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ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi

Year 2022, Volume: 3 Issue: 2, 70 - 82, 25.11.2022

Abstract

Perifer dokularda aşırı yağ birikimi ile meydana gelen lipotoksisite, metabolik hastalıklara neden olan en önemli faktörlerden biridir. Lipid metabolizmasının anahtar enzimlerinden olan Asetil-KoA karboksilaz (ACC), yağ asitlerinin biyosentezinin ve oksidasyonunun düzenlenmesinde önemli fonksiyonlara sahiptir, aşırı yağ konsantrasyonunun azaltılmasına yönelik stratejiler ile diyabet, non-alkolik yağlı karaciğer hastalığı, kanser, mikrobiyal enfeksiyon, metabolik sendrom, obezite, gibi hastalıkların tedavisinde büyük bir ilgi görerek dikkat çekici bir hedef hâline gelmiştir. Onlarca yıllık araştırmalar sonucunda, ACC enziminin çok sayıda inhibitörü keşfedilmiştir ve yeni inhibitörlerin tasarlanmasına yönelik çalışmalar günümüzde de devam etmektedir. Bu çalışmada ACC enziminin yapısı, fonksiyonu ve katalitik mekanizmasının anlaşılmasına yönelik güncel bilgilere değinilmiştir ve ACC enzim inhibisyonunun moleküler temelleri incelenerek, güçlü ACC inhibitörleri ile ilgili son gelişmeler özetlenmiştir.

References

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  • [2] . Smedley, I. and Lubrzynska, E. (1913). The biochemical synthesis of the fatty acids. Biochemistry Journal. 7, 364–374.
  • [3] Batchuluun, B., Pinkosky, S. L. and Steinberg, G. R. (2022). Lipogenesis inhibitors: therapeutic opportunities and challenges. Nature Reviews | Drug Discover.
  • [4] Lenhard, J. M. (2011). Lipogenic Enzymes as Therapeutic Targets for Obesity and Diabetes. Current Pharmaceutical Design. 17, 325-331.
  • [5] Chen, L. Duan, Y. Wei, H. Ning, H. Bi, C. Zhao, Y. Qin, Y. & Yiliang, L. (2019). Acetyl-CoA carboxylase (ACC) as a therapeutictarget for metabolic syndrome and recent developments in ACC1/2 inhibitors. Expert Opinion on Investigational Drugs.
  • [6] Xin, W. & Tonghui, H. (2020). Recent development in acetyl-CoA carboxylase inhibitors and their potential as novel drugs. Future Medicinal Chemistry.
  • [7] Harriman, G., Greenwood, J., Bhat, S., Huang, X., Wang, R.,Paul, D., Tong, L., Saha, A. K., Westlin, W. F., Kapeller, R., and Harwood, H. J., Jr. (2016). Acetyl-CoA carboxylase inhibition by ND630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. The Proceedings of the National Academy of Sciences U. S. A. 113, E1796−E1805.
  • [8] Wei, J. and Tong, L. (2018). How does polymerization regulate human acetyl-CoA carboxylase 1? Biochemistry. 57(38), 5495–5496.
  • [9] Wei, J. and Tong, L. (2015).Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer. Nature. 526(7575), 723–727.
  • [10] Hunkeler, M., Hagmann, A., Stuttfeld, E., Chami, M., Guri, Y., Stahlberg, H. and Maier, T. (2018). Structural basis for regulation of human acetyl-CoA carboxylase. Nature. 558(7710), 470–474.
  • [11] Wei, J. and Zhang, Y. X. , Yu, T. Y. (2016). A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation.. Cell Discovery. 2, 16044–16055.
  • [12] Tong, L. (2005). Acetyl-coenzyme a carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cellular and Molecular Life Sciences. 62(16), 1784–1803.
  • [13] Kim, K. H. (1997). Regulation of mammalian acetyl-coenzymeA carboxylase. Annual Review of Nutrition. 17:77–99.
  • [14] Tong, L. (2013). Structure and function of biotin-dependent carboxylases. Cellular and Molecular Life Science. 70(5), 863–891.
  • [15] Perham, R. N. (2000). Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annual Review of Biochemistry. 69:961–1004.
  • [16] Christopher, L. C., Kim, C-W., Young-Ah, M., Lisa, H., Maya, P., William, B. M., Kevin, F., Johann, D., Jay, D. H., and Hyock J. K. (2010). Crystal structure of Spot 14, a modulator of fatty acid synthesis. Biochemistry. 107 (44) 18820-18825.
  • [17] Abu-Elheiga L, Brinkley WR, Zhong L, et al. (2000). The subcellular localization of acetyl-CoA carboxylase 2. The Proceedings of the National Academy of Sciences U. S. A. 97: 1444–1449.
  • [18] Harwood, H. J., Jr.; Petras, S. F.; Shelly, L. D.; Zaccaro, L. M.;Perry, D. A.; Makowski, M. R.; Hargrove, D. M.; Martin, K. A.;Tracey, W. R.; Chapman, J. G.; Magee, W. P.; Dalvie, D. K.; Soliman,V. F.; Martin, W. H.; Mularski, C. J.; Eisenbeis, S. A. (2003). IsozymeNonselective N-Substituted Bipiperidylcarboxamide Acetyl-CoA Carboxylase Inhibitors Reduce Tissue Malonyl-CoA Concentrations, Inhibit Fatty Acid Synthesis, and Increase Fatty Acid Oxidation in Cultured Cells and in Experimental Animals. J. Biol. Chem. 278, 37099−37111.
  • [19] Lane, M. D., Wolfgang, M., Cha, S. H., Dai, Y., (2008). Regulation of food intake and energy expenditure by hypothalamic malonyl-CoA. International Journal of Obesity. 32:S49–S54.
  • [20] Saggerson D. (2008). Malonyl-CoA, a key signaling molecule in mammalian cells. Annual Review of Nutrition. 28: 253-72.
  • [21] Pinkosky, S. L., Scott, J. W.,. Desjardins, E. M., Smith,B. K., Day,E. A., Ford, J. R., Langendorf, C. G., Ling, N. X. Y., Nero, T. L., Loh, K., Galic, S., Hoque, A., Smiles, W. J., Ngoei, K. R. W., Parker, M. W., Yan, Y., Melcher, K., Kemp, B. E., Oakhill, J. S., and Steinberg, R. G. (2020). Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nature Metabolism. 2, 873–881.
  • [22] Takagi, H., Tanimoto, K., Shimazaki, A., Tonomura, Y., Momosaki, S., Sakamoto, S., Abe, K., Notoya, M., and Yukioka, H. (2019). A Novel Acetyl-CoA Carboxylase 2 Selective Inhibitor ImprovesWhole-Body Insulin Resistance and Hyperglycemia in Diabetic Mice through Target-Dependent Pathways. The Journal of Pharmacology and Experimental Therapeutics. 372: 256–263.
  • [23] Abu-Elheiga, L., Oh, W., Kordari, P., Wakil, S. J. (2003). Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/highcarbohydrate diets. The Proceedings of the National Academy of Sciences U. S. A. 100:10207–10212.
  • [24] Olson, D. P., Pulinilkunnil, T., Cline, G. W., Shulman, G. I., and Lowell, B. B. (2010). Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake. . The Proceedings of the National Academy of Sciences U. S. A. 107:7598–7603.
  • [25] Mizojiri, R., Asano, M., Tomita, D., Banno, H., Nii, N., Sasaki, M., Sumi, H., Satoh, Y., Yamamoto, Y., Moriya, T., Satomi, Y., and Maezaki, H. (2018). Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1Inhibitors. Journal of Medicinal Chemistr. 8;61(3):1098-1117.
  • [26] Savage, D. B., Choi, C. S., Samuel, V. T., Liu, Z. X., Zhang, D., Wang, A., Zhang, X. M., Cline, G. W., Yu, X. X., Geisler, J. G., Bhanot, S., Monia, B. P., Shulman, G. I. (2006). Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. Journal of Clinical Investigation. 116, 817–824.
  • [27] Takagi, H., Ikehara, T., Kashiwagi, Y., Hashimoto, K., Nanchi, I., Shimazaki, A., Nambu, H., Yukioka, H. (2018). ACC2 deletion enhances IMCL reduction along with acetyl-CoA metabolism and improves insulin sensitivity in male mice. Endocrinology 159, 3007–3019.
  • [28] Alkhouri, N.; Lawitz, E.; Noureddin, M.; DeFronzo, R.;Shulman, G. I. (2020). GS-0976 (Firsocostat): An Investigational LiverDirected Acetyl-CoA Carboxylase (ACC) Inhibitor for the Treatmentof Non-Alcoholic Steatohepatitis (NASH). Expert Opinion on Investigational Drugs. 29, 135−141.
  • [29] Stiede, K., Miao, W., Blanchette, H. S., Beysen, C., Harriman, G., Harwood, H. J., Kelley, H., Kapeller, R., Schmalbach, T., Westlin, W. F. (2017). Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology 66, 324–334.
  • [30] Vyas, V. K., Dabasia, M., Qureshi, G., Gulamnizami, Qureshi., Patel, P., & Ghate, M. (2017). Molecular modeling study for the design of novel Acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulation. Journal of Biomolecular Structure and Dynamics. 35: 2003-2015.
  • [31] Zhang, H., Tweel, B., Li. J., Tong, L. (2004). Crystal structure of the carboxytransferase domain Accepted Manuscript Information Classification: General of acetyl-CoA carboxylase in complex with CP-640186. Structure. 12: 1683−1691.
  • [32] Liu, T., Gou, L., Yan, S. & Huang, T. (2020). Inhibition of acetyl-CoA carboxylase by PP-7a exerts beneficial effects on metabolic dysregulation in a mouse model of diet-induced obesity. Experimental and Therapeutic Medicine. 20, 521–529.
  • [33] Calle, R. A., Amin, N. B., Carvajal-Gonzalez, S., Ross, T.T., Bergman, A., Aggarwal, S., Crowley, C., Rinaldi, A., Mancuso, J., Aggarwal, N., Somayaji,V., Inglot, M., Tuthill, T. A., Kou, K., Boucher, M., Tesz, G., Dullea, R.,. Bence, K., Kim, A. M., Pfefferkorn, J. A. & Esler, W. P. (2021). ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-aclhoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trial. Nat. Med. 27, 1836–1848.
  • [34] Bergman, A., Gonzalez, S. C., Tarabar, S., Saxena, A. R., Esler W. P., Amin, N. B. (2020). Safety, tolerability, pharmacokinetics and pharmacodynamics of a liver-targeting ACC inhibitor (PF-05221304) following single and multiple oral doses. J Hepatol. 2018; 68 (Suppl 1): S582.
  • [35] Esler W. P., Amin, N. B., Ross, T., Bergman, A., Crowley, C., Gonzalez, S. C., Pfefferkorn, J. A. And Beebe, D. (2019). Partial inhibition of de novo lipogenesis with the acetyl-CoA carboxylase inhibitor PF-05221304 does not increase circulating triglycerides in humans and is sufficient to lower steatosis in rats. Journal of Hepatology. 70(1): e69.
  • [36] Bergman, A.; Carvajal-Gonzalez, S., Tarabar, S.; Saxena, A. R., Esler, W. P., Amin, N. B. (2020). Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304): A Three-Part Randomized Phase 1 Study. Clinical Pharmacology in Drug Development. 9, 514−526.
  • [37] Kim, C. W., Addy, C., Kusunoki J, Anderson, N. N., Deja, S., Fu, X., Burgess, S. C., Li, C., Chakravarthy, M., Previs, S., Milstein, S., Fitzgerald, K., Kelley, D. E., and Horton, J. D. (2017). Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metabolism. 26: 394–406 e6.
  • [38] Hunt, D. W., Winters, G. C., Brownsey, R. W., Kulpa, J. E., Gilliland, K. L., Thiboutot, D. M., Hofland, H. E. (2017). Inhibition of sebum production with the acetyl coenzyme a carboxylase inhibitor olumacostat glasaretil. Journal of Investigative Dermatology.137: 1415-1423.
  • [39] Bissonnette, R., Poulin, Y., Drew, J., Hofland, H., and Tan, J. (2017). Olumacostat glasaretil, a novel topical sebum inhibitor, in the treatment of acne vulgaris: A phase IIa, multicenter, randomized, vehicle-controlled study. Journal of the American Academy of Dermatology. 76: 33-39.
Year 2022, Volume: 3 Issue: 2, 70 - 82, 25.11.2022

