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Biomedical subjects

K Einarsson

Publications and source records attributed to K Einarsson.

At least 91 records · Page 5Linked to original sources
PubMed1989

On the saturation of the cholesterol 7 alpha-hydroxylase in human liver microsomes.

The relationships between cholesterol 7 alpha-hydroxylase activity, pool of free microsomal cholesterol, and degree of substrate saturation of the enzyme were studied in untreated (n = 5), cholesterol-fed (n = 4), and cholestyramine-treated (n = 6) gallstone patients undergoing cholecystectomy. Highly accurate methods based on isotope dilution-mass spectrometry were used for assay of the cholesterol 7 alpha-hydroxylase activity and for determination of the concentration of free cholesterol in the microsomes. The cholesterol-enriched diet increased the cholesterol 7 alpha-hydroxylase activity about twofold. Cholestyramine treatment was associated with a five- to sixfold increase of the cholesterol 7 alpha-hydroxylase activity. The concentration of free microsomal cholesterol remained essentially unchanged. The apparent degree of saturation of the enzyme was calculated to be 85% in the untreated patients, 86% in the cholesterol-fed patients, and 67% in those treated with cholestyramine. A significant negative correlation was obtained between enzyme activity and apparent substrate saturation. It is concluded that the apparent substrate saturation of the cholesterol 7 alpha-hydroxylase in human liver microsomes is high but that availability of cholesterol may limit the enzyme activity to some extent a high bile acid synthesis rates.

Adult↗
PubMed1989

Studies on acyl-coenzyme A: cholesterol acyltransferase activity in human liver microsomes.

The aim of the present study was to characterize the acyl-coenzyme A: cholesterol acyltransferase (ACAT) activity in human liver microsomes. Liver biopsies were obtained from patients undergoing elