Abstract |
Nonalcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatocyte triglycerides, the synthesis of which is catalyzed by diacylglycerol acyltransferases (DGATs). Here, we investigate DGAT2 as a potential therapeutic target using an orally administered, selective DGAT2 inhibitor, PF-06427878. Treatment with PF-06427878 resulted in the reduction of hepatic and circulating plasma triglyceride concentrations and decreased lipogenic gene expression in rats maintained on a Western-type diet. In a mouse model of NASH, histological improvements in steatosis, ballooning, and fibrosis were evident in the livers of animals receiving PF-06427878 compared with mice treated with vehicle alone. We extended these nonclinical studies to two phase 1 studies in humans [NCT02855177 (n = 24) and NCT02391623 (n = 39; n = 38 completed)] and observed that PF-06427878 was well tolerated and influenced markers of liver function ( alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin) in healthy adults, with statistically significant reductions from baseline at day 14 in participants treated with PF-06427878 1500 milligrams per day (P < 0.05). Moreover, magnetic resonance imaging using proton density fat fraction showed that PF-06427878 1500 milligrams per day reduced hepatic steatosis in healthy adult participants. Our findings highlight DGAT2 inhibition by a small, potent, selective compound as a potential therapeutic approach for the treatment of NASH.
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Authors | Neeta B Amin, Santos Carvajal-Gonzalez, Julie Purkal, Tong Zhu, Collin Crowley, Sylvie Perez, Kristin Chidsey, Albert M Kim, Bryan Goodwin |
Journal | Science translational medicine
(Sci Transl Med)
Vol. 11
Issue 520
(11 27 2019)
ISSN: 1946-6242 [Electronic] United States |
PMID | 31776293
(Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. |
Chemical References |
- Lipids
- Pyridines
- Diacylglycerol O-Acyltransferase
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Topics |
- Administration, Oral
- Adult
- Animals
- Diacylglycerol O-Acyltransferase
(antagonists & inhibitors, metabolism)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Female
- Gene Expression Regulation
(drug effects)
- Humans
- Lipids
- Lipogenesis
(drug effects, genetics)
- Liver
(drug effects, metabolism, pathology, physiopathology)
- Liver Function Tests
- Mice, Inbred C57BL
- Molecular Targeted Therapy
- Non-alcoholic Fatty Liver Disease
(drug therapy, enzymology, pathology, physiopathology)
- Pyridines
(adverse effects, pharmacokinetics, therapeutic use)
- Rats, Sprague-Dawley
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