Abstract

References

  • [1] Hotamisligil, G. S. and Ertunc, M. E. (2016). Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. Journal of Lipid Research. 57: 2099–2114.
  • [2] . Smedley, I. and Lubrzynska, E. (1913). The biochemical synthesis of the fatty acids. Biochemistry Journal. 7, 364–374.
  • [3] Batchuluun, B., Pinkosky, S. L. and Steinberg, G. R. (2022). Lipogenesis inhibitors: therapeutic opportunities and challenges. Nature Reviews | Drug Discover.
  • [4] Lenhard, J. M. (2011). Lipogenic Enzymes as Therapeutic Targets for Obesity and Diabetes. Current Pharmaceutical Design. 17, 325-331.
  • [5] Chen, L. Duan, Y. Wei, H. Ning, H. Bi, C. Zhao, Y. Qin, Y. & Yiliang, L. (2019). Acetyl-CoA carboxylase (ACC) as a therapeutictarget for metabolic syndrome and recent developments in ACC1/2 inhibitors. Expert Opinion on Investigational Drugs.
  • [6] Xin, W. & Tonghui, H. (2020). Recent development in acetyl-CoA carboxylase inhibitors and their potential as novel drugs. Future Medicinal Chemistry.
  • [7] Harriman, G., Greenwood, J., Bhat, S., Huang, X., Wang, R.,Paul, D., Tong, L., Saha, A. K., Westlin, W. F., Kapeller, R., and Harwood, H. J., Jr. (2016). Acetyl-CoA carboxylase inhibition by ND630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. The Proceedings of the National Academy of Sciences U. S. A. 113, E1796−E1805.
  • [8] Wei, J. and Tong, L. (2018). How does polymerization regulate human acetyl-CoA carboxylase 1? Biochemistry. 57(38), 5495–5496.
  • [9] Wei, J. and Tong, L. (2015).Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer. Nature. 526(7575), 723–727.
  • [10] Hunkeler, M., Hagmann, A., Stuttfeld, E., Chami, M., Guri, Y., Stahlberg, H. and Maier, T. (2018). Structural basis for regulation of human acetyl-CoA carboxylase. Nature. 558(7710), 470–474.
  • [11] Wei, J. and Zhang, Y. X. , Yu, T. Y. (2016). A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation.. Cell Discovery. 2, 16044–16055.
  • [12] Tong, L. (2005). Acetyl-coenzyme a carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cellular and Molecular Life Sciences. 62(16), 1784–1803.
  • [13] Kim, K. H. (1997). Regulation of mammalian acetyl-coenzymeA carboxylase. Annual Review of Nutrition. 17:77–99.
  • [14] Tong, L. (2013). Structure and function of biotin-dependent carboxylases. Cellular and Molecular Life Science. 70(5), 863–891.
  • [15] Perham, R. N. (2000). Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annual Review of Biochemistry. 69:961–1004.
  • [16] Christopher, L. C., Kim, C-W., Young-Ah, M., Lisa, H., Maya, P., William, B. M., Kevin, F., Johann, D., Jay, D. H., and Hyock J. K. (2010). Crystal structure of Spot 14, a modulator of fatty acid synthesis. Biochemistry. 107 (44) 18820-18825.
  • [17] Abu-Elheiga L, Brinkley WR, Zhong L, et al. (2000). The subcellular localization of acetyl-CoA carboxylase 2. The Proceedings of the National Academy of Sciences U. S. A. 97: 1444–1449.
  • [18] Harwood, H. J., Jr.; Petras, S. F.; Shelly, L. D.; Zaccaro, L. M.;Perry, D. A.; Makowski, M. R.; Hargrove, D. M.; Martin, K. A.;Tracey, W. R.; Chapman, J. G.; Magee, W. P.; Dalvie, D. K.; Soliman,V. F.; Martin, W. H.; Mularski, C. J.; Eisenbeis, S. A. (2003). IsozymeNonselective N-Substituted Bipiperidylcarboxamide Acetyl-CoA Carboxylase Inhibitors Reduce Tissue Malonyl-CoA Concentrations, Inhibit Fatty Acid Synthesis, and Increase Fatty Acid Oxidation in Cultured Cells and in Experimental Animals. J. Biol. Chem. 278, 37099−37111.
  • [19] Lane, M. D., Wolfgang, M., Cha, S. H., Dai, Y., (2008). Regulation of food intake and energy expenditure by hypothalamic malonyl-CoA. International Journal of Obesity. 32:S49–S54.
  • [20] Saggerson D. (2008). Malonyl-CoA, a key signaling molecule in mammalian cells. Annual Review of Nutrition. 28: 253-72.
  • [21] Pinkosky, S. L., Scott, J. W.,. Desjardins, E. M., Smith,B. K., Day,E. A., Ford, J. R., Langendorf, C. G., Ling, N. X. Y., Nero, T. L., Loh, K., Galic, S., Hoque, A., Smiles, W. J., Ngoei, K. R. W., Parker, M. W., Yan, Y., Melcher, K., Kemp, B. E., Oakhill, J. S., and Steinberg, R. G. (2020). Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nature Metabolism. 2, 873–881.
  • [22] Takagi, H., Tanimoto, K., Shimazaki, A., Tonomura, Y., Momosaki, S., Sakamoto, S., Abe, K., Notoya, M., and Yukioka, H. (2019). A Novel Acetyl-CoA Carboxylase 2 Selective Inhibitor ImprovesWhole-Body Insulin Resistance and Hyperglycemia in Diabetic Mice through Target-Dependent Pathways. The Journal of Pharmacology and Experimental Therapeutics. 372: 256–263.
  • [23] Abu-Elheiga, L., Oh, W., Kordari, P., Wakil, S. J. (2003). Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/highcarbohydrate diets. The Proceedings of the National Academy of Sciences U. S. A. 100:10207–10212.
