Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis

Sci Transl Med. 2019 Nov 27;11(520):eaav9701. doi: 10.1126/scitranslmed.aav9701.


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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Animals
  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Diacylglycerol O-Acyltransferase / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Lipids
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver / physiopathology
  • Liver Function Tests
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy*
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / enzymology*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Non-alcoholic Fatty Liver Disease / physiopathology
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use
  • Rats, Sprague-Dawley


  • Lipids
  • Pyridines
  • Diacylglycerol O-Acyltransferase

Associated data