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C Einarsson

Publications and source records attributed to C Einarsson.

28 records · Page 2Linked to original sources
PubMed1999

Thyroid hormone suppresses hepatic sterol 12alpha-hydroxylase (CYP8B1) activity and messenger ribonucleic acid in rat liver: failure to define known thyroid hormone response elements in the gene.

Sterol 12alpha-hydroxylase (CYP 8B1) is a microsomal cytochrome P450 enzyme involved in bile acid synthesis that is of critical importance for the composition of bile acids formed in the liver. Thyroidectomy of rats caused a more than twofold increase of CYP8B1 and an almost fourfold increase of the corresponding mRNA levels compared to sham-operated rats. Treatment of intact rats with thyroxine caused a 60% reduction of enzyme activity and a 50% reduction of mRNA levels compared to rats injected with saline only. To investigate whether the promoter of the gene contains thyroid hormone response elements, the complete structure of the rat gene was defined. In similarity with the corresponding gene in mouse, rabbit and man, the rat gene was found to lack introns. It had an open reading frame containing 1500 bp corresponding to a protein of 499 amino acid residues. Although thyroid hormone decreased CYP8B1 activity and mRNA in vivo, no hitherto described thyroid hormone response elements were identified 1883 bases upstream of the transcription start site. It is concluded that rat CYP8B1 is regulated by thyroid hormone at the mRNA level. The results are discussed in relation to the structure of the gene coding for the enzyme.

Amino Acid Sequence↗
PubMed1999

Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol 7alpha-hydroxylase activity.

UNLABELLED: Hillebrant C-G, Nyberg B, Angelin B, Axelson M, Björkhem I, Rudling M, Einarsson C (Huddinge University Hospital and Karolinska Hospital, Karolinska Institute, Stockholm, Sweden). Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol 7alpha-hydroxylase activity. J Intern Med 1999; 246: 399-407. OBJECTIVES: Based on animal studies, hydrophobic bile acids have been postulated to be particularly strong inhibitors of bile acid synthesis. The present study was undertaken to characterize in humans the effects of one of the most hydrophobic of the common bile acids, deoxycholic acid (DCA), on the transcriptional regulation and activity of the cholesterol 7alpha-hydroxylase, on hepatic cholesterol metabolism and on biliary lipid metabolism and plasma lipids. DESIGN, SUBJECTS AND SETTINGS: Thirteen patients with cholesterol gallstone disease were treated with DCA (750 mg day-1) for 3 weeks prior to cholecystectomy. Blood samples were collected before and during treatment. At operation, a liver biopsy and gallbladder bile were obtained. Twenty-eight untreated gallstone patients undergoing cholecystectomy served as controls. The study was carried out at a university hospital. RESULTS: Deoxycholic acid comprised 72 +/- 6% (mean +/- SEM) of total biliary bile acids in DCA-treated patients (n = 8), and 21 +/- 2% in the controls (n = 16; P < 0.001). Cholesterol saturation of gallbladder bile averaged 102% in both treated (n = 7) and untreated (n = 16) patients. Cholesterol 7alpha-hydroxylase and HMG CoA reductase activities and mRNA levels were not different between DCA-treated and untreated gallstone patients. The LDL receptor mRNA levels were similar in both groups of patients. Plasma levels of total cholesterol were lowered by 10% upon DCA treatment (P < 0.05). CONCLUSIONS: Treatment with DCA did not significantly affect mRNA levels and activity of hepatic cholesterol 7alpha-hydroxylase or HMG CoA reductase in patients with cholesterol gallstones. There was no effect on the saturation of gallbladder bile, Thus, the present study could not verify that the hydrophobicity of the bile acid pool is a major factor regulating human hepatic cholesterol 7alpha-hydroxylase activity.

Adult↗
PubMed1999

Formation of fatty acid ethyl esters in rat liver microsomes. Evidence for a key role for acyl-CoA: ethanol O-acyltransferase.

Fatty acid ethyl esters have been detected in high concentrations in organs commonly damaged by alcohol abuse and are regarded as being important non-oxidative metabolites of ethanol. The formation of fatty acid ethyl esters (FAEEs) has been ascribed to two enzymic activities, acyl-CoA : ethanol O-acyltransferase (AEAT) and FAEE synthase. In the present study we determined AEAT and FAEE synthase activities in isolated rat liver microsomes and further characterized the microsomal AEAT activity in more detail. The determined AEAT and FAEE synthase activities were found to be similar (about 1.7 nmol.min-1.mg-1). However, the AEAT activity was increased about sixfold by the addition of 250 microm bis-(4-nitrophenyl) phosphate (a serine esterase inhibitor) to the incubation whereas FAEE synthase activity was completely inhibited. p-Hydroxymercuribenzoic acid (a cysteine-reacting compound) also stimulated AEAT activity (about fourfold) but had no effect on FAEE synthase activity. The effects of the inhibitors suggest that the formation of FAEEs by AEAT was severely counteracted by enzymic hydrolysis of the substrate (acyl-CoA) and to a lesser extent the product by serine esterases. dl-Melinamide, a hypocholesterolaemic drug, was found to be a very potent inhibitor of AEAT activity with an IC50 value of about 2.5 microm. Furthermore, we compared the activities of two purified microsomal carboxylesterases, ES-4 and ES-10, and identified ES-4 as the enzyme responsible for hydrolysis of FAEEs. The two carboxyesterases were also tested for FAEE synthase activity, but neither had any detectable activity. Esterase ES-4 was found to have some AEAT activity, but it was low. When measured under optimal conditions without competing hydrolysis the capacity of AEAT is thus considerably higher than FAEE synthase and the results are consistent with an important role for AEAT in the formation of ethyl esters. As the ratio acyl-CoA/non-esterified fatty acids is high under normal conditions, AEAT is probably the most important enzyme in fatty acid ethyl ester formation.

