Disease relevance of CI 976

• CI-976 decreased non-high density lipoprotein (HDL)-cholesterol and increased HDL-cholesterol in rats with pre-established dyslipidemia [1].

High impact information on CI 976

• Inhibition of the Golgi LPAT was achieved by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976), a previously characterized antagonist of acyl-CoA cholesterol acyltransferase [2].
• Moreover, preincubation of cells with PLA2 antagonists inhibited the ability of CI-976 to induce tubules [2].
• Here, we show that CI-976 stimulates tubule formation from all subcompartments of the Golgi complex, and often these tubules formed independently, i.e. individual tubules usually did not contain markers from different subcompartments [3].
• Tf and TfRs accumulated in centrally located, Rab11-positive vesicles indicating that CI-976 inhibits export of cargo from the central endocytic recycling compartment [3].
• Previous studies have shown that inhibition of a Golgi-complex-associated lysophospholipid acyltransferase (LPAT) activity by the drug CI-976 stimulates Golgi tubule formation and subsequent redistribution of resident Golgi proteins to the endoplasmic reticulum (ER) [3].

Biological context of CI 976

• In contrast, CI-976, a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, did not affect the uptake of free cholesterol into the intestines while inhibiting cholesterol esterification (98% inhibition).(ABSTRACT TRUNCATED AT 400 WORDS)[4]
• Since leukotriene B4 (LTB4) is known to promote leukocyte-endothelial cell adhesion, endothelial cell production of this leukotriene was examined after incubation with CI-976 [5].
• In summary, CI-976 exhibits moderate absorption and bioavailability in the rat, but lower absorption and bioavailability in monkey [6].
• It also inhibited ACAT from the mouse macrophage cell line J774 A.1, and its IC50 value (0.067 microM) was much lower than that of CI-976 (4.1 microM) [7].

Anatomical context of CI 976

• CI-976 treatment lowered ACAT mRNA14b levels by 60% and 40% in liver and aorta, respectively, in comparison to the HFHC controls; again there was no change in adrenal or small intestine levels [8].
• CI-976 treatment of endothelial cells also decreased endothelial cell ACAT activity [5].
• To examine the potential role of this enzyme in monocyte adhesion, a specific ACAT inhibitor, CI-976, was utilized [5].
• The CE content of the injured left femoral, left iliac and abdominal aorta and uninjured right femoral and iliac arteries and thoracic aorta was reduced 62-78% by CI-976 [9].
• The accuracy of membrane partitioning analysis based on kinetic data was verified for CI-976 by direct measurements of [14C]CI-976 partitioning into phospholipid membranes [10].

Associations of CI 976 with other chemical compounds

• ACAT activity and cholesteryl ester mass were dose-dependently decreased in the livers from cholesterol-fed rats treated with CI-976, suggesting a direct effect on the liver [1].
• Monocyte adhesion to LPS-treated endothelial cells was markedly inhibited by CI-976 treatment of the endothelial cells [5].
• METHODS AND RESULTS: Rats with puromycin-induced NS were treated with either the ACAT inhibitor CI-976 or placebo for 2 weeks [11].

Gene context of CI 976

• Finally, CI-976 produced an apparently irreversible block in the endocytic recycling pathway of transferrin (Tf) and Tf receptors (TfRs) but had no direct effect on Tf uptake from the cell surface [3].
• The combined data strongly supports the hypothesis that orally administered CI-976 inhibits both intestinal and hepatic ACAT, and that both of these enzymes may be determinants of plasma lipid concentrations in the rat [1].
• Nevertheless, in cholesterol-fed rabbits, both systemically available (7b, 36c) and poorly absorbed inhibitors (1, 36d) were more effective in lowering plasma total cholesterol than the fatty acid amide CI-976 [12].
• Inhibition of cholesterol esterification in the arterial wall was observed also in a reference group of animals treated with the specific ACAT inhibitor CI-976 [13].
• A new ACAT inhibitor, PD128042 (CI-976), was first characterized [14].

Analytical, diagnostic and therapeutic context of CI 976

• Northern blot analysis showed that CaARE2 was activated by HWY-289, but not by CI-976 (a human acyl-coenzyme A:cholesterol acyltransferase inhibitor), in a dose-dependent manner (up to 5mg/L), suggesting different selectivities of action between HWY-289 and CI-976 on Ca-ASAT activity [15].
• The metabolism of CI-976, a potent inhibitor of liver and intestinal acyl coenzyme A:cholesterol acyltransferase, was investigated in isolated rat hepatocytes and Wistar rats after oral administration [16].

References