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• W3212131704 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. 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. IntroductionNonalcoholic fatty liver disease (NAFLD) is characterized by triglyceride accumulation within hepatocytes (hepatic steatosis) and affects up to 1 billion humans worldwide.1Younossi 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. 2016; 64: 1577-1586Google Scholar NAFLD by itself can be relatively benign but is often part of a sequel of liver conditions in obesity and type 2 diabetes (T2D) varying in severity of injury. Most notably, NAFLD can precede the occurrence of nonalcoholic steatohepatitis (NASH), which is associated with increased liver inflammation through resident and infiltrating immune cell activation as well as scarring and fibrosis through activation of resident stellate cells to produce collagen.2Younossi 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. 2016; 64: 73-84Google Scholar Currently, it is estimated that ∼20%–25% of NAFLD patients will progress to develop NASH and, if left untreated, the risk of developing cirrhosis, severe liver failure, and hepatocellular carcinoma greatly increases.3Alexander M. Loomis A.K. van der Lei J. Duarte-Salles T. Prieto-Alhambra D. Ansell D. Pasqua A. Lapi F. Rijnbeek P. Mosseveld M. et al.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. 2019; 17: 95https://doi.org/10.1186/s12916-019-1321-xGoogle Scholar, 4Lomonaco 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. 2012; 55: 1389-1397Google Scholar, 5Estes 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. 2018; 67: 123-133Google Scholar, 6Diehl A.M. Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.New Engl. J. Med. 2017; 377: 2063-2072Google Scholar Collectively, the various pathologies associated with dysfunctional liver lipid metabolism, inflammation, and fibrosis represent a huge and burgeoning burden on the health care system, with increasing rates among young adults and even children projected to continue.3Alexander M. Loomis A.K. van der Lei J. Duarte-Salles T. Prieto-Alhambra D. Ansell D. Pasqua A. Lapi F. Rijnbeek P. Mosseveld M. et al.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. 2019; 17: 95https://doi.org/10.1186/s12916-019-1321-xGoogle Scholar,4Lomonaco 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. 2012; 55: 1389-1397Google Scholar While lifestyle improvements, including weight loss, can alleviate NASH, behavioral modifications are difficult to execute and have not provided a solid solution to the problem.4Lomonaco 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. 2012; 55: 1389-1397Google Scholar, 5Estes 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. 2018; 67: 123-133Google Scholar, 6Diehl A.M. Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.New Engl. J. Med. 2017; 377: 2063-2072Google Scholar Despite the high prevalence of NASH, there is no US Food and Drug Administration (FDA)-approved therapeutic agent that can specifically alleviate it,7Friedman S.L. Neuschwander-Tetri B.A. Rinella M. Sanyal A.J. Mechanisms of NAFLD development and therapeutic strategies.Nat. Med. 2018; : 24 908-922Google Scholar, 8Romeo S. Sanyal A. Valenti L. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat. Genet. 2008; 40: 1461-1465Google Scholar, 9Speliotes 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. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Google Scholar indicating an urgent unmet medical need.9Speliotes 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. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Google ScholarOne of the major unresolved questions in this field is whether the hepatic steatosis in NAFLD alone drives the inflammation and fibrosis that occur in NASH, independent of other liver perturbations that occur in obesity and T2D. If this is the case, might therapeutic targeting of the hepatic steatosis in NAFLD alleviate its progression to NASH? Strong support for the idea that hepatic steatosis is the major independent initiator of NASH has been derived from human genome-wide association studies showing its strong link with single-nucleotide polymorphisms in genes related to lipid metabolism. These include PNLP3, TM6SF2, LYPLAL1, GCKR, and PPP1R3B, which can harbor polymorphisms that not only track with steatosis but also with steatohepatitis and hepatic fibrosis.10Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. Nobili V. Mozzi E. Roviaro G. Vanni E. et al.Homozygosity for the patatin-like phospholipase-3/adiponutrin i148m polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1209-1217Google Scholar, 11Liu Y.L. Reeves H.L. Burt A.D. Tiniakos D. McPherson S. Leathart J.B. Allison M.E. Alexander G.J. Piguet A.C. Anty R. et al.TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.Nat. Commun. 2014; 5: 1Google Scholar, 12Wong V.W.S. Singal A.K. Emerging medical therapies for non-alcoholic fatty liver disease and for alcoholic hepatitis.Translational Gastroenterol. Hepatol. 2019; 4: 53https://doi.org/10.21037/tgh.2019.06.06Google Scholar These findings strengthen the idea that hepatic steatosis drives the inflammation/fibrosis aspects of the pathology and have resulted in major investment toward therapeutic targets within lipid metabolism pathways. On the other hand, clinical trials13Singh 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. 2015; 62: 1417-1432Google Scholar, 14Musso 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. 2012; 55: 885-904Google Scholar, 15Mahady 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. 2011; 55: 1383-1390Google Scholar, 16Macauley 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. 2015; 100: 1578-1585Google Scholar, 17Cui J. Philo L. Nguyen P. Hofflich H. Hernandez C. Bettencourt R. Richards L. Salotti J. Bhatt A. Hooker J. et al.Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial.J. Hepatol. 2016; 65: 369-376Google Scholar, 18Mudaliar S. Henry R.R. Sanyal A.J. Morrow L. Marschall H.U. Kipnes M. Adorini L. Sciacca C.I. Clopton P. Castelloe E. et al.Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.Gastroenterology. 2013; 145: 574Google Scholar, 19Neuschwander-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. et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965Google Scholar, 20Pockros P.J. Fuchs M. Freilich B. Schiff E. Kohli A. Lawitz E.J. Hellstern P.A. Owens-Grillo J. Van Biene C. Shringarpure R. et al.CONTROL: a randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients.Liver Int. 2019; 39: 2082-2093Google Scholar, 21Younossi Z.M. Ratziu V. Loomba R. Rinella M. Anstee Q.M. Goodman Z. Bedossa P. Geier A. Beckebaum S. Newsome P.N. et al.Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.Lancet. 2019; 394: 2184-2196Google Scholar, 22Harrison S.A. Alkhouri N. Davison B.A. Sanyal A. Edwards C. Colca J.R. Lee B.H. Loomba R. Cusi K. Kolterman O. et al.Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study.J. Hepatol. 2020; 72: 613-626Google Scholar, 23Friedman S.L. Ratziu V. Harrison S.A. Abdelmalek M.F. Aithal G.P. Caballeria J. Francque S. Farrell G. Kowdley K.V. Craxi A. et al.A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.Hepatology. 2018; 67: 1754-1767Google Scholar, 24Ratziu V. Sanyal A. Harrison S.A. Wong V.W. Francque S. Goodman Z. Aithal G.P. Kowdley K.V. Seyedkazemi S. Fischer L. et al.Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study.Hepatology. 2020; 72: 892-905Google Scholar, 25Harrison S.A. Wong V.W. Okanoue T. Bzowej N. Vuppalanchi R. Younes Z. Kohli A. Sarin S. Caldwell S.H. Alkhouri N. Shiffman M.L. et al.Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.J. Hepatol. 2020; 73: 26-39Google Scholar, 26Lawitz E.J. Coste A. Poordad F. Alkhouri N. Loo N. McColgan B.J. Tarrant J.M. Nguyen T. Han L. Chung C. et al.Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis.Clin. Gastroenterol. Hepatol. 2018; 16: 1983-1991.e3Google Scholar, 27Loomba R. Kayali Z. Noureddin M. Ruane P. Lawitz E.J. Bennett M. Wang L. Harting E. Tarrant J.M. McColgan B.J. et al.GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.Gastroenterology. 2018; 155: 1463-1473.e6Google Scholar, 28Goedeke L. Bates J. Vatner D.F. Perry R.J. Wang T. Ramirez R. Li L. Ellis M.W. Zhang D. Wong K.E. et al.Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents.Hepatology. 2018; 68: 2197-2211Google Scholar, 29Kim C.W. Addy C. Kusunoki J. Anderson N.N. Deja S. Fu X. Burgess S.C. Li C. Ruddy M. Chakravarthy M. et al.Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.Cell Metab. 2017; 26: 394-406.e6Google Scholar, 30Harrison S.A. Abdelmalek M.F. Caldwell S. Shiffman M.L. Diehl A.M. Ghalib R. Lawitz E.J. Rockey D.C. Schall R.A. Jia C. et al.Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis.Gastroenterology. 2018; 155: 1140-1153Google Scholar, 31Harrison S.A. Goodman Z. Jabbar A. Vemulapalli R. Younes Z.H. Freilich B. Sheikh M.Y. Schattenberg J.M. Kayali Z. Zivony A. et al.A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.J. Hepatol. 2020; 72: 816-827Google Scholar, 32Garcia-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. et al.Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension.J. Hepatol. 2020; 72: 885-895Google Scholar with agents that target such proteins, for example thiazolidinediones (TZDs), FXR agonists,18Mudaliar S. Henry R.R. Sanyal A.J. Morrow L. Marschall H.U. Kipnes M. Adorini L. Sciacca C.I. Clopton P. Castelloe E. et al.Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.Gastroenterology. 2013; 145: 574Google Scholar, 19Neuschwander-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. et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965Google Scholar, 20Pockros P.J. Fuchs M. Freilich B. Schiff E. Kohli A. Lawitz E.J. Hellstern P.A. Owens-Grillo J. Van Biene C. Shringarpure R. et al.CONTROL: a randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients.Liver Int. 2019; 39: 2082-2093Google Scholar, 21Younossi Z.M. Ratziu V. Loomba R. Rinella M. Anstee Q.M. Goodman Z. Bedossa P. Geier A. Beckebaum S. Newsome P.N. et al.Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.Lancet. 2019; 394: 2184-2196Google Scholar and acetyl coenzyme A (CoA) carboxylase (ACC) inhibitors,26Lawitz E.J. Coste A. Poordad F. Alkhouri N. Loo N. McColgan B.J. Tarrant J.M. Nguyen T. Han L. Chung C. et al.Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis.Clin. Gastroenterol. Hepatol. 2018; 16: 1983-1991.e3Google Scholar, 27Loomba R. Kayali Z. Noureddin M. Ruane P. Lawitz E.J. Bennett M. Wang L. Harting E. Tarrant J.M. McColgan B.J. et al.GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.Gastroenterology. 2018; 155: 1463-1473.e6Google Scholar, 28Goedeke L. Bates J. Vatner D.F. Perry R.J. Wang T. Ramirez R. Li L. Ellis M.W. Zhang D. Wong K.E. et al.Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents.Hepatology. 2018; 68: 2197-2211Google Scholar, 29Kim C.W. Addy C. Kusunoki J. Anderson N.N. Deja S. Fu X. Burgess S.C. Li C. Ruddy M. Chakravarthy M. et al.Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.Cell Metab. 2017; 26: 394-406.e6Google Scholar have not succeeded, due to either adverse effects or lack of improvement in inflammation and fibrosis.13Singh 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. 2015; 62: 1417-1432Google Scholar, 14Musso 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. 2012; 55: 885-904Google Scholar, 15Mahady 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. 2011; 55: 1383-1390Google Scholar, 16Macauley 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. 2015; 100: 1578-1585Google Scholar, 17Cui J. Philo L. Nguyen P. Hofflich H. Hernandez C. Bettencourt R. Richards L. Salotti J. Bhatt A. Hooker J. et al.Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial.J. Hepatol. 2016; 65: 369-376Google Scholar, 18Mudaliar S. Henry R.R. Sanyal A.J. Morrow L. Marschall H.U. Kipnes M. Adorini L. Sciacca C.I. Clopton P. Castelloe E. et al.Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.Gastroenterology. 2013; 145: 574Google Scholar, 19Neuschwander-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. et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965Google Scholar, 20Pockros P.J. Fuchs M. Freilich B. Schiff E. Kohli A. Lawitz E.J. Hellstern P.A. Owens-Grillo J. Van Biene C. Shringarpure R. et al.CONTROL: a randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients.Liver Int. 2019; 39: 2082-2093Google Scholar, 21Younossi Z.M. Ratziu V. Loomba R. Rinella M. Anstee Q.M. Goodman Z. Bedossa P. Geier A. Beckebaum S. Newsome P.N. et al.Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.Lancet. 2019; 394: 2184-2196Google Scholar, 22Harrison S.A. Alkhouri N. Davison B.A. Sanyal A. Edwards C. Colca J.R. Lee B.H. Loomba R. Cusi K. Kolterman O. et al.Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study.J. Hepatol. 2020; 72: 613-626Google Scholar, 23Friedman S.L. Ratziu V. Harrison S.A. Abdelmalek M.F. Aithal G.P. Caballeria J. Francque S. Farrell G. Kowdley K.V. Craxi A. et al.A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.Hepatology. 2018; 67: 1754-1767Google Scholar, 24Ratziu V. Sanyal A. Harrison S.A. Wong V.W. Francque S. Goodman Z. Aithal G.P. Kowdley K.V. Seyedkazemi S. Fischer L. et al.Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study.Hepatology. 2020; 72: 892-905Google Scholar, 25Harrison S.A. Wong V.W. Okanoue T. Bzowej N. Vuppalanchi R. Younes Z. Kohli A. Sarin S. Caldwell S.H. Alkhouri N. Shiffman M.L. et al.Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.J. Hepatol. 2020; 73: 26-39Google Scholar, 26Lawitz E.J. Coste A. Poordad F. Alkhouri N. Loo N. McColgan B.J. Tarrant J.M. Nguyen T. Han L. Chung C. et al.Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis.Clin. Gastroenterol. Hepatol. 2018; 16: 1983-1991.e3Google Scholar, 27Loomba R. Kayali Z. Noureddin M. Ruane P. Lawitz E.J. Bennett M. Wang L. Harting E. Tarrant J.M. McColgan B.J. et al.GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.Gastroenterology. 2018; 155: 1463-1473.e6Google Scholar, 28Goedeke L. Bates J. Vatner D.F. Perry R.J. Wang T. Ramirez R. Li L. Ellis M.W. Zhang D. Wong K.E. et al.Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents.Hepatology. 2018; 68: 2197-2211Google Scholar, 29Kim C.W. Addy C. Kusunoki J. Anderson N.N. Deja S. Fu X. Burgess S.C. Li C. Ruddy M. Chakravarthy M. et al.Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.Cell Metab. 2017; 26: 394-406.e6Google Scholar, 30Harrison S.A. Abdelmalek M.F. Caldwell S. Shiffman M.L. Diehl A.M. Ghalib R. Lawitz E.J. Rockey D.C. Schall R.A. Jia C. et al.Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis.Gastroenterology. 2018; 155: 1140-1153Google Scholar, 31Harrison S.A. Goodman Z. Jabbar A. Vemulapalli R. Younes Z.H. Freilich B. Sheikh M.Y. Schattenberg J.M. Kayali Z. Zivony A. et al.A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.J. Hepatol. 2020; 72: 816-827Google Scholar, 32Garcia-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. et al.Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension.J. Hepatol. 2020; 72: 885-895Google Scholar These failures suggest the possibility that additional perturbations of gene products in the inflammation and fibrosis pathways, independent of those initiated by hepatic steatosis, are critical to the progression of NASH. Thus, hepatic steatosis may be required but not sufficient to initiate NASH.On a similar note, candidate therapeutics designed to attack the end-stage inflammation and fibrosis pathways of NASH, such as C-C chemokine receptor (CCR)2/5 antagonists,23Friedman S.L. Ratziu V. Harrison S.A. Abdelmalek M.F. Aithal G.P. Caballeria J. Francque S. Farrell G. Kowdley K.V. Craxi A. et al.A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.Hepatology. 