  • [24] Olson, D. P., Pulinilkunnil, T., Cline, G. W., Shulman, G. I., and Lowell, B. B. (2010). Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake. . The Proceedings of the National Academy of Sciences U. S. A. 107:7598–7603.
  • [25] Mizojiri, R., Asano, M., Tomita, D., Banno, H., Nii, N., Sasaki, M., Sumi, H., Satoh, Y., Yamamoto, Y., Moriya, T., Satomi, Y., and Maezaki, H. (2018). Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1Inhibitors. Journal of Medicinal Chemistr. 8;61(3):1098-1117.
  • [26] Savage, D. B., Choi, C. S., Samuel, V. T., Liu, Z. X., Zhang, D., Wang, A., Zhang, X. M., Cline, G. W., Yu, X. X., Geisler, J. G., Bhanot, S., Monia, B. P., Shulman, G. I. (2006). Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. Journal of Clinical Investigation. 116, 817–824.
  • [27] Takagi, H., Ikehara, T., Kashiwagi, Y., Hashimoto, K., Nanchi, I., Shimazaki, A., Nambu, H., Yukioka, H. (2018). ACC2 deletion enhances IMCL reduction along with acetyl-CoA metabolism and improves insulin sensitivity in male mice. Endocrinology 159, 3007–3019.
  • [28] Alkhouri, N.; Lawitz, E.; Noureddin, M.; DeFronzo, R.;Shulman, G. I. (2020). GS-0976 (Firsocostat): An Investigational LiverDirected Acetyl-CoA Carboxylase (ACC) Inhibitor for the Treatmentof Non-Alcoholic Steatohepatitis (NASH). Expert Opinion on Investigational Drugs. 29, 135−141.
  • [29] Stiede, K., Miao, W., Blanchette, H. S., Beysen, C., Harriman, G., Harwood, H. J., Kelley, H., Kapeller, R., Schmalbach, T., Westlin, W. F. (2017). Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology 66, 324–334.
  • [30] Vyas, V. K., Dabasia, M., Qureshi, G., Gulamnizami, Qureshi., Patel, P., & Ghate, M. (2017). Molecular modeling study for the design of novel Acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulation. Journal of Biomolecular Structure and Dynamics. 35: 2003-2015.
  • [31] Zhang, H., Tweel, B., Li. J., Tong, L. (2004). Crystal structure of the carboxytransferase domain Accepted Manuscript Information Classification: General of acetyl-CoA carboxylase in complex with CP-640186. Structure. 12: 1683−1691.
  • [32] Liu, T., Gou, L., Yan, S. & Huang, T. (2020). Inhibition of acetyl-CoA carboxylase by PP-7a exerts beneficial effects on metabolic dysregulation in a mouse model of diet-induced obesity. Experimental and Therapeutic Medicine. 20, 521–529.
  • [33] Calle, R. A., Amin, N. B., Carvajal-Gonzalez, S., Ross, T.T., Bergman, A., Aggarwal, S., Crowley, C., Rinaldi, A., Mancuso, J., Aggarwal, N., Somayaji,V., Inglot, M., Tuthill, T. A., Kou, K., Boucher, M., Tesz, G., Dullea, R.,. Bence, K., Kim, A. M., Pfefferkorn, J. A. & Esler, W. P. (2021). ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-aclhoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trial. Nat. Med. 27, 1836–1848.
  • [34] Bergman, A., Gonzalez, S. C., Tarabar, S., Saxena, A. R., Esler W. P., Amin, N. B. (2020). Safety, tolerability, pharmacokinetics and pharmacodynamics of a liver-targeting ACC inhibitor (PF-05221304) following single and multiple oral doses. J Hepatol. 2018; 68 (Suppl 1): S582.
  • [35] Esler W. P., Amin, N. B., Ross, T., Bergman, A., Crowley, C., Gonzalez, S. C., Pfefferkorn, J. A. And Beebe, D. (2019). Partial inhibition of de novo lipogenesis with the acetyl-CoA carboxylase inhibitor PF-05221304 does not increase circulating triglycerides in humans and is sufficient to lower steatosis in rats. Journal of Hepatology. 70(1): e69.
  • [36] Bergman, A.; Carvajal-Gonzalez, S., Tarabar, S.; Saxena, A. R., Esler, W. P., Amin, N. B. (2020). Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304): A Three-Part Randomized Phase 1 Study. Clinical Pharmacology in Drug Development. 9, 514−526.
  • [37] Kim, C. W., Addy, C., Kusunoki J, Anderson, N. N., Deja, S., Fu, X., Burgess, S. C., Li, C., Chakravarthy, M., Previs, S., Milstein, S., Fitzgerald, K., Kelley, D. E., and Horton, J. D. (2017). Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metabolism. 26: 394–406 e6.
  • [38] Hunt, D. W., Winters, G. C., Brownsey, R. W., Kulpa, J. E., Gilliland, K. L., Thiboutot, D. M., Hofland, H. E. (2017). Inhibition of sebum production with the acetyl coenzyme a carboxylase inhibitor olumacostat glasaretil. Journal of Investigative Dermatology.137: 1415-1423.
  • [39] Bissonnette, R., Poulin, Y., Drew, J., Hofland, H., and Tan, J. (2017). Olumacostat glasaretil, a novel topical sebum inhibitor, in the treatment of acne vulgaris: A phase IIa, multicenter, randomized, vehicle-controlled study. Journal of the American Academy of Dermatology. 76: 33-39.
There are 39 citations in total.

