Rat‐Liver Cholesterol 7α‐Hydroxylase

Gielen, Jacques; J, Van Cantfort; Robaye, B; Renson, J

doi:10.1111/j.1432-1033.1975.tb02136.x

Cited by 72 publications

(24 citation statements)

References 34 publications

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“…Previous studies have also reported that the diurnal rhythm of C7␣OH activity is attenuated or abolished in Hx rats (42,43). This finding could not be confirmed in the present study, however.…”

Section: Discussioncontrasting

confidence: 57%

Growth hormone and bile acid synthesis. Key role for the activity of hepatic microsomal cholesterol 7alpha-hydroxylase in the rat.

Rudling

Parini²,

Angelin³

1997

J. Clin. Invest.

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Growth hormone (GH) has an important role in the regulation of hepatic LDL receptor expression and plasma lipoprotein levels. This investigation was undertaken to characterize the effects of GH on hepatic cholesterol and bile acid metabolism in the rat.In hypophysectomized (Hx) rats, the activities of the ratelimiting enzymes in cholesterol and bile acid biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) and cholesterol 7 ␣ -hydroxylase (C7 ␣ OH), were reduced by 71 and 64%, respectively. HMG CoA reductase mRNA levels were reduced by 37%, whereas C7 ␣ OH mRNA was increased by 81%. LDL receptor expression was reduced by 18% in Hx rats, without any change in the LDL receptor mRNA levels. Although the normal diurnal variation of C7 ␣ OH activity was preserved in Hx rats, the activity of C7 ␣ OH was much reduced both at midday and midnight. Total hepatic cholesterol was increased by 14% in Hx animals whereas microsomal cholesterol was unchanged. The rate of cholesterol esterification was enhanced (by 38%) in liver microsomes from Hx rats.Stepwise hormonal substitution of Hx rats showed that GH, but not thyroid hormone or cortisone, was essential to normalize the enzymatic activity of C7 ␣ OH. GH also normalized the altered plasma lipoprotein pattern in Hx rats, and increased the fecal output of bile acids. The latter effect was particularly evident when GH was combined with cortisone and thyroid hormone. Also in normal rats, GH stimulated C7 ␣ OH activity.In conclusion, GH has an essential role to maintain a normal enzymatic activity of C7 ␣ OH, and this, at least in part, explains the effects of GH on hepatic cholesterol metabolism. GH is also of critical importance to normalize the al-

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Section: Discussioncontrasting

confidence: 57%

Growth hormone and bile acid synthesis. Key role for the activity of hepatic microsomal cholesterol 7alpha-hydroxylase in the rat.

Rudling

Parini²,

Angelin³

1997

J. Clin. Invest.

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“…Cholesterol 7a-hydroxylase is different from most of the liver microsomal mixed-function oxidases in certain aspects. For example it exhibits a marked diurnal rhythm in a similar way to hydroxymethylglutaryl-CoA reductase [9]. The interruption of the enterohepatic circulation of bile salts by the establishment of a total biliary fistula, or the oral administration of a bile salt-sequestering agent such as cholestyramine causes a several-fold increase in cholesterol 7a-hydroxylase activity without causing any change in the total hepatic Etzzymes.…”

mentioning

confidence: 99%

Cholesterol 7α‐Hydroxylase of Rat Liver

Ozasa

Boyd

1981

European Journal of Biochemistry

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1. Cytochrome P-450 was prepared from the liver microsomes of cholestyramine-fed rats by solubilisation with the non-ionic detergent Nonidet P42 followed by chromatography on a DEAE-cellulose column and on hydroxyapatite. NADPH -cytochrome P-450 reductase was prepared by a technique of affinity column chromatography using 2',5'ADP Sepharose.2. The activity of cholesterol 7a-hydroxylase was measured in a reconstituted system of microsomal mixedfunction oxidase containing cytochrome P-450 and NADPH -cytochrome P-450 reductase from rat liver plus cholesterol and NADPH. Endogenous cholesterol was largely depleted from the enzyme preparations by the treatment of the microsomes with cold n-butmollacetone.3. The reconstituted system of mixed-function oxidase catalysed a highly effective and specific 7a-hydroxylation of cholesterol. The reconstituted system showed a higher activity of cholesterol 7a-hydroxylase than was observed in native liver microsomes. The reconstituted system had an absolute requirement for cytochrome P-450, NADPHcytochrome P-450 reductase and NADPH.4. The apparent K,,, for cholesterol in the reconstituted system was 15pM and the V was 1.4nmol 7a-hydroxycholesterol formed min-(nmol cytochrome P-450)-5. The reconstituted system also catalysed the 7a-hydroxylation of taurodeoxycholic acid, the 7a-hydroxylation of 26-norcholesterol and to a limited degree the 12a-hydroxylation of cholest-4-ene-3-one-7a-ol. The ability of this reconstituted system to effect these two 7a-hydroxylation reactions and the 12a-hydroxylation reaction was significantly less than the ability of the system to 7a-hydroxylate cholesterol.

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“…Compared to the enzyme apparent K,,, (110 x M) [8,35] the apparent Ki for pregnenolone (80 x M) pregnenolone acetate (60 x M), 7-dehydrocholesterol (25 x M) and 7-oxocholesterol (7 x M) demonstrated that these molecules have a stronger affinity for the enzyme than the theoretical substrate itself. The fact that other molecules very closely related to cholesterol, like most of its esters or the main biliary acids, do not inhibit significantly cholesterol 7a-hydroxylase, suggests that (a) the enzyme active site has very specific structural requirements, (b) certain steroids in low concentration might play a role in the regulation of the enzyme, (c) hormonal steroids endogenously produced or administered for a therapeutic effect could interfere with cholesterol metabolism.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol 7 α‐Hydroxylase

Cantfort

Gielen

1975

European Journal of Biochemistry

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70% of the microsome‐bound cholesterol is directly accessible to cholesterol 7α‐hydroxylase in an assay in vitro. After 5 min of incubation this endogenous cholesterol makes a single pool with the exogenously added substrate and modifies its specific radioactivity. Thus, an accurate estimation of the enzymic activity should take the participation of endogenous cholesterol into account. Cholesterol 7α‐hydroxylase activity is enhanced in vitro by thiol‐containing substances like mercaptoethanol, dithiothreitol, or cysteamine. On the contrary, the enzymic activity is inhibited by heavy cations (Hg2+, Pb2+, Cu2+, Zn2+), or −SH‐blocking agents (mersalic acid, p‐chloro‐mercuribenzoic acid). Several steroids are potent inhibitors (Ki < Km) of the enzyme, among them pregnenolone and its acetate derivative and the cholesterol closely related 7‐oxocholesterol and 7‐dehydrocholesterol. The cholesterol esters are neither substrates nor inhibitors of cholesterol 7α‐hydroxylase. Only a high concentration (1 mM) of biliary acids or of their glyco or tauro derivatives inhibits cholesterol 7α‐hydroxylase. The quantitatively less important lithocholic acid and deoxycholic acid are the strongest inhibitors; the most common cholic acid does not affect the enzymic activity even at 1 mM.

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Rat‐Liver Cholesterol 7α‐Hydroxylase

Cited by 72 publications

References 34 publications

Growth hormone and bile acid synthesis. Key role for the activity of hepatic microsomal cholesterol 7alpha-hydroxylase in the rat.

Growth hormone and bile acid synthesis. Key role for the activity of hepatic microsomal cholesterol 7alpha-hydroxylase in the rat.

Cholesterol 7α‐Hydroxylase of Rat Liver

Cholesterol 7 α‐Hydroxylase

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