Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and secretions of apolipoprotein B-containing lipoprotein and bile acids in HepG2

Jpn J Pharmacol. 1999 Feb;79(2):151-8. doi: 10.1254/jjp.79.151.

Abstract

We studied the effect of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl) ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on intracellular cholesterol esterification and the secretion of apolipoprotein B100 (apoB)-containing lipoprotein and bile acids in the human hepatoma cell line HepG2. NTE-122 markably inhibited [3H]oleate incorporation into cholesteryl esters in HepG2 cells incubated with 5 microg/ml 25-hydroxycholesterol as a stimulus for ACAT (IC50=6.0 nM). On the other hand, NTE-122 did not affect [3H]oleate incorporation into triglycerides and phospholipids and [14C]acetate incorporation into cholesterol. The stimulation of ACAT by 25-hydroxycholesterol caused significant increases in the secretion of radiolabeled cholesteryl esters, radiolabeled triglycerides and apoB mass. NTE-122 pronouncedly inhibited the secretion of radiolabeled cholesteryl esters in proportion to the inhibition of cellular cholesterol esterification, and it significantly reduced the secretion of radiolabeled triglycerides and apoB mass in HepG2 cells incubated with 25-hydroxycholesterol. Furthermore, NTE-122 increased the secretion of bile acids synthesized from [14C]-cholesterol. These results suggest that NTE-122 is capable of exhibiting anti-hyperlipidemic effects by reducing both the cholesterol content and the amount of secreted very low-density lipoprotein and enhancing the excretion of bile acid from the liver.

MeSH terms

  • Acetates / metabolism
  • Anilides / pharmacology
  • Aniline Compounds / pharmacology*
  • Apolipoproteins B / metabolism*
  • Bile Acids and Salts / chemistry*
  • Bile Acids and Salts / metabolism
  • Carcinoma, Hepatocellular / metabolism*
  • Cholesterol / metabolism*
  • Cyclohexanes / pharmacology*
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydroxycholesterols / pharmacology
  • Lipoproteins / chemistry
  • Oleic Acid / metabolism
  • Phenylurea Compounds / pharmacology
  • Phospholipids / biosynthesis
  • Sterol O-Acyltransferase / antagonists & inhibitors*
  • Triglycerides / biosynthesis
  • Tumor Cells, Cultured

Substances

  • Acetates
  • Anilides
  • Aniline Compounds
  • Apolipoproteins B
  • Bile Acids and Salts
  • Cyclohexanes
  • Enzyme Inhibitors
  • Hydroxycholesterols
  • Lipoproteins
  • NTE 122
  • Phenylurea Compounds
  • Phospholipids
  • Triglycerides
  • PD 128042
  • E 5324
  • Oleic Acid
  • Cholesterol
  • Sterol O-Acyltransferase