Manipulation of cholesterol and cholesteryl ester synthesis has multiple effects on the metabolism of apolipoprotein B and the secretion of very-low-density lipoprotein by primary hepatocyte cultures

Article

Author: David Wiggins ; Anna-Marie Brown ; Geoffrey F Gibbons

Inhibition of esterified and non-esterified cholesterol synthesis by lovastatin in primary rat hepatocytes suppressed the net synthesis and very-low-density lipoprotein (VLDL) secretion of apolipoprotein B (apoB)-48 and apoB-100. Lovastatin did not alter the rates of apoB-48 and apoB-100 post-translational degradation. 25-Hydroxycholesterol, which inhibited non-esterified cholesterol synthesis but increased the synthesis of cholesteryl ester, showed differential effects on the metabolism of apoB-48 and apoB-100. Whereas the secretion of apoB-48 VLDL was suppressed there was no effect on the secretion of apoB-100 VLDL. The post-translational degradation of apoB-48, but not of apoB-100, was enhanced by 25-hydroxycholesterol. The net synthesis rates of apoB-48 and apoB-100 were unaffected by 25-hydroxycholesterol. The inhibitory effect of lovastatin alone on the net synthesis of apoB-48 and apoB-100 was reversed by the simultaneous presence of 25-hydroxycholesterol, suggesting a role for newly synthesised cholesteryl ester. Prevention of the reversal effect by the acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor YM 17E supported this interpretation. In the presence of lovastatin, restoration of the net synthesis of apoB by 25-hydroxycholesterol was not accompanied by an increased VLDL output of apoB-48 and apoB-100. However, under these conditions there was an increased post-translational degradation of apoB-48 and apoB-100. These results suggest that interference with intracellular cholesterol and cholesteryl ester metabolism interrupts VLDL assembly at sites of both apoB net synthesis and post-translational degradation.

01 Mar 1998·AtherosclerosisQ2 · MEDICINE

Relationship between bioavailability and hypocholesterolemic activity of YM17E, an inhibitor of ACAT, in cholesterol-fed rats

Q2 · MEDICINE

Article

Author: Saburo Higuchi ; Kouji Aoyama ; Taisuke Uchida ; Takashi Watanabe

The relationship between bioavailability and the serum cholesterol-lowering effect of YM17E, an ACAT inhibitor was investigated. Serum cholesterol levels in cholesterol-fed rats decreased after both oral and intravenous administration of YM17E. Marked inhibition of cholesterol absorption was observed after oral administration, but not after intravenous administration. YM17E and its five active metabolites were primarily distributed in the liver after intravenous administration, but in small intestine and liver after oral administration. Hepatic ACAT activity in cholesterol-fed rats was inhibited by intravenous administration. Cholesteryl ester input into plasma by Triton WR-1339 treatment to the rats was inhibited by intravenous administration of YM17E. Plasma clearance of 125I-LDL in cholesterol-fed rats increased after YM17E treatment suggesting a decrease in LDL production. These results indicate that the hypocholesterolemic effect of intravenous YM17E was due to hepatic ACAT inhibition, not an inhibition of intestinal cholesterol absorption. The contribution of ACAT inhibition in small intestine and liver on the pharmacological effect could be explained by plasma inhibitor concentration after oral or intravenous administration of YM17E. From these results, it is concluded that the change in bioavailability of ACAT inhibitors change the mechanism of hypocholesterolemic effects, shifting the relative contributions of small intestinal and hepatic ACAT inhibition.

01 Jan 1998·Japanese Journal of Pharmacology

Effects of F-1394, an Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitor, on ACAT Activity in HepG2 Cells and on Hepatic Secretion of Lipids in Triton WR-1339-Induced Hyperlipidemic Rats: Possible Role of Hepatic ACAT in Very Low Density Lipoprotein Secretion

Article

Author: Katsumi Aragane ; Jun Kusunoki ; Tetsuaki Yamaura ; Haruo Ohnishi ; Tetsuya Kitamine

We examined the inhibitory potency of F-1394 ((1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane -1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity and its hypolipidemic effect. F-1394 inhibited whole-cell ACAT activity in HepG2 cells with an IC50 value of 42 nM. The potency of F-1394 was greater than that of the five other ACAT inhibitors tested (YM-17E, CI-976, 57-118, CL-277,082 and DL-melinamide). In rats made hyperlipidemic by Triton WR-1339, F-1394 caused a reduction in the hepatic secretion rate of cholesterol. These data suggest that inhibition of hepatic ACAT activity helps to reduce very low density lipoprotein secretion from the liver into the circulation.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 1	JP	Yamanouchi Pharmaceutical Co. Ltd. /Over-the-Counter Phar Bus	-
Hyperlipidemias	Phase 1	-	Astellas Pharma, Inc.	-

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