phosphate-activated protein kinase (AMPK).[23] It works by:

  • Inhibition of ACL

Inhibition of Adenosine triphosphate-citrate lyase, an enzyme responsible for the production of ATP citrate, reduces the levels of acetyl co-enzyme A (acetyl-CoA - an important precursor to HMG-CoA which is a vital component in cholesterol and ketone synthesis).

Inhibition of SRB-1 Protein Activity

Table

Class Drug Company Agent Name Mechanism of Action Efficacy on Lowering LDL-C Route of Administration Adverse Effects Published Clinical Trials
Inhibition of Apo B/Antisense oligonucleotides ISIS Pharmaceuticals ISIS-301012 or Mipomersen Inhibits apo B mRNA gene expression Up to 50% reduction Subcutaneous injection (SC) Injection site reactions, flu-like illness, 3-fold asymptomatic elevation of liver transaminases I, II, III
PCSK9 Inhibition
MTP Inhibition Aegerion Pharmaceuticals, Pfizer, Surface Logix Intestinal non-specific (lometapide, implitapide, CP-34086); Intestinal-specific (SLx-4090, dirlotapide, JTT-130) Inhibits Microsomal triglyceride transfer protein Lometapide (up to 50%), CP-34086 (up to 70%) PO Intestinal non-specific agents causes GI adverse effects, increases in hepatic fat Lometapide (I, II, III), JTT-130 (I, II)
Thyromimetics
Squalene Synthase Inhibitors