Acyltransferases↗
PubMed1998

The level of 7-dehydrocholesterol in plasma reflects the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the human liver.

Plasma levels of the cholesterol precursor 7-dehydrocholesterol (7-DHC) were compared with activities of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase assayed in liver biopsies from patients undergoing cholecystectomy. Some patients were treated with cholestyramine, deoxycholic acid or chenodeoxycholic acid prior to surgery in order to alter the activity of the enzyme. The median level of 7-DHC and the activity of HMG-CoA reductase in the untreated group were 55 ng/ml and 98 pmol/min/mg protein, respectively. The sterol levels and enzyme activities were increased in patients treated with cholestyramine (85 ng/ml and 439 pmol/min/mg protein) and deoxycholic acid (86 ng/ml and 173 pmol/min/mg protein) and decreased in patients treated with chenodeoxycholic acid (38 ng/ml and 51 pmol/min/mg protein). There was a strong positive correlation (rs=0.75, P<0.0005) between the plasma levels of 7-DHC and the activities of hepatic HMG-CoA reductase in these patients. This correlation was further improved when the plasma levels of 7-DHC were expressed relative to those of cholesterol (rs=0.90, P<0.0001). The results show that the level of 7-DHC in plasma reflects the activity of HMG-CoA reductase in the liver.

Adult↗
PubMed1998

Bile acid synthesis in primary cultures of rat and human hepatocytes.

The regulation of hepatic bile acid formation is incompletely understood. Primary cultures of mammalian hepatocytes offer an opportunity to examine putative regulatory factors in relative isolation. Using rat and human hepatocytes in primary culture, we examined bile acid composition and the expression of the rate-limiting enzyme of formation, cholesterol 7alpha-hydroxylase. Control rat hepatocytes showed a declining bile acid production over 4 days, from 156 +/- 24 ng/mL (67% cholic acid) on day 1 to 55 +/- 11 ng/mL (55% cholic acid) on day 4. In addition to cholic acid, chenodeoxycholic acid, alpha-muricholic acid, and beta-muricholic acid were formed. Treatment with triidothyronine (T3) or dexamethasone alone had no significant effect on bile acid production. A combination of T3 and dexamethasone significantly increased the total bile acid production on day 4 (224 +/- 54 ng/mL) and resulted in a marked change in composition to 23% cholic acid and 77% non-12alpha-hydroxylated bile acids. Control rat hepatocytes had a cholesterol 7alpha-hydroxylase activity of 3.3 +/- 0.6 pmol/mg protein/min after 4 days in culture. Cells treated with the combination of dexamethasone and T3 had an activity of 16.4 +/- 3.6 pmol/mg protein/min. The cholesterol 7alpha-hydroxylase messenger RNA (mRNA) levels, determined by solution hybridization after 4 days of culture, showed results similar to those for the activity data; control cells had 5.3 +/- 0.9 cpm/microg total nucleic acids (tNAs). T3 or dexamethasone-treated cells did not differ from control cells, whereas the combination of T3 and dexamethasone increased the mRNA levels to 20.6 +/- 2.8 cpm/microg tNAs. In human hepatocytes, isolated from donor liver, bile acid formation increased from 206 +/- 79 ng/mL on day 2 to 1490 +/- 594 ng/mL on day 6 and then declined slightly. Cholic acid and chenodeoxycholic acid were formed, constituting about 80% and 20%, respectively. The combined addition of T3 and dexamethasone had a tendency to decrease rather than increase bile acid formation. Also, mRNA levels of the cholesterol 7alpha-hydroxylase increased severalfold in the human hepatocytes from day 2 to day 4 and then declined. The addition of T3 or dexamethasone did not effect the mRNA levels in any consistent way. It is noteworthy that the capacity of the cultured human hepatocytes to produce bile acids was higher than that of cultured rat hepatocytes, in spite of the fact that the production of bile acids in rat liver is 3- to 5-fold higher than that in human liver in vivo. It is also evident that while hormonal factors appear to regulate bile acid synthesis in the rat, no evidence for this was found in human hepatocytes. As the composition of bile acids secreted by human hepatocytes in primary culture closely resembles that found in vivo, this represents a useful model for further studies of the synthesis and regulation of bile acids.

