Your browser doesn't support javascript.
loading
Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice.
Desjardins, Eric M; Wu, Jianhan; Lavoie, Declan C T; Ahmadi, Elham; Townsend, Logan K; Morrow, Marisa R; Wang, Dongdong; Tsakiridis, Evangelia E; Batchuluun, Battsetseg; Fayyazi, Russta; Kwiecien, Jacek M; Tsakiridis, Theodoros; Lally, James S V; Paré, Guillaume; Pinkosky, Stephen L; Steinberg, Gregory R.
Affiliation
  • Desjardins EM; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Wu J; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada; Population Health Research Institute, McMaster University, Hamilton, ON L8L 2X2,
  • Lavoie DCT; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Ahmadi E; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Townsend LK; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Morrow MR; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Wang D; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Tsakiridis EE; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Batchuluun B; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Fayyazi R; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Kwiecien JM; Department of Pathology, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Tsakiridis T; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Department of Oncology, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Lally JSV; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • Paré G; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Population Health Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada.
  • Pinkosky SL; Esperion Therapeutics, Inc., Ann Arbor, MI, USA.
  • Steinberg GR; Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilto
Cell Rep Med ; 4(9): 101193, 2023 09 19.
Article in En | MEDLINE | ID: mdl-37729871
Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning, and fibrosis and inhibits activation of hepatic stellate cells. Glucagon-like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance, and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared with clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
Subject(s)
Key words
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Insulin Resistance / Non-alcoholic Fatty Liver Disease Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cell Rep Med Year: 2023 Document type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Insulin Resistance / Non-alcoholic Fatty Liver Disease Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cell Rep Med Year: 2023 Document type: Article