A novel inhibitor of stearoyl-CoA desaturase-1 attenuates hepatic lipid accumulation, liver injury and inflammation in model of nonalcoholic steatohepatitis

Biol Pharm Bull. 2013;36(2):259-67. doi: 10.1248/bpb.b12-00702.


Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the biosynthesis of monounsaturated fatty acids, and their abnormality is possibly responsible for obesity, insulin resistance, hepatic steatosis and nonalcoholic steatohepatitis (NASH). A novel SCD-1 inhibitor, N-(2-hydroxy-2-phenylethyl)-6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxamide, has been obtained. The compound inhibited liver SCD-1 activity and increased liver triglyceride accumulation in mice fed with non-fat, high-sucrose diets. In order to evaluate the effects of the SCD-1 inhibitor on NASH development, rats were fed with lipogenic methionine and choline-deficient (MCD) diets for 8 weeks. The SCD-1 inhibitor was administered once-daily at a dose of 30 or 100 mg/kg/d by oral gavage. Administration of a high dose of the SCD-1 inhibitor decreased triglyceride accumulation in the liver of NASH rats by 80%. Administration of a high dose of the SCD-1 inhibitor attenuated the increase of aspartate aminotransferase (AST) and alanine transaminase (ALT) by 86% and 78%, respectively. Hepatic steatosis, hepatocellular degeneration and inflammatory cell infiltration were histologically observed in the liver of NASH rats, and administration of the SCD-1 inhibitor ameliorated these crucial observations in NASH. In summary, an SCD-1 inhibitor ameliorated hepatic triglyceride accumulation, liver injury, hepatocellular degeneration and inflammation in experimental NASH models. These results suggest that SCD-1 maybe a promising target for the treatment of NASH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use*
  • Pyridazines / pharmacology
  • Pyridazines / therapeutic use*
  • Rats
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Stearoyl-CoA Desaturase / metabolism
  • Triglycerides / metabolism


  • Enzyme Inhibitors
  • N-(2-hydroxy-2-phenylethyl)-6-(4-(2-methylbenzoyl)piperidin-1-yl)pyridazine-3-carboxamide
  • Piperidines
  • Protective Agents
  • Pyridazines
  • Triglycerides
  • Stearoyl-CoA Desaturase
  • Alanine Transaminase