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ANGPTL3 Deficiency and Risk of Hepatic Steatosis.
D'Erasmo, Laura; Di Martino, Michele; Neufeld, Thomas; Fraum, Tyler J; Kang, Chul Joo; Burks, Kendall H; Di Costanzo, Alessia; Minicocci, Ilenia; Bini, Simone; Maranghi, Marianna; Pigna, Giovanni; Labbadia, Giancarlo; Zheng, Jie; Fierro, Davide; Montali, Anna; Ceci, Fabrizio; Catalano, Carlo; Davidson, Nicholas O; Lucisano, Giuseppe; Nicolucci, Antonio; Arca, Marcello; Stitziel, Nathan O.
Afiliação
  • D'Erasmo L; Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
  • Di Martino M; Radiological Sciences, Oncology, Anatomical Pathology (M.D.M., C.C.), Sapienza University of Rome, Italy.
  • Neufeld T; Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine (T.N., K.H.B., N.O.S.), Washington University School of Medicine, St. Louis, MO.
  • Fraum TJ; Mallinckrodt Institute of Radiology (T.D.F., J.Z.), Washington University School of Medicine, St. Louis, MO.
  • Kang CJ; McDonnell Genome Institute (C.J.K., N.O.S.), Washington University School of Medicine, St. Louis, MO.
  • Burks KH; Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine (T.N., K.H.B., N.O.S.), Washington University School of Medicine, St. Louis, MO.
  • Di Costanzo A; Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
  • Minicocci I; Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
  • Bini S; Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
  • Maranghi M; Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
  • Pigna G; Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
  • Labbadia G; Internal Medicine, Anesthesiology, and Cardiovascular Sciences (G.L.), Sapienza University of Rome, Italy.
  • Zheng J; Mallinckrodt Institute of Radiology (T.D.F., J.Z.), Washington University School of Medicine, St. Louis, MO.
  • Fierro D; Castelli Romani Hospital, Rome, Italy (D.F.).
  • Montali A; Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
  • Ceci F; Experimental Medicine (F.C.), Sapienza University of Rome, Italy.
  • Catalano C; Radiological Sciences, Oncology, Anatomical Pathology (M.D.M., C.C.), Sapienza University of Rome, Italy.
  • Davidson NO; Division of Gastroenterology, Department of Medicine (N.O.D.), Washington University School of Medicine, St. Louis, MO.
  • Lucisano G; CORESEARCH Srl - Center for Outcomes Research and Clinical Epidemiology - Co. Ltd, Pescara, Italy (G.L., A.N.).
  • Nicolucci A; CORESEARCH Srl - Center for Outcomes Research and Clinical Epidemiology - Co. Ltd, Pescara, Italy (G.L., A.N.).
  • Arca M; Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
  • Stitziel NO; Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine (T.N., K.H.B., N.O.S.), Washington University School of Medicine, St. Louis, MO.
Circulation ; 148(19): 1479-1489, 2023 11 07.
Article em En | MEDLINE | ID: mdl-37712257
BACKGROUND: ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3. METHODS: We recruited participants with ANGPTL3 deficiency related to ANGPTL3 loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study. RESULTS: We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to ANGPTL3 LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; P<0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; P<0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 9.8%; partial deficiency, 10.1%; WT, 9.9%; P>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (P=1.7×10-17) and triglycerides (P=3.2×10-18) but not with hepatic fat (P=0.22). CONCLUSIONS: ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína 3 Semelhante a Angiopoietina Tipo de estudo: Clinical_trials / Etiology_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Circulation Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína 3 Semelhante a Angiopoietina Tipo de estudo: Clinical_trials / Etiology_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Circulation Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Itália