References

  1. ↑ van der Steeg, WA.; Boekholdt, SM.; Stein, EA.; El-Harchaoui, K.; Stroes, ES.; Sandhu, MS.; Wareham, NJ.; Jukema, JW.; Luben, R. (2007). "Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk". Ann Intern Med. 146 (9): 640–8. PMID 17470832. Unknown parameter |month= ignored (help)
  2. ↑ Hussain, MM.; Strickland, DK.; Bakillah, A. (1999). "The mammalian low-density lipoprotein receptor family". Annu Rev Nutr. 19: 141–72. doi:10.1146/annurev.nutr.19.1.141. PMID 10448520.
  3. ↑ Humphries, SE.; Whittall, RA.; Hubbart, CS.; Maplebeck, S.; Cooper, JA.; Soutar, AK.; Naoumova, R.; Thompson, GR.; Seed, M. (2006). "Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk". J Med Genet. 43 (12): 943–9. doi:10.1136/jmg.2006.038356. PMID 17142622. Unknown parameter |month= ignored (help)
  4. ↑ Marsh, JB.; Welty, FK.; Lichtenstein, AH.; Lamon-Fava, S.; Schaefer, EJ. (2002). "Apolipoprotein B metabolism in humans: studies with stable isotope-labeled amino acid precursors". Atherosclerosis. 162 (2): 227–44. PMID 11996942. Unknown parameter |month= ignored (help)
  5. ↑ Schonfeld, G.; Lin, X.; Yue, P. (2005). "Familial hypobetalipoproteinemia: genetics and metabolism". Cell Mol Life Sci. 62 (12): 1372–8. doi:10.1007/s00018-005-4473-0. PMID 15818469. Unknown parameter |month= ignored (help)
  6. ↑ Bennett, CF.; Swayze, EE. (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annu Rev Pharmacol Toxicol. 50: 259–93. doi:10.1146/annurev.pharmtox.010909.105654. PMID 20055705.
  7. ↑ Ito, MK. (2007). "ISIS 301012 gene therapy for hypercholesterolemia: sense, antisense, or nonsense?". Ann Pharmacother. 41 (10): 1669–78. doi:10.1345/aph.1K065. PMID 17848425. Unknown parameter |month= ignored (help)
  8. ↑ Kastelein, JJ.; Wedel, MK.; Baker, BF.; Su, J.; Bradley, JD.; Yu, RZ.; Chuang, E.; Graham, MJ.; Crooke, RM. (2006). "Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B.". Circulation. 114 (16): 1729–35. doi:10.1161/CIRCULATIONAHA.105.606442. PMID 17030687. Unknown parameter |month= ignored (help)
  9. ↑ Akdim, F.; Visser, ME.; Tribble, DL.; Baker, BF.; Stroes, ES.; Yu, R.; Flaim, JD.; Su, J.; Stein, EA. (2010). "Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia". Am J Cardiol. 105 (10): 1413–9. doi:10.1016/j.amjcard.2010.01.003. PMID 20451687. Unknown parameter |month= ignored (help)
  10. ↑ Akdim, F.; Tribble, DL.; Flaim, JD.; Yu, R.; Su, J.; Geary, RS.; Baker, BF.; Fuhr, R.; Wedel, MK. (2011). "Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia". Eur Heart J. 32 (21): 2650–9. doi:10.1093/eurheartj/ehr148. PMID 21593041. Unknown parameter |month= ignored (help)
  11. ↑ Raal, FJ.; Santos, RD.; Blom, DJ.; Marais, AD.; Charng, MJ.; Cromwell, WC.; Lachmann, RH.; Gaudet, D.; Tan, JL. (2010). "Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial". Lancet. 375 (9719): 998–1006. doi:10.1016/S0140-6736(10)60284-X. PMID 20227758. Unknown parameter |month= ignored (help)
  12. ↑ *"The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol". 2012-11-11.
  13. ↑ Maxwell, KN.; Soccio, RE.; Duncan, EM.; Sehayek, E.; Breslow, JL. (2003). "Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice". J Lipid Res. 44 (11): 2109–19. doi:10.1194/jlr.M300203-JLR200. PMID 12897189. Unknown parameter |month= ignored (help)
  14. ↑ Le May, C.; Kourimate, S.; Langhi, C.; Chétiveaux, M.; Jarry, A.; Comera, C.; Collet, X.; Kuipers, F.; Krempf, M. (2009). "Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia". Arterioscler Thromb Vasc Biol. 29 (5): 684–90. doi:10.1161/ATVBAHA.108.181586. PMID 19265033. Unknown parameter |month= ignored (help)
  15. ↑ Sun, H.; Samarghandi, A.; Zhang, N.; Yao, Z.; Xiong, M.; Teng, BB. (2012). "Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor". Arterioscler Thromb Vasc Biol. 32 (7): 1585–95. doi:10.1161/ATVBAHA.112.250043. PMID 22580899. Unknown parameter |month= ignored (help)
  16. ↑ Wetterau, JR.; Lin, MC.; Jamil, H. (1997). "Microsomal triglyceride transfer protein". Biochim Biophys Acta. 1345 (2): 136–50. PMID 9106493. Unknown parameter |month= ignored (help)
  17. ↑ Sharp, D.; Blinderman, L.; Combs, KA.; Kienzle, B.; Ricci, B.; Wager-Smith, K.; Gil, CM.; Turck, CW.; Bouma, ME. (1993). "Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia". Nature. 365 (6441): 65–9. doi:10.1038/365065a0. PMID 8361539. Unknown parameter |month= ignored (help)
  18. ↑ Rader, DJ.; Brewer, HB. (1993). "Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease". JAMA. 270 (7): 865–9. PMID 8340987. Unknown parameter |month= ignored (help)
  19. ↑ Cuchel, M.; Bloedon, LT.; Szapary, PO.; Kolansky, DM.; Wolfe, ML.; Sarkis, A.; Millar, JS.; Ikewaki, K.; Siegelman, ES. (2007). "Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia". N Engl J Med. 356 (2): 148–56. doi:10.1056/NEJMoa061189. PMID 17215532. Unknown parameter |month= ignored (help)
  20. ↑ Samaha, FF.; McKenney, J.; Bloedon, LT.; Sasiela, WJ.; Rader, DJ. (2008). "Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia". Nat Clin Pract Cardiovasc Med. 5 (8): 497–505. doi:10.1038/ncpcardio1250. PMID 18506154. Unknown parameter |month= ignored (help)
  21. ↑ Chandler, CE.; Wilder, DE.; Pettini, JL.; Savoy, YE.; Petras, SF.; Chang, G.; Vincent, J.; Harwood, HJ. (2003). "CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans". J Lipid Res. 44 (10): 1887–901. doi:10.1194/jlr.M300094-JLR200. PMID 12837854. Unknown parameter |month= ignored (help)
  22. ↑ Li, J.; Bronk, BS.; Dirlam, JP.; Blize, AE.; Bertinato, P.; Jaynes, BH.; Hickman, A.; Miskell, C.; Pillai, UA. (2007). "In vitro and in vivo profile of 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity". Bioorg Med Chem Lett. 17 (7): 1996–9. doi:10.1016/j.bmcl.2007.01.018. PMID 17276061. Unknown parameter |month= ignored (help)
  23. ↑ Pinkosky, SL.; Filippov, S.; Srivastava, RA.; Hanselman, JC.; Bradshaw, CD.; Hurley, TR.; Cramer, CT.; Spahr, MA.; Brant, AF. (2013). "AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism". J Lipid Res. 54 (1): 134–51. doi:10.1194/jlr.M030528. PMID 23118444. Unknown parameter |month= ignored (help)



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