Adolescent↗
PubMed1998

Bile composition in patients with ileal resection due to Crohn's disease.

Patients with Crohn's disease (CD) have an increased risk of developing gallstones, but the mechanisms are unknown. In a previous study, we found a subnormal cholesterol saturation in the bile of patients with short ileal resections due to CD. The aim of this study was to test the hypothesis that (a) CD patients with a long ileal resection have an altered biliary composition and (b) that CD patients with short or long ileal resection have an increased content of bilirubin in their bile. Biliary lipid composition, cholesterol saturation, bile acid pattern, and bilirubin concentration were determined in fasting duodenal bile of 10 CD patients with long ileal resections and in 4 patients with short resections. Ten healthy subjects served as controls. Cholesterol saturation was significantly lower in those CD patients who had a long or short resection compared with the healthy subjects. Bile acid composition in the CD patients was characterized by a significant decrease in the deoxycholic acid fraction and a prominent increase in the ursodeoxycholic acid fraction. The bilirubin concentrations, expressed as micromoles of bilirubin per millimole bile acid, were 45-50% higher in patients who had a long or a short ileal resection compared with healthy controls. Based on these results, CD patients who had had an ileal resection seem not to be at an increased risk of cholesterol gallstone formation but rather at risk of developing pigment stones.

Adult↗
PubMed1998

Ursodeoxycholic acid increased bile flow and affects bile composition in the early postoperative phase following liver transplantation.

Orally given ursodeoxycholic acid (UDCA) has beneficial effects on laboratory parameters in different cholestatic conditions. In order to investigate the effect on early graft function after liver transplantation, 33 patients were randomized to receive either UDCA 15 mg/kg per day or placebo from the 1st postoperative day until 3 months after transplantation. All liver grafts produced bile within 24 h after revascularization. In both groups there was an increasing bile flow each day until day 5 after transplantation. This increase was more pronounced in the UDCA group where the flow on day 2 reached a mean value of 183 +/- 28 ml/day compared to 106 +/- 17 ml/day in the placebo group (P < 0.05). The average daily volume of bile produced during the first 10 days was also found to be higher in the UDCA group compared to the placebo group (242 +/- 20 ml vs 176 +/- 18 ml, P < 0.02). In the UDCA group a significant decrease in total bile acid output between the 5th and 10th postoperative days was found, while in the placebo group the amount of bile acids excreted remained stable over time. The composition of bile differed between the two groups with an increase in the portion of UDCA in the UDCA group from the 2nd postoperative day (25% vs 4.6%, P < 0.0003). The fraction of UDCA then remained high during the whole study period with a peak at day 3 when 38.1 +/- 6.6% of the bile acids consisted of UDCA. In the placebo group, the fraction of UDCA was low from the beginning and diminished further over time. Prophylactic UDCA treatment was found to have a significant positive impact on the ALT level during the 4th and 5th postoperative days, but had no effect on bilirubin or GGT in the early postoperative phase (days 1-10). No differences in cyclosporine requirement were found between the two groups.

Adult↗
PubMed1998

Effects of short-term treatment with pravastatin on the hepatic synthesis of cholesterol and bile acids in gallstone patients.

BACKGROUND: HMG-CoA reductase inhibitors are now the therapy of choice in the treatment of hypercholesterolaemia. The effects of long-term treatment with these substances on plasma lipoproteins, cholesterol metabolism and biliary secretion of lipids have been extensively studied in humans. Much less is known about the effects of short-term treatment. The aim of this study was to determine the time course of the effects of HMG-CoA reductase inhibitors on plasma lipoprotein levels as well as cholesterol and bile acid synthesis in gallstone patients. METHODS: Thirty-six patients undergoing elective cholecystectomy were included in the study. Except for the gallstone disease, these patients were otherwise healthy. Four groups of subjects were treated with the HMG-CoA reductase inhibitor pravastatin (Pravachol), 20 mg twice daily for 12, 24, 48 and 72 h preoperatively. Plasma lipoproteins and plasma levels of lathosterol and 7 alpha-hydroxy-4-cholesten-3-one were determined before initiation of pravastatin treatment and on the morning of the day of the operation, lathosterol reflecting hepatic HMG-CoA reductase activity and 7 alpha-hydroxy-4-cholesten-3-one the activity of cholesterol 7 alpha-hydroxylase, the rate-determining enzyme in bile acid synthesis. RESULTS: All treatment groups displayed a significant decrease in total cholesterol and low-density lipoprotein (LDL)-cholesterol, by about 12% and 17% respectively. Lathosterol was reduced by about 50% in all treatment groups. Of great interest was the finding that 7 alpha-hydroxy-4-cholesten-3-one was unaffected in all treatment groups. CONCLUSION: The results show that short-term pravastatin treatment in gallstone patients rapidly inhibits cholesterol synthesis and lowers plasma LDL-cholesterol levels without effects on bile acid synthesis.

Adult↗