Cholesterol metabolism. Effect of 26-thiacholesterol and 26-aminocholesterol, analogues of 26-hydroxycholesterol, on cholesterol synthesis and low-density-lipoprotein-receptor binding

Miao, Edward A.; Wilson, Steve; Javitt, Norman B.

doi:10.1042/bj2551049

Cited by 14 publications

(10 citation statements)

References 23 publications

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“…The effect of 7␣-hydroxycholesterol in the regulation of the LDLR is even less clear, with previous effects clearly dependent on oxysterol cellular concentration (29,31). These results suggest a differential effect of 7␣-hydroxycholesterol on HMGR and LDLR regulation.…”

Section: Discussionmentioning

confidence: 80%

Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis

Pandak¹,

Schwarz²,

Hylemon

et al. 2001

American Journal of Physiology-Gastrointestinal and Liver Physi

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The initial and rate-limiting step in the classic pathway of bile acid biosynthesis is 7alpha-hydroxylation of cholesterol, a reaction catalyzed by cholesterol 7alpha-hydroxylase (CYP7A1). The effect of CYP7A1 overexpression on cholesterol homeostasis in human liver cells has not been examined. The specific aim of this study was to determine the effects of overexpression of CYP7A1 on key regulatory steps involved in hepatocellular cholesterol homeostasis, using primary human hepatocytes (PHH) and HepG2 cells. Overexpression of CYP7A1 in HepG2 cells and PHH was accomplished by using a recombinant adenovirus encoding a CYP7A1 cDNA (AdCMV-CYP7A1). CYP7A1 overexpression resulted in a marked activation of the classic pathway of bile acid biosynthesis in both PHH and HepG2 cells. In response, there was decreased HMG-CoA-reductase (HMGR) activity, decreased acyl CoA:cholesterol acyltransferase (ACAT) activity, increased cholesteryl ester hydrolase (CEH) activity, and increased low-density lipoprotein receptor (LDLR) mRNA expression. Changes observed in HMGR, ACAT, and CEH mRNA levels paralleled changes in enzyme specific activities. More specifically, LDLR expression, ACAT activity, and CEH activity appeared responsive to an increase in cholesterol degradation after increased CYP7A1 expression. Conversely, accumulation of the oxysterol 7alpha-hydroxycholesterol in the microsomes after CYP7A1 overexpression was correlated with a decrease in HMGR activity.

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Section: Discussionmentioning

confidence: 80%

Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis

Pandak¹,

Schwarz²,

Hylemon

et al. 2001

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…; twice in the same solvent system). 2H2O (99.6 %) was purchased from Merck Stable Isotopes, St. Louis, MO, U.S.A. Hep G2 cells were a gift from Dr. Barbara Knowles of the Wistar Institute, Philadelphia, PA, U.S.A. Materials for maintenance of the cell line in our facility have been described previously [4].…”

Section: Experimental Materialsmentioning

confidence: 99%

Cholesterol and bile acid synthesis in Hep G2 cells. Metabolic effects of 26- and 7 α-hydroxycholesterol

Javitt

Budai

1989

Biochemical Journal

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1. Using a human hepatoma (Hep G2) cell line that continually synthesizes 3 beta-hydroxy-5-cholenoic acid, lithocholic acid, chenodeoxycholic acid and cholic acid we have determined the metabolism and biological effects of 26-hydroxycholesterol and 7 alpha-hydroxycholesterol. 2. Addition of 26-hydroxycholesterol to the medium (6 microM) downregulated cholesterol and chenodeoxycholic acid synthesis. 3. The predominant metabolite of 26-hydroxycholesterol was 3 beta-hydroxy-5-cholenoic acid. 4. Cholesterol synthesis was not affected by the addition of 7 alpha-hydroxycholesterol (6 and 12 microM). The predominant metabolite of 7 alpha-hydroxycholesterol was chenodeoxycholic acid. 5. In Hep G2 cells 7 alpha-hydroxylation of 26-hydroxycholesterol is not well expressed.

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“…The shorter periods of incubation with oxysterols required to achieve 50% i~ibition of LDL uptake and degradation could reflect a different rate of diffusion has been recently reported [21] than an analogue of into the cell. In fact cholesterol has to equilibrate with 27-hydroxycholesterol, 26aminocholestero1, that has a large membrane pool (about 90% of total cellular the same polarity of 27-hydroxycholesterol, possesses a cholesterol) and must increase the cellular free cholestsimilar ability in regulating cellular cholesterol homeoerol content before eliciting its effect on the expression stasis.…”

Section: Resultsmentioning

confidence: 90%

“…On the contrary another analogue, 26&a-of the genes regulating the synthesis of both LDL-recepcholesterol, which is less polar than 27-hytor and HMG-CoA reductase [l]. Moreover, cholestdroxycholesterol and 26-aminocholesterol, is less effecerol is less polar than its oxygenated derivatives and it tive in suppressing the expression of LDL-receptor [21]. These results suggest that sterol polarity could be more important than the presence of an oxygenated function on the molecule.…”

Section: Resultsmentioning

confidence: 99%

“…These data suggest that the physiological regulator of cholesterol homeostasis is likely to be an oxygenated cholesterol species formed in a cytochrome P,,,-catalyzed reaction. 25-Hydroxycholesterol and 27-hydroxycholesterol are among the most potent inhibitors of the HMO-CoA reductase [ 1 3 and, in addition, they decrease the receptor-mediated uptake and degradation of low density ~~prote~~ in cultured cells [17,[20][21][22], thus interfering with both the endogenous and exo~nous supply of cholesterol to the cells. 2% Hydroxyeholesterol seems to be an autoxidation product of cholesterol and its presence in vivo is disputed .…”

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confidence: 99%

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27‐Hydroxycholesterol modulation of low density lipoprotein metabolism in cultured human hepatic and extrahepatic cells

et al. 1993

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-Hydr~xych~~~tero~*~, 25-hy~oxycholesterol and choiesterol suppressed LDL uptake and degradation in human extrahepatic and hepatic cell lines in a concentrationdependent manner. Cholesterol was the least potent, and the inhibitory et&ct of oxysterols was more pronounced in skin fibroblasts and in endothelial cell line EAhy 926 than in hepatoma HepG2 cells. Shorter incubations were required for oxysterols to achieve 50% inhibition of LDL uptake and degradation in all cultured cells. The inhibition of LDL catabolism in extrahepatic cells by 27.hydroxycholesterol occurred at concentrations close to those observed in human plasma (0.2-0.6 PM). The results support a possible role of 27-hydroxycholesterol, a physiological oxysterol, in the regulation of cellular cholesterol homeostasis in non-hepatic tissues.

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Cholesterol metabolism. Effect of 26-thiacholesterol and 26-aminocholesterol, analogues of 26-hydroxycholesterol, on cholesterol synthesis and low-density-lipoprotein-receptor binding

Cited by 14 publications

References 23 publications

Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis

Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis

Cholesterol and bile acid synthesis in Hep G2 cells. Metabolic effects of 26- and 7 α-hydroxycholesterol

27‐Hydroxycholesterol modulation of low density lipoprotein metabolism in cultured human hepatic and extrahepatic cells

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