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Cited by 46Liver Disease Diagnosis and TreatmentRNA Interference and Gene DeliveryLipid metabolism and disorders

An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis

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Yenilmez, Batuhan, Wetoska, Nicole, Kelly, Mark, Echeverria, Dimas, Min, Kyounghee, Lifshitz, Lawrence, Alterman, Julia F., Hassler, Matthew R. +10 more·2022·Molecular Therapy
DOI 10.1016/j.ymthe.2021.11.007PMC PMC8899521
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Abstract

Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%-90%, p < 0.0001) in wild-type and NSG-PiZ "humanized" mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.

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  • Dgat2 and Gpam are critical enzymes in triglyceride synthesis, and Dgat2 is currently being inhibited in NASH clinical trials.

    “Dgat2 and Gpam are critical enzymes in triglyceride synthesis, and Dgat2 is currently being inhibited in NASH clinical trials15,16.”

    From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [16]

    The Introduction identifies DGAT2 as catalyzing the final step of triglyceride synthesis and reports human trials targeting it; the Discussion also mentions a phase 2 trial of a DGAT2 inhibitor (page numbers unavailable). Our copy does not establish Gpam’s role in triglyceride synthesis, so it supports only the DGAT2 portion of the claim. (LLM, conf=0.86)

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  1. [1]Younossi Z.M. Blissett D. Blissett R. Henry L. Stepanova M. Younossi Y. Racila A. Hunt S. Beckerman R. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe Hepatology 64 2016 1577 1586 27543837
  2. [2]Younossi Z.M. Koenig A.B. Abdelatif D. Fazel Y. Henry L. Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes Hepatology 64 2016 73 84 26707365
  3. [3]Alexander M. Loomis A.K. van der Lei J. Duarte-Salles T. Prieto-Alhambra D. Ansell D. Pasqua A. Lapi F. Rijnbeek P. Mosseveld M. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts BMC Med. 17 2019 95 10.1186/s12916-019-1321-x 31104631 PMC6526616 · DOI · Paper page
  4. [4]Lomonaco R. Ortiz-Lopez C. Orsak B. Webb A. Hardies J. Darland C. Finch J. Gastaldelli A. Harrison S. Tio F. Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease Hepatology 55 2012 1389 1397 22183689
  5. [5]Estes C. Razavi H. Loomba R. Younossi Z. Sanyal A.J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease Hepatology 67 2018 123 133 28802062 PMC5767767
  6. [7]Friedman S.L. Neuschwander-Tetri B.A. Rinella M. Sanyal A.J. Mechanisms of NAFLD development and therapeutic strategies Nat. Med. 2018 24 908 922 PMC6553468 29967350
  7. [8]Romeo S. Sanyal A. Valenti L. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease Nat. Genet. 40 2008 1461 1465 18820647 PMC2597056
  8. [9]Speliotes E.K. Yerges-Armstrong L.M. Wu J. Hernaez R. Kim L.J. Palmer C.D. Gudnason V. Eiriksdottir G. Garcia M.E. Launer L.J. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits PLoS Genet. 7 2011 e1001324 21423719 PMC3053321
  9. [10]Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. Nobili V. Mozzi E. Roviaro G. Vanni E. Homozygosity for the patatin-like phospholipase-3/adiponutrin i148m polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease Hepatology 51 2010 1209 1217 20373368
  10. [12]Wong V.W.S. Singal A.K. Emerging medical therapies for non-alcoholic fatty liver disease and for alcoholic hepatitis Translational Gastroenterol. Hepatol. 4 2019 53 10.21037/tgh.2019.06.06 PMC6691078 31463412 · DOI
  11. [13]Singh S. Khera R. Allen A.M. Murad M.H. Loomba R. Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: a systematic review and network meta-analysis Hepatology 62 2015 1417 1432 26189925
  12. [14]Musso G. Cassader M. Rosina F. Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials Diabetologia 55 2012 885 904 22278337
  13. [15]Mahady S.E. Webster A.C. Walker S. Sanyal A. George J. The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta analysis J. Hepatol. 55 2011 1383 1390 21703200
  14. [16]Macauley M. Hollingsworth K.G. Smith F.E. Thelwall P.E. Al-Mrabeh A. Schweizer A. Foley J.E. Taylor R. Effect of vildagliptin on hepatic steatosis J. Clin. Endocrinol. Metab. 100 2015 1578 1585 25664602 PMC4399299
  15. [17]Cui J. Philo L. Nguyen P. Hofflich H. Hernandez C. Bettencourt R. Richards L. Salotti J. Bhatt A. Hooker J. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial J. Hepatol. 65 2016 369 376 27151177 PMC5081213
  16. [19]Neuschwander-Tetri B.A. Loomba R. Sanyal A.J. Lavine J.E. Van Natta M.L. Abdelmalek M.F. Chalasani N. Dasarathy S. Diehl A.M. Hameed B. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial Lancet 385 2015 956 965 25468160 PMC4447192
  17. [20]Pockros P.J. Fuchs M. Freilich B. Schiff E. Kohli A. Lawitz E.J. Hellstern P.A. Owens-Grillo J. Van Biene C. Shringarpure R. CONTROL: a randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients Liver Int. 39 2019 2082 2093 31402538
  18. [22]Harrison S.A. Alkhouri N. Davison B.A. Sanyal A. Edwards C. Colca J.R. Lee B.H. Loomba R. Cusi K. Kolterman O. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study J. Hepatol. 72 2020 613 626 31697972
  19. [24]Ratziu V. Sanyal A. Harrison S.A. Wong V.W. Francque S. Goodman Z. Aithal G.P. Kowdley K.V. Seyedkazemi S. Fischer L. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study Hepatology 72 2020 892 905 31943293
  20. [26]Lawitz E.J. Coste A. Poordad F. Alkhouri N. Loo N. McColgan B.J. Tarrant J.M. Nguyen T. Han L. Chung C. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis Clin. Gastroenterol. Hepatol. 16 2018 1983 1991.e3 29705265
  21. [27]Loomba R. Kayali Z. Noureddin M. Ruane P. Lawitz E.J. Bennett M. Wang L. Harting E. Tarrant J.M. McColgan B.J. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease Gastroenterology 155 2018 1463 1473.e6 30059671 PMC6318218
  22. [28]Goedeke L. Bates J. Vatner D.F. Perry R.J. Wang T. Ramirez R. Li L. Ellis M.W. Zhang D. Wong K.E. Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents Hepatology 68 2018 2197 2211 29790582 PMC6251774
  23. [29]Kim C.W. Addy C. Kusunoki J. Anderson N.N. Deja S. Fu X. Burgess S.C. Li C. Ruddy M. Chakravarthy M. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation Cell Metab. 26 2017 394 406.e6 28768177 PMC5603267
  24. [32]Garcia-Tsao G. Bosch J. Kayali Z. Harrison S.A. Abdelmalek M.F. Lawitz E. Satapathy S.K. Ghabril M. Shiffman M.L. Younes Z.H. Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension J. Hepatol. 72 2020 885 895 31870950
  25. [33]Muthiah M.D. Sanyal A.J. Current management of non-alcoholic steatohepatitis Liver Int. 40 2020 89 95 32077609 PMC7654093
  26. [34]Woodcock J. Griffin J.P. Behrman R.E. Development of novel combination therapies New Engl. J. Med. 364 2011 985 987 21323535
  27. [35]Yen C.L.E. Stone S.J. Koliwad S. Harris C. Farese R.V. DGAT enzymes and triacylglycerol biosynthesis J. Lipid Res. 49 2008 2283 2301 18757836 PMC3837458
  28. [36]Zammit V.A. Hepatic triacylglycerol synthesis and secretion: DGAT2 as the link between glycaemia and triglyceridaemia Biochem. J. 451 2013 1 12 23489367
  29. [37]Yu X.X. Murray S.F. Pandey S.K. Booten S.L. Bao D. Song X.Z. Kelly S. Chen S. McKay R. Monia B.P. Bhanot S. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice Hepatology 42 2005 362 371 16001399
  30. [38]Yamaguchi K. Yang L. McCall S. Huang J. Yu X.X. Pandey S.K. Bhanot S. Monia B.P. Li Y.X. Diehl A.M. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis Hepatology 45 2007 1366 1374 17476695
  31. [40]Amin N.B. Carvajal-Gonzalez S. Purkal J. Zhu T. Crowley C. Perez S. Chidsey K. Kim A.M. Goodwin B. Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis Sci. Transl. Med. 11 2019 9701 31776293
  32. [41]Loomba R. Morgan E. Watts L. Xia S. Hannan L.A. Geary R.S. Baker B.F. Bhanot S. Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial Lancet Gastroenterol. Hepatol. 5 2020 829 838 32553151
  33. [42]Khvorova A. Watts J.K. The chemical evolution of oligonucleotide therapies of clinical utility Nat. Biotechnol. 2017 35 238 248 28244990 PMC5517098
  34. [43]Fire A. Xu S. Montgomery M.K. Kostas S.A. Driver S.E. Mello C.C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans Nature 391 1998 806 811 9486653
  35. [44]Zamore P.D. RNA interference: listening to the sound of silence Nat. Struct. Biol. 8 2001 746 750 11524674
  36. [47]Coelho T. Adams D. Silva A. Lozeron P. Hawkins P.N. Mant T. Perez J. Chiesa J. Warrington S. Tranter E. Safety and efficacy of RNAi therapy for transthyretin amyloidosis New Engl. J. Med. 369 2013 819 829 23984729
  37. [48]Springer A.D. Dowdy S.F. GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics Nucleic Acid Ther. 2018 28 109 118 PMC5994659 29792572
  38. [49]Nair J.K. Willoughby J.L. Chan A. Charisse K. Alam M.R. Wang Q. Hoekstra M. Kandasamy P. Kel'in A.V. Milstein S. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing J. Am. Chem. Soc. 136 2014 16958 16961 25434769
  39. [50]Parmar R. Willoughby J.L. Liu J. Foster D.J. Brigham B. Theile C.S. Charisse K. Akinc A. Guidry E. Pei Y. 5′-(E)-vinylphosphonate: a stable phosphate mimic can improve the RNAi activity of siRNA-GalNAc conjugates ChemBioChem 17 2016 985 989 27121751
  40. [51]Zimmermann T.S. Karsten V. Chan A. Chiesa J. Boyce M. Bettencourt B.R. Hutabarat R. Nochur S. Vaishnaw A. Gollob J. Clinical proof of concept for a novel hepatocyte-targeting GalNAc-siRNA conjugate Mol. Ther. 25 2017 71 78 28129130 PMC5363199
  41. [52]Nair J.K. Attarwala H. Sehgal A. Wang Q. Aluri K. Zhang X. Gao M. Liu J. Indrakanti R. Schofield S. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates Nucleic Acids Res. 45 2017 10969 10977 28981809 PMC5737438
  42. [53]Schlegel M.K. Foster D.J. Kel'in A.V. Zlatev I. Bisbe A. Jayaraman M. Lackey J.G. Rajeev K.G. Charissé K. Harp J. Chirality dependent potency enhancement and structural impact of glycol nucleic acid modification on siRNA J. Am. Chem. Soc. 139 2017 8537 8546 28570818
  43. [54]Hassler M.R. Turanov A.A. Alterman J.F. Haraszti R.A. Coles A.H. Osborn M.F. Echeverria D. Nikan M. Salomon W.E. Roux L. Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo Nucleic Acids Res. 46 2018 2185 2196 29432571 PMC5861422
  44. [56]Haraszti R.A. Roux L. Coles A.H. Turanov A.A. Alterman J.F. Echeverria D. Godinho B.M.D.C. Aronin N. Khvorova A. 5’-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo Nucleic Acids Res. 45 2017 7581 7592 28591791 PMC5570069
  45. [57]Janas M.M. Schlegel M.K. Harbison C.E. Yilmaz V.O. Jiang Y. Parmar R. Zlatev I. Castoreno A. Xu H. Shulga-Morskaya S. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity Nat. Commun. 9 2018 1 29459660 PMC5818625
  46. [59]Choung S. Kim Y.J. Kim S. Park H.O. Choi Y.C. Early blood-brain barrier dysfunction predicts neurological outcome following aneurysmal subarachnoid hemorrhage EBioMedicine 43 2019 460 472 31162113 PMC6558266
  47. [60]Wittrup A. Lieberman J. Early blood-brain barrier dysfunction predicts neurological outcome following aneurysmal subarachnoid hemorrhage EBioMedicine 43 2019 460 472 31162113 PMC6558266
  48. [61]Czauderna F. Fechtner M. Dames S. Aygün H. Klippel A. Pronk G.J. Giese K. Kaufmann J. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells Nucleic Acids Res. 31 2003 2705 2716 12771196 PMC156727
  49. [63]Yasuda M. Gan L. Chen B. Kadirvel S. Yu C. Phillips J.D. New M.I. Liebow A. Fitzgerald K. Querbes W. Desnick R.J. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice Proc. Natl. Acad. Sci. U S A 111 2014 7777 7782 24821812 PMC4040563
  50. [64]Fitzgerald K. Frank-Kamenetsky M. Shulga-Morskaya S. Liebow A. Bettencourt B.R. Sutherland J.E. Hutabarat R.M. Clausen V.A. Karsten V. Cehelsky J. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial The Lancet 383 2014 60 68 PMC4387547 24094767
  51. [65]Ray K.K. Landmesser U. Leiter L.A. Kallend D. Dufour R. Karakas M. Hall T. Troquay R.P. Turner T. Visseren F.L. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol New Engl. J. Med. 376 2017 1430 1440 28306389
  52. [66]Adams D. Gonzalez-Duarte A. O'Riordan W.D. Yang C.C. Ueda M. Kristen A.V. Tournev I. Schmidt H.H. Coelho T. Berk J.L. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis New Engl. J. Med. 379 2018 11 21 29972753
  53. [67]Solomon S.D. Adams D. Kristen A. Grogan M. González-Duarte A. Maurer M.S. Merlini G. Damy T. Slama M.S. Brannagan T.H. 3rd Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis: analysis of the APOLLO study Circulation 139 2019 431 443 30586695 PMC12611557
  54. [68]Huang Y. Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics Mol. Ther. Nucleic Acids 6 2017 116 132 28325278 PMC5363494
  55. [69]Coles A.H. Osborn M.F. Alterman J.F. Turanov A.A. Godinho B.M. Kennington L. Chase K. Aronin N. Khvorova A. A high-throughput method for direct detection of therapeutic oligonucleotide-induced gene silencing in vivo Nucleic Acid Ther. 26 2016 86 92 26595721 PMC4834514
  56. [70]Nikan M. Osborn M.F. Coles A.H. Godinho B.M. Hall L.M. Haraszti R.A. Hassler M.R. Echeverria D. Aronin N. Khvorova A. Docosahexaenoic acid conjugation enhances distribution and safety of siRNA upon local administration in mouse brain Mol. Ther. Nucleic Acids 5 2016 e344 27504598 PMC5023396
  57. [71]Gluchowski N.L. Gabriel K.R. Chitraju C. Bronson R.T. Mejhert N. Boland S. Wang K. Lai Z.W. Farese R.V. Jr. Walther T.C. Hepatocyte deletion of triglyceride-synthesis enzyme acyl CoA: diacylglycerol acyltransferase 2 reduces steatosis without increasing inflammation or fibrosis in mice Hepatology 70 2019 1972 1985 31081165 PMC6893913
  58. [72]Borel F. Tang Q. Gernoux G. Greer C. Wang Z. Barzel A. Kay M.A. Shultz L.D. Greiner D.L. Flotte T.R. Survival advantage of both human hepatocyte xenografts and genome-edited hepatocytes for treatment of α-1 antitrypsin deficiency Mol. Ther. 25 2017 2477 2489 29032169 PMC5675605
  59. [73]Linden A.G. Li S. Choi H.Y. Fang F. Fukasawa M. Uyeda K. Hammer R.E. Horton J.D. Engelking L.J. Liang G. Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice J. Lipid Res. 59 2018 475 487 29335275 PMC5832931
  60. [74]Wang X. Sommerfeld M.R. Jahn-Hofmann K. Cai B. Filliol A. Remotti H.E. Schwabe R.F. Kannt A. Tabas I. A therapeutic silencing RNA targeting hepatocyte TAZ prevents and reverses fibrosis in nonalcoholic steatohepatitis in mice Hepatol. Commun. 3 2019 1221 1234 31497743 PMC6719739
  61. [75]Frank-Kamenetsky M. Grefhorst A. Anderson N.N. Racie T.S. Bramlage B. Akinc A. Butler D. Charisse K. Dorkin R. Fan Y. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates Proc. Natl. Acad. Sci. U S A 105 2008 11915 11920 18695239 PMC2575310
  62. [76]Chan A. Liebow A. Yasuda M. Gan L. Racie T. Maier M. Kuchimanchi S. Foster D. Milstein S. Charisse K. Preclinical development of a subcutaneous ALAS1 RNAi therapeutic for treatment of hepatic porphyrias using circulating RNA quantification Mol. Ther. Nucleic Acids 4 2015 e263 26528940 PMC4877445
  63. [77]Allerson C.R. Sioufi N. Jarres R. Prakash T.P. Naik N. Berdeja A. Wanders L. Griffey R.H. Swayze E.E. Bhat B. Fully 2′-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA J. Med. Chem. 48 2005 901 904 15715458
  64. [78]McLaren D.G. Han S. Murphy B.A. Wilsie L. Stout S.J. Zhou H. Roddy T.P. Gorski J.N. Metzger D.E. Shin M.K. DGAT2 inhibition alters aspects of triglyceride metabolism in rodents but not in non-human primates Cell Metab. 27 2018 1236 1248.e6 29706567
  65. [79]Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver J. Clin. Invest. 109 2002 1125 1131 11994399 PMC150968
  66. [81]Tian J. Goldstein J.L. Brown M.S. Insulin induction of SREBP-1c in rodent liver requires LXRα-c/EBPβ complex Proc. Natl. Acad. Sci. U S A 113 2016 8182 8187 27382175 PMC4961151
  67. [82]Brown M.S. Goldstein J.L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood Proc. Natl. Acad. Sci. U S A 96 1999 11041 11048 10500120 PMC34238
  68. [83]Iizuka K. Miller B. Uyeda K. Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob/ob) mice Am. J. Physiol. - Endocrinol. Metab. 291 2006 358 364 16705063
  69. [84]Dentin R. Benhamed F. Hainault I. Fauveau V. Foufelle F. Dyck J.R. Girard J. Postic C. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice Diabetes 55 2006 2159 2170 16873678
  70. [85]Erion D.M. Popov V. Hsiao J.J. Vatner D. Mitchell K. Yonemitsu S. Nagai Y. Kahn M. Gillum M.P. Dong J. The role of the carbohydrate response element-binding protein in male fructose-fed rats Endocrinology 154 2013 36 44 23161873 PMC3529388
  71. [86]Walker A.K. Jacobs R.L. Watts J.L. Rottiers V. Jiang K. Finnegan D.M. Shioda T. Hansen M. Yang F. Niebergall L.J. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans Cell 147 2011 840 852 22035958 PMC3384509
  72. [87]Calle R.A. Amin N.B. Carvajal-Gonzalez S. Ross T.T. Bergman A. Aggarwal S. Crowley C. Rinaldi A. Mancuso J. Aggarwal N. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials Nat. Med. 27 2021 1836 1848 34635855
  73. [89]Livak K.J. Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method Methods 25 2001 402 408 11846609
  74. [90]Han X. Lipidomics: Comprehensive Mass Spectrometry of Lipids. Lipidomics: Comprehensive Mass Spectrometry of Lipids 2016 Wiley-Blackwell 10.1002/9781119085263 · DOI
  75. [91]Wang M. Han X. Multidimensional mass spectrometry-based shotgun lipidomics Methods Mol. Biol. 1198 2014 203 220 25270931 PMC4261229
  76. [93]Yang K. Cheng H. Gross R.W. Han X. Automated lipid identification and quantification by multidimensional mass spectrometry-based shotgun lipidomics Anal. Chem. 81 2009 4356 4368 19408941 PMC2728582
  77. [94]Kucukural A. Yukselen O. Ozata D.M. Moore M.J. Garber M. DEBrowser: interactive differential expression analysis and visualization tool for count data BMC Genomics 20 2019 6 30611200 PMC6321710
  78. [95]Yukselen O. Turkyilmaz O. Ozturk A.R. Garber M. Kucukural A. DolphinNext: a distributed data processing platform for high throughput genomics BMC Genom. 21 2020 310 PMC7168977 32306927
  79. [96]Bolger A.M. Lohse M. Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data Bioinformatics 30 2014 2114 2120 24695404 PMC4103590
  80. [97]Love M.I. Huber W. Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 15 2014 550 25516281 PMC4302049

Authors
Yenilmez, B., Wetoska, N., Kelly, M., Echeverria, D., Min, K., Lifshitz, L., Alterman, J. F., Hassler, M. R., Hildebrand, S., DiMarzio, C., McHugh, N., Vangjeli, L., Sousa, J., Pan, M., Han, X., Brehm, M. A., Khvorova, A., & Czech, M. P.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
  • Khvorova, Anastasia
  • Czech, Michael P.
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2022-03
Volume
30
Issue
3
Pages
1329-1342
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2021.11.007
PMC
PMC8899521
OpenAlex
W3212131704
Cited by
46
References
100
Citations by year
2026: 6 · 2025: 8 · 2024: 15 · 2023: 14 · 2022: 3
FWCI
5.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • American Heart Association (19PRE34460013)
  • National Institutes of Health (DK103047, R35GM131839, S10OD020012)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
nonalcoholic steatohepatitis, DGAT2, RNAi therapeutics, siRNA, GalNAc-conjugated siRNA, hepatic steatosis, triglyceride synthesis, obesity, liver fibrosis, liver inflammation, gene silencing
MeSH terms
RNAi Therapeutics, Animals, Disease Models, Animal, Fibrosis, Inflammation, Liver, Mice, Inbred C57BL, Mice, Obese, Obesity, Triglycerides, Diacylglycerol O-Acyltransferase, Mice, Non-alcoholic Fatty Liver Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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