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Biomedical subjects

G C Ness

Publications and source records attributed to G C Ness.

At least 37 records · Page 2Linked to original sources
PubMed1995

Transcriptional regulation of rat hepatic low-density lipoprotein receptor and cholesterol 7 alpha hydroxylase by thyroid hormone.

Utilizing hypophysectomized and thyroidectomized rats, it is demonstrated that the rapid increase in expression of hepatic low-density lipoprotein (LDL) receptor and cholesterol 7 alpha-hydroxylase in response to thyroid hormone is due to increases in the rates of transcription of these genes. An increase in transcription of the hepatic LDL receptor gene was seen within 30 min after administration of triiodothyronine. The increase in transcription fully accounted for the increase in hepatic LDL receptor protein. Stimulation of transcription of these two genes provides for enhanced removal of LDL from serum and elimination from the body.

Animals↗
PubMed1995

Treatment of the cholesterol biosynthetic defect in Smith-Lemli-Opitz syndrome reproduced in rats by BM 15.766.

BACKGROUND & AIMS: The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurological developmental defects and dysmorphic features with a defect in cholesterol synthesis at the conversion of 7-dehydrocholesterol to cholesterol. BM 15.766 inhibits 7-dehydrocholesterol-delta 7-reductase and reproduces the biochemical defect. The aim of this study was to investigate the effects of cholesterol, cholic acid, and lovastatin feeding on rats fed BM 15.766. METHODS: Plasma cholesterol and 7-dehydrocholesterol concentrations were related to the hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. RESULTS: With the inhibitor treatment, plasma cholesterol concentrations decreased 67%; 7-dehydrocholesterol concentrations increased from trace to 17 mg/dL; and hepatic HMG-CoA reductase activity and messenger RNA levels were stimulated 74% and two times, respectively. In inhibitor-treated rats, feeding cholesterol increased plasma cholesterol concentrations 3.7 times, decreased 7-dehydrocholesterol concentrations 88%, and reduced elevated HMG-CoA reductase activity and messenger RNA levels 74% and 49%. Feeding cholic acid increased plasma cholesterol without reducing 7-dehydrocholesterol concentrations. The combination of cholic acid and cholesterol enhanced plasma cholesterol 9.5 times without decreasing 7-dehydrocholesterol levels. Feeding lovastatin depressed plasma cholesterol further without reducing 7-dehydrocholesterol levels. CONCLUSIONS: Cholesterol is essential to correct abnormal cholesterol synthesis induced by BM 15.766 in rats by expanding the pool and inhibiting HMG-CoA reductase. Neither cholic acid nor lovastatin are effective separately, but cholic acid plus cholesterol may offer some additional benefit.

Acyl Coenzyme A↗
PubMed1995

Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats.

The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurologic developmental defects and dysmorphic features in many organs. Recently, abnormal cholesterol biosynthesis with impaired conversion of 7-dehydrocholesterol to cholesterol has been discovered in homozygotes. To reproduce the biochemical abnormality, BM 15.766, a competitive inhibitor of 7-dehydrocholesterol-delta 7-reductase, the enzyme that catalyzes the conversion of 7-dehydrocholesterol into cholesterol was fed by gavage to rats. After 14 d, plasma cholesterol concentrations declined from 48 mg/dl to 16 mg/dl and 7-dehydro-cholesterol levels rose from trace to 17 mg/dl. Hepatocytes surrounding the central vein developed balloon necrosis. Stimulating cholesterol synthesis with cholestyramine followed by BM 15.766 produced an additional 40% decline (P < 0.05) in plasma cholesterol and 34% increase in 7-dehydrocholesterol levels compared to the inhibitor alone. Adding 2% cholesterol to the diet during the second week of BM 15.766 treatment increased plasma cholesterol threefold and decreased 7-dehydrocholesterol concentrations 55%. Hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity increased 73% with a 3.9-fold rise in mRNA levels but cholesterol 7 alpha-hydroxylase activity decreased slightly though mRNA levels increased 1.4 times with BM 15.766 treatment. These results demonstrate that BM 15.766 is a potent inhibitor of 7-dehydrocholesterol-delta 7-reductase. The model reproduces abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome and is useful to test different treatment strategies. Stimulating early steps of cholesterol synthesis worsens the biochemical abnormalities while feeding cholesterol inhibits abnormal synthesis, improves the biochemical abnormalities and prevents liver damage.

Abnormalities, Multiple↗
PubMed1995

Unexpected inhibition of cholesterol 7 alpha-hydroxylase by cholesterol in New Zealand white and Watanabe heritable hyperlipidemic rabbits.

We investigated the effect of cholesterol feeding on plasma cholesterol concentrations, hepatic activities and mRNA levels of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase and hepatic LDL receptor function and mRNA levels in 23 New Zealand White (NZW) and 17 Watanabe heritable hyperlipidemic (WHHL) rabbits. Plasma cholesterol concentrations were 9.9 times greater in WHHL than NZW rabbits and rose significantly in both groups when cholesterol was fed. Baseline liver cholesterol levels were 50% higher but rose only 26% in WHHL as compared with 3.6-fold increase with the cholesterol diet in NZW rabbits. In both rabbit groups, hepatic total HMG-CoA reductase activity was similar and declined > 60% without changing enzyme mRNA levels after cholesterol was fed. In NZW rabbits, cholesterol feeding inhibited LDL receptor function but not mRNA levels. As expected, receptor-mediated LDL binding was reduced in WHHL rabbits. Hepatic cholesterol 7 alpha-hydroxylase activity and mRNA levels were 2.8 and 10.4 times greater in NZW than WHHL rabbits. Unexpectedly, cholesterol 7 alpha-hydroxylase activity was reduced 53% and mRNA levels were reduced 79% in NZW rabbits with 2% cholesterol feeding. These results demonstrate that WHHL as compared with NZW rabbits have markedly elevated plasma and higher liver cholesterol concentrations, less hepatic LDL receptor function, and very low hepatic cholesterol 7 alpha-hydroxylase activity and mRNA levels. Feeding cholesterol to NZW rabbits increased plasma and hepatic concentrations greatly, inhibited LDL receptor-mediated binding, and unexpectedly suppressed cholesterol 7 alpha-hydroxylase activity and mRNA to minimum levels similar to WHHL rabbits. Dietary cholesterol accumulates in the plasma of NZW rabbits, and WHHL rabbits are hypercholesterolemic because reduced LDL receptor function is combined with decreased catabolism of cholesterol to bile acids.

Alanine Transaminase↗
PubMed1994

Insulin and glucagon modulate hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity by affecting immunoreactive protein levels.

The question of whether the effects of insulin and glucagon on hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity are mediated largely by changes in the phosphorylation state of the enzyme or by changes in the quantity of enzyme protein was investigated by measuring enzyme protein and mRNA levels. If phosphorylation/dephosphorylation is responsible for the observed changes in HMG-CoA reductase activity, one would not expect to see changes in immunoreactive protein or mRNA levels in response to induction of diabetes, administration of insulin, or administration of insulin and glucagon. It was found that hepatic HMG-CoA reductase mRNA levels were decreased to 12% of control in diabetic rats. Immunoreactive protein was reduced to essentially undetectable levels. Administration of insulin restored both mRNA and immunoreactive protein levels. Glucagon blocked these effects. Enzyme activity changes were fully accounted for by changes in HMG-CoA reductase mRNA and immunoreactive protein. Fasting caused parallel falls in HMG-CoA reductase activity and immunoreactive protein levels with a lesser effect on mRNA levels. The insulin-mediated changes in HMG-CoA reductase gene expression correlated well with changes in blood glucose levels, indicating a physiological effect. Taken together, these results indicate that insulin and glucagon regulate HMG-CoA reductase gene expression largely at the level of enzyme protein through changes in mRNA concentrations.

Animals↗
PubMed1994

Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in hypophysectomized rats.

The effects of hypophysectomy and thyroid hormone treatment on the expression of the hepatic LDL receptor gene was studied in young male rats. Hypophysectomy lowered levels of LDL receptor mRNA and protein. It was found that increased levels of LDL receptor mRNA could be detected 30 min after giving hypophysectomized rats an intramuscular injection of 10 micrograms of L-triiodothyronine (T3) per 100 g of body weight. This dose of T3 also increased hepatic LDL receptor protein levels within 1 h. A T3 dose of only 0.25 microgram per 100 g increased LDL receptor mRNA levels more than threefold. The half-life of the hepatic LDL receptor mRNA was found to be about 30 min and was unaffected by T3. The data suggests that thyroid hormone acts physiologically to induce hepatic LDL receptor expression. This action may explain, in part, the hypocholesterolemic effect of the hormone.

Animals↗
PubMed1994

Thyroid hormone rapidly increases cholesterol 7 alpha-hydroxylase mRNA levels in hypophysectomized rats.

The induction of hepatic cholesterol 7 alpha-hydroxylase mRNA by triiodothyronine was investigated in hypophysectomized rats. These rats exhibited markedly decreased levels of cholesterol 7 alpha-hydroxylase mRNA compared to normal controls. An increase in this mRNA could be detected within 30 min after giving triiodothyronine. A triiodothyronine dose of 0.25 microgram per 100 g of body weight, which produces 50% occupancy of hepatic nuclear thyroid hormone receptors, caused significant increases in hydroxylase mRNA levels. The half-life of cholesterol 7 alpha-hydroxylase mRNA was about 30 min and was not affected by thyroid hormone. Administration of the protein synthesis inhibitor, cycloheximide, after triiodothyronine caused superinduction. Hepatic HMG-CoA reductase mRNA levels, which are also low in livers from hypophysectomized rats, were unaffected by these doses of hormone within the 2 h time-frame examined in these studies. The results suggest that thyroid hormone may exert a primary affect on the expression of the hepatic cholesterol 7 alpha-hydroxylase gene. This could explain, in part, the hypocholesterolemic effect of thyroid hormone.

Animals↗
PubMed1994

Developmental regulation of the expression of genes encoding proteins involved in cholesterol homeostasis.

The developmental patterns of expression of HMG-CoA reductase, farnesyl pyrophosphate synthase, cholesterol 7 alpha-hydroxylase, and LDL receptor were investigated using Northern blotting analysis to quantitate mRNA levels. It was found that HMG-CoA reductase and farnesyl pyrophosphate synthase mRNA levels in brain reached peaks at age 4 days which correlates with the time of peak enzyme activity and the onset of rapid brain growth and myelination. In liver, HMG-CoA reductase and cholesterol 7 alpha-hydroxylase mRNA both rose dramatically at weaning. This is consistent with the concept that de novo synthesized cholesterol is the preferred substrate for cholesterol 7 alpha-hydroxylase and may also be involved in the induction of the enzyme. In testes, HMG-CoA reductase activity was highest at age 21 days and then declined, while LDL receptor mRNA levels rose from age 31 to 120 days. These studies suggest a major role for de novo cholesterol synthesis in developing brain, liver, and testes.

Animals↗
PubMed1994

Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression by sterols and nonsterols in rat liver.

The mechanisms by which sterols and nonsterols regulate hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene expression was investigated by measuring mRNA, protein, and enzyme activity in rats fed cholesterol or given drugs that deplete both endogenous sterols and nonsterols or that selectively deplete sterols. It was found that while dietary cholesterol had little effect on HMG-CoA reductase mRNA levels; immunoreactive protein was reduced to barely detectable levels, as was enzyme activity. Any possible effect on catalytic efficiency is thus ruled out. When rats were fed diets containing Lovastatin, a potent HMG-CoA reductase inhibitor which blocks synthesis of both nonsterols and sterols, similar 15- to 20-fold increases were observed for both HMG-CoA reductase mRNA and activity. However, HMG-CoA reductase immunoreactive protein was increased more than 200-fold. When endogenous sterols were selectively depleted by inhibiting squalene synthase with Zargozic acid A, the increase observed in reductase mRNA was similar to that seen in immunoreactive protein and enzyme activity. This is consistent with the concept that endogenous sterols exert their effects at the level of transcription while endogenous nonsterols act at the level of translation. The results suggest that in whole animals, sterols likely act at the level of mRNA while nonsterols exert their regulatory effects at the level of HMG-CoA reductase protein.

Animals↗
PubMed1994

Effect of squalene synthase inhibition on the expression of hepatic cholesterol biosynthetic enzymes, LDL receptor, and cholesterol 7 alpha hydroxylase.

Squalene synthase catalyzes the committed step in the biosynthesis of sterols. Treating rats with zaragozic acid A, a potent inhibitor of squalene synthase, caused marked increases in hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, HMG-CoA reductase, squalene synthase, and LDL receptor mRNA levels. The increase in HMG-CoA reductase mRNA fully accounted for the increases seen in enzyme protein and activity. Farnesyl pyrophosphate synthase mRNA and activity were only slightly increased by zaragozic acid A, while cholesterol 7 alpha hydroxylase mRNA levels were decreased substantially. When rats were pretreated with zaragozic acid A, there was no change in mRNA levels for the cholesterol biosynthetic enzymes or cholesterol 7 alpha hydroxylase upon subsequent treatment with mevalonolactone. Under these same conditions, the enzymatic activity of HMG-CoA reductase was also unaffected. Mevalonolactone treatment reduced the zaragozic acid A-mediated increase in hepatic LDL receptor mRNA levels. Feeding cholesterol eliminated the zaragozic acid A-induced increase in HMG-CoA reductase mRNA levels. These results suggest that inhibition of squalene synthase decreases the level of a squalene-derived regulatory product, resulting in altered amounts of several mRNAs and coordinate increases in HMG-CoA reductase mRNA, protein, and activity. The increase in HMG-CoA reductase gene expression was closely related to the degree of inhibition of cholesterol synthesis caused by zaragozic acid A.

Animals↗
PubMed1994

Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in the rat ileum: effects of bile acids and lovastatin.

We investigated the effects of intestinal bile acid flux, orientation of the 7-hydroxy group, and administration of lovastatin on the regulation of intestinal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity in the rat ileum. HMG-CoA reductase activities in villous and crypt cells from the ileal mucosa were similar, and the study was performed on whole mucosa that contained both cell types. Taurocholate feeding decreased ileal reductase activity 48%, whereas tauroursocholate, the 7 beta-hydroxy epimer of taurocholate, had no effect. Feeding lovastatin (inhibitor of HMG-CoA reductase) stimulated total ileal HMG-CoA reductase activity threefold in washed microsomes, which were dissociated from the inhibitor. However, the proportion of active enzyme in the ileum of lovastatin-fed rats was 50% lower than in controls, whereas there was no change in the percentage of expressed enzyme with bile acid treatments. Interruption of the enterohepatic circulation (bile fistula) increased HMG-CoA reductase activity in the ileum 73%. Duodenal infusion of taurocholate to bile-fistula rats significantly decreased microsomal HMG-CoA reductase activity in the ileal mucosa. In contrast, infusion of the 7 beta-hydroxy epimer tauroursocholate failed to inhibit the derepressed HMG-CoA reductase activity in the ileum of bile-fistula rats. The inhibition of intestinal HMG-CoA reductase activity by taurocholate occurred without accumulation of mucosal cholesterol. Furthermore, the stimulation of total ileal HMG-CoA reductase activity by lovastatin treatment was observed without a decrease in mucosal cholesterol. In summary, the regulation of ileal HMG-CoA reductase activity by the intestinal luminal flux of bile acids is dependent on the orientation of the hydroxyl groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl Coenzyme A↗
PubMed1994

Effects of stimulated growth hormone secretion on age-related changes in plasma cholesterol and hepatic low density lipoprotein messenger RNA concentrations.

Growth hormone (GH) secretion declines during aging. Since GH alters plasma cholesterol (PC) concentrations, it was of interest to determine how GH secretagogues affect age-related hypercholesterolemia. Fischer 344 rats (3 and 14 months old) were co-administered (s.c.) GH releasing hormone (3 micrograms/kg; GHRH) and GH releasing hexapeptide (100 micrograms/kg; GHRP) for 120 consecutive days. Aging was associated with a progressive increase in PC, which was reduced in rats administered GHRH and GHRP compared to those administered vehicle, i.e. changes in PC during the study were 26.5 +/- 1.2 mg/dl vs. 40.1 +/- 0.9 mg/dl (P < 0.05) in the younger rats and 17.6 +/- 2.3 mg/dl vs. 31.6 +/- 5.3 mg/dl (P < 0.05) in the older rats, respectively. The lower concentrations of PC in GH secretagogue-treated older rats were associated with higher mean concentrations of hepatic LDL receptor mRNA (1.27 +/- 0.4 vs. 0.4 +/- 0.1; P < 0.05) but not cholesterol 7-alpha hydroxylase mRNA. Although GH secretagogue treatment was also associated with lower plasma cholesterol in the younger rats, it was not accompanied by quantitative changes in mean group concentrations of hepatic LDL receptor mRNA. Instead, daily administration of GHRH and GHRP in the younger rats correlated with a significant reciprocal relationship (P < 0.05) between PC and hepatic LDL receptor mRNA for individual group members. The results of this study suggest that reduced GH secretion during aging contributes, at least in part, to a progressive increase in plasma cholesterol that can be partially prevented with GH secretagogues. Furthermore, the effects on PC may result from GH-mediated, qualitative and quantitative changes in hepatic LDL receptor mRNA that increase receptor-mediated cholesterol clearance.

Aging↗
PubMed1994

The effect of increased hepatic sitosterol on the regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol 7 alpha-hydroxylase in the rat and sitosterolemic homozygotes.

We investigated hepatic cholesterol homeostasis in four homozygous sitosterolemic subjects from two unrelated families who showed enhanced absorption, diminished removal and increased tissue and plasma concentrations of sitosterol (24-ethyl cholesterol). Measurements of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were correlated with steady state messenger RNA levels and related to cholesterol 7 alpha-hydroxylase activities in the sitosterolemic homozygotes and nine controls. Similar determinations were made in rats infused intravenously with sitosterol so that hepatic and plasma sitosterol concentrations increased to about 10% of total sterols to resemble the human disease sitosterolemia. In the four sitosterolemic homozygotes, hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were markedly reduced (12% of normal), and steady state 3-hydroxy-3-methylglutaryl coenzyme A reductase messenger RNA levels barely detected. In contrast, hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities and messenger RNA levels were not decreased in rats with similarly elevated hepatic sitosterol concentrations. However, hepatic cholesterol 7 alpha-hydroxylase activity was inhibited 30% in both the sitosterolemic homozygotes and rats with high liver sitosterol concentrations. Plasma cholesterol concentrations increased 120% in the sitosterol-infused rats and 29% in the untreated human homozygotes. These results demonstrate that high-tissue sitosterol concentrations do not inhibit hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activityor steady state messenger RNA levels and that they competitively block cholesterol 7 alpha-hydroxylase activity and raise plasma cholesterol levels. Thus the deficiency of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the liver of sitosterolemic homozygotes is inherited and not due to the hepatic accumulation of sitosterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Inverse relationship between plasma cholestanol concentrations and bile acid synthesis in sitosterolemia.

We investigated the relationship between plasma cholestanol (5 alpha-dihydrocholesterol) concentrations and the activity and mRNA levels of cholesterol 7 alpha-hydroxylase, the rate-controlling enzyme for bile acid synthesis, in three female sitosterolemic homozygotes. In this lipid storage disease, large amounts of plant sterols and cholestanol accumulate because of hyperabsorption and endogenous synthesis, respectively. Plasma cholestanol concentrations were 14 times greater in the three sitosterolemic homozygotes than the mean for five control subjects. To investigate the cholestanol biosynthetic pathway, tracer doses of two putative precursors, [1,2-3H]4-cholesten-3-one and [4-14C]7 alpha-hydroxycholesterol were injected intravenously into a homozygote, and radioactivity was sought in cholestanol, bile acids, cholesterol, and sitosterol fractions isolated from plasma and bile. Tritium was concentrated only in cholestanol; neither cholesterol, sitosterol nor bile acids were derived from [1,2-3H]4-cholesten-3-one. In contrast, bile acids were labeled exclusively with 14C from [4-14C]7 alpha-hydroxycholesterol; no 14C radioactivity was detected in cholestanol. Mathematical analysis of specific activity versus time curves for [3H]cholestanol revealed very slow decay, large exchangeable pools, and enhanced synthesis in the sitosterolemic homozygote. Measurements of cholesterol 7 alpha-hydroxylase activity were 39% lower in whole liver microsomes from three sitosterolemic homozygotes that contained 19% plant sterols as compared to the mean value for six control microsomal specimens that contained 0.1% plant sterols. Removal of the excess plant sterols from the microsomes, in vitro, normalized microsomal cholesterol 7 alpha-hydroxylase activity in the homozygotes but did not affect enzyme activity in the controls. Equal amounts of cholesterol 7 alpha-hydroxylase mRNA were detected in the livers of both control and sitosterolemic subjects. Bile acid malabsorption after ileal bypass surgery stimulated cholesterol 7 alpha-hydroxylase activity 78% in sitosterolemic whole liver microsomes and reduced plasma cholesterol, sitosterol, and cholestanol levels 61%, 55% and 91%, respectively, producing a pronounced decrease in the cholestanol/cholesterol ratio without changing the sitosterol/cholesterol ratio. These results demonstrate that increased cholestanol is synthesized from 4-cholesten-3-one and not 7 alpha-hydroxycholesterol in sitosterolemia. Enhanced pools and plasma concentrations are related inversely to hepatic cholesterol 7 alpha-hydroxylase activity. Competitive inhibition of cholesterol 7 alpha-hydroxylase by the large microsomal plant sterol pool diverts cholesterol into cholestanol. Alternatively, stimulating cholesterol 7 alpha-hydroxylase activity after ileal bypass surgery markedly diminished plasma cholestanol levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Different feedback regulation of hepatic cholesterol and bile acid synthesis by glycodeoxycholic acid in rabbits.

