ACAT inhibitor HL-004 accelerates the regression of hypercholesterolemia in stroke-prone spontaneously hypertensive rats (SHRSP): stimulation of bile acid production by HL-004

Murakami, Shigeru; Yamagishi, Izumi; Sato, Masakazu; Tomisawa, Kazuyuki; Nara, Yasuo; Yamori, Yukio

doi:10.1016/s0021-9150(97)00121-4

Cited by 22 publications

(10 citation statements)

References 38 publications

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“…The ACAT inhibitor 58-034, DuP-128, and HL-004 showed an increase in bile acid synthesis in rat and hamster hepatocytes and in HepG2 cell, respectively. [41][42][43] In our study, we investigated the biochemical background to the induction of bile acid synthesis by the ACAT inhibitor avasimibe and showed that this is owing to an increased expression of cholesterol 7␣-hydroxylase both in control cells as well as in cells with a higher cholesterol content owing to the addition of ␤VLDL. Remarkably, avasimibe even enhanced cholesterol 7␣-hydroxylase expression significantly above the level induced by ␤VLDL.…”

Section: Discussionmentioning

confidence: 96%

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat

et al. 1999

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Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors are currently in clinical development as potential lipid-lowering and antiatherosclerotic agents. We investigated the effect of avasimibe (Cl-1011), a novel ACAT inhibitor, on bile acid synthesis and cholesterol 7␣-hydroxylase in cultured rat hepatocytes and rats fed different diets. Avasimibe dose-dependently decreased ACAT activity in rat hepatocytes in the presence and absence of ␤-migrating very low-density lipoproteins (␤VLDL) (by 93% and 75% at 10 mol/L) and reduced intracellular storage of cholesteryl esters. Avasimibe (3 mol/L) increased bile acid synthesis (2.9-fold) after preincubation with ␤VLDL and cholesterol 7␣-hydroxylase activity (1.7-and 2.6-fold, with or without ␤VLDL), the latter paralleled by a similar induction of its messenger RNA (mRNA). Hepatocytes treated with avasimibe showed a shift from storage and secretion of cholesteryl esters to conversion of cholesterol into bile acids. In rats fed diets containing different amounts of cholesterol and cholate, avasimibe reduced plasma cholesterol (by 52% to 71%) and triglyceride levels (by 28% to 62%). Avasimibe did not further increase cholesterol 7␣-hydroxylase activity and mRNA in cholesterol-fed rats, but prevented down-regulation by cholate. Avasimibe did not affect sterol 27-hydroxylase and oxysterol 7␣-hydroxylase, 2 enzymes in the alternative pathway in bile acid synthesis. No increase in the ratio of biliary excreted cholesterol to bile acids was found, indicating that ACAT inhibition does not result in a more lithogenic bile. Avasimibe increases bile acid synthesis in cultured hepatocytes by enhancing the supply of free cholesterol both as substrate and inducer of cholesterol 7␣-hydroxylase. These effects may partially explain the potent cholesterol-lowering effects of avasimibe in the rat. (HEPATOLOGY 1999;30:491-500.)

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Section: Discussionmentioning

confidence: 96%

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat

et al. 1999

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“…To date, most studies have been focused on ACAT, the biosynthetic component of the CE cycle in the liver and most other tissues. Several investigators have used ACAT inhibitors to shift the balance toward net hydrolysis, relying on an unspecified endogenous CE hydrolase to mobilize endogenous CE (30)(31)(32). The resulting increases in FC were associated with decreased activity and mRNA for enzymes of cholesterol biosynthesis and increased activity and mRNA for CYP7A1, the rate-limiting enzyme in the acidic bile acid biosynthetic pathway.…”

Section: Discussionmentioning

confidence: 99%

Over‐expression of hepatic neutral cytosolic cholesteryl ester hydrolase in mice increases free cholesterol and reduces expression of HMG‐CoAR, CYP27, and CYP7A1

Langston

Hylemon

Grogan

2005

Lipids

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Hepatic neutral cytosolic cholesteryl ester hydrolase (hncCEH) is a key enzyme in the regulation of hepatic free cholesterol (FC). In examining the effects of over-expression of this enzyme on cholesterol homeostasis, mice were infected with a recombinant adenovirus construct (AdCEH) of the rat hncCEH cDNA driven by the human cytomegalovirus promoter. Cholesteryl esterase and p-nitrophenylcaprylate (PNPC) esterase activities were measured in liver postmitochondrial supernatants at 1, 3, 7, and 11 d after infection with AdCEH or a control virus expressing beta-galactosidase (AdbetaGAL). The PNPC esterase activity of AdCEH mice peaked threefold higher than controls on day 2, declining on subsequent days. In contrast, cholesteryl esterase peaked eightfold higher than controls on day 3, indicating a shift in substrate selectivity of hncCEH. Hepatic FC peaked at 144% of controls, 7 d postinfection. The mRNAs for cholesterol 7alpha-hydroxylase, sterol 27-hydroxylase, and HMG-CoA reductase decreased to 47, 46, and 58% of controls, respectively, on day 7, coinciding with peak FC concentrations. Coinciding with increased cholesteryl esterase activity, hepatic esterified cholesterol dropped precipitously from day 3 onward, to 11% of controls by day 11. Hepatic TAG levels also declined, consistent with the reported TAG lipase activity of hncCEH. These results demonstrate elevation of FC and depletion of cholesteryl esters by over-expression of hncCEH, which were resistant to compensatory responses by other enzymes of cholesterol homeostasis.

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“…The ACAT activity was measured by the method described by Helgerud et al 38 with minor modification. 39 The reaction mixture included 100 mmol/L potassium phosphate (pH 7.4), 0.5 mg fatty acid-poor bovine serum albumin, 0.1 mmol/L [1-14 C]oleoyl CoA, and 200 lg liver microsomal protein, in a final volume of 0.5 mL. The assay mixture was preincubated at 37°C for 10 min before adding [1-14 C]oleoyl CoA to start the reaction.…”

Section: Assay Of Acatmentioning

confidence: 99%

Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high‐cholesterol‐fed rats

Murakami¹,

Fujita

Nakamura

et al. 2016

Clin Exp Pharma Physio

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This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high-cholesterol-fed rats. Male Sprague-Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high-cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high-cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine-treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine-conjugated bile acids by 61% and decreased glycine-conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine-conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme for bile acid synthesis, by three- and two-fold, respectively. Taurine also decreased the enzymatic activity of acyl-CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine-conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels.

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ACAT inhibitor HL-004 accelerates the regression of hypercholesterolemia in stroke-prone spontaneously hypertensive rats (SHRSP): stimulation of bile acid production by HL-004

Cited by 22 publications

References 38 publications

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat

Over‐expression of hepatic neutral cytosolic cholesteryl ester hydrolase in mice increases free cholesterol and reduces expression of HMG‐CoAR, CYP27, and CYP7A1

Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high‐cholesterol‐fed rats

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