Details

Primary Language Turkish
Journal Section Derlemeler
Authors

Mehtap Şahin 0000-0002-8889-3661

Özlem Yıldırım 0000-0003-1018-0335

Publication Date November 25, 2022
Published in Issue Year 2022 Volume: 3 Issue: 2

Cite

APA Şahin, M., & Yıldırım, Ö. (2022). ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi. Gazi Üniversitesi Fen Fakültesi Dergisi, 3(2), 70-82.
AMA Şahin M, Yıldırım Ö. ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi. GÜFFD. November 2022;3(2):70-82.
Chicago Şahin, Mehtap, and Özlem Yıldırım. “ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi”. Gazi Üniversitesi Fen Fakültesi Dergisi 3, no. 2 (November 2022): 70-82.
EndNote Şahin M, Yıldırım Ö (November 1, 2022) ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi. Gazi Üniversitesi Fen Fakültesi Dergisi 3 2 70–82.
IEEE M. Şahin and Ö. Yıldırım, “ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi”, GÜFFD, vol. 3, no. 2, pp. 70–82, 2022.
ISNAD Şahin, Mehtap - Yıldırım, Özlem. “ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi”. Gazi Üniversitesi Fen Fakültesi Dergisi 3/2 (November 2022), 70-82.
JAMA Şahin M, Yıldırım Ö. ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi. GÜFFD. 2022;3:70–82.
MLA Şahin, Mehtap and Özlem Yıldırım. “ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi”. Gazi Üniversitesi Fen Fakültesi Dergisi, vol. 3, no. 2, 2022, pp. 70-82.
Vancouver Şahin M, Yıldırım Ö. ACC Enziminin Metabolik Hastalıklarda Terapötik Hedef Olarak Değerlendirilmesi. GÜFFD. 2022;3(2):70-82.