BACKGROUND: To explore the sexual difference in the feedback regulation of hepatic bile acid synthesis, glycodeoxycholic acid (GDCA) was administered to 15 male and 14 female rabbits. METHODS: After bile diversion, GDCA equivalent to the hepatic bile acid influx was infused intraduodenally. Biliary cholic acid output represented bile acid synthesis. Hepatic 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase activities and steady state messenger RNA (mRNA) levels were determined. RESULTS: GDCA inhibited bile acid synthesis less in female than in male rabbits. Hepatic HMG-CoA reductase activity decreased 39% in males, but increased 48% in females. Hepatic cholesterol 7 alpha-hydroxylase activity decreased similarly in males and females, and mRNA levels decreased 86% in males but were unchanged in females. CONCLUSIONS: (1) Total bile diversion stimulated both hepatic cholesterol and bile acid synthesis by activating the rate-controlling enzymes and increasing mRNA levels. (2) GDCA decreased mRNA levels of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase in males, but mRNA levels did not decrease in females. (3) Bile acid synthesis was sustained in females because continued biosynthesis of cholesterol provided a substrate for cholesterol 7 alpha-hydroxylase and stimulus for enzyme formation.

Animals↗
PubMed1992

Glycocholic acid and glycodeoxycholic acid but not glycoursocholic acid inhibit bile acid synthesis in the rabbit.

Feedback regulation of derepressed hepatic bile acid biosynthesis was studied individually with glycocholic, glycodeoxycholic, and glycoursocholic acids by infusion into bile acid-depleted rabbits. Construction of a bile fistula drained the endogenous bile acid pool (90% glycodeoxycholic acid, 10% glycocholic acid) within 24 hours and elicited maximal bile acid synthesis after about 72 hours, at which time glycocholic acid became the only biliary bile acid (greater than 98%). Replacement of the bile acid pool with glycocholic acid or glycodeoxycholic acid at a rate equivalent to the hepatic endogenous bile acid flux inhibited endogenous biosynthesis by 40%. In contrast, glycoursocholic acid, the 7 beta-hydroxy epimer of glycocholic acid, failed to suppress synthesis. Hepatic bile acid depletion increased hydroxymethyglutary coenzyme A (HMG-CoA) reductase activity fourfold and cholesterol 7 alpha-hydroxylase activity threefold, which were reduced 48% and 51%, respectively, from their maximum levels during replacement with glycocholic acid. Glycodeoxycholic acid infusion depressed cholesterol 7 alpha-hydroxylase activity by 59% without reducing HMG-CoA reductase activity significantly. There was no significant change in the activity of either enzyme during glycoursocholic acid infusion. Biliary cholesterol and cholestanol secretion declined 13% and 53%, respectively, during glycocholic acid infusion, were not affected by glycodeoxycholic acid infusion, but increased 19% and 43%, respectively, during glycoursocholic acid infusion. These results show that in rabbits the feedback regulation of hepatic bile acid synthesis depends on the hepatic flux of the normally present endogenous bile acids glycocholic acid and glycodeoxycholic acid but does not respond to the 7 beta-hydroxy glycoursocholic acid. Glycocholic acid inhibits both HMG-CoA reductase and cholesterol 7 alpha-hydroxylase while glycodeoxycholic acid affects primarily cholesterol 7 alpha-hydroxylase. Thus, the regulation of bile acid synthesis may be mediated by both the availability of cholesterol substrate and the activity of the rate-determining enzyme for bile acid synthesis.

Animals↗