2018; 67: 1754-1767Google Scholar,24Ratziu V. Sanyal A. Harrison S.A. Wong V.W. Francque S. Goodman Z. Aithal G.P. Kowdley K.V. Seyedkazemi S. Fischer L. et al.Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study.Hepatology. 2020; 72: 892-905Google Scholar ASK1 inhibitors,25Harrison S.A. Wong V.W. Okanoue T. Bzowej N. Vuppalanchi R. Younes Z. Kohli A. Sarin S. Caldwell S.H. Alkhouri N. Shiffman M.L. et al.Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.J. Hepatol. 2020; 73: 26-39Google Scholar or caspase inhibitors,31Harrison S.A. Goodman Z. Jabbar A. Vemulapalli R. Younes Z.H. Freilich B. Sheikh M.Y. Schattenberg J.M. Kayali Z. Zivony A. et al.A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.J. Hepatol. 2020; 72: 816-827Google Scholar,32Garcia-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. et al.Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension.J. Hepatol. 2020; 72: 885-895Google Scholar have also failed to achieve FDA approval.7Friedman S.L. Neuschwander-Tetri B.A. Rinella M. Sanyal A.J. Mechanisms of NAFLD development and therapeutic strategies.Nat. Med. 2018; : 24 908-922Google Scholar,33Muthiah M.D. Sanyal A.J. Current management of non-alcoholic steatohepatitis.Liver Int. 2020; 40: 89-95Google Scholar,34Woodcock J. Griffin J.P. Behrman R.E. Development of novel combination therapies.New Engl. J. Med. 2011; 364: 985-987Google Scholar Together, these unfavorable results raise the likelihood that the multiple pathways contributing to NASH must be simultaneously targeted by therapeutics to be successful.Based on the above considerations, the aims of the present study were 2-fold: first, we addressed the unsolved question of whether specific inhibition of liver triglyceride synthesis would also diminish inflammation and fibrosis in the livers of a novel mouse model whereby NASH is rapidly developed by high fat-high cholesterol-high fructose (GAN) diet feeding. For this aim, we targeted diacylglycerol (DAG) acyltransferase 2 (DGAT2), which catalyzes the last step in the synthesis of triacylglycerol through the esterification of fatty acyl-CoA to DAG.35Yen C.L.E. Stone S.J. Koliwad S. Harris C. Farese R.V. DGAT enzymes and triacylglycerol biosynthesis.J. Lipid Res. 2008; 49: 2283-2301Google Scholar DGAT2 is expressed prominently in liver and adipose tissue, while the DGAT1 isoform is expressed mostly in intestine and much less so in other tissues.36Zammit V.A. Hepatic triacylglycerol synthesis and secretion: DGAT2 as the link between glycaemia and triglyceridaemia.Biochem. J. 2013; 451: 1-12Google Scholar It has been shown previously that depletion of liver DGAT2 by antisense oligonucleotide (ASO) does alleviate hepatic steatosis in mouse37Yu 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. 2005; 42: 362-371Google Scholar,38Yamaguchi 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. 2007; 45: 1366-1374Google Scholar and rat39Choi C.S. Savage D.B. Kulkarni A. Yu X.X. Liu Z.X. Morino K. Kim S. Distefano A. Samuel V.T. Neschen S. et al.Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance.J. Biol. Chem. 2007; 282: 22678-22688Google Scholar models, but the effects on inflammation and fibrosis were not evaluated in these studies. In a study using a choline deficient diet-induced mouse NASH model, liver damage appeared to actually be increased by liver DGAT2 loss.38Yamaguchi 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." @default.
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• W3212131704 date "2022-03-01" @default.
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• W3212131704 title "An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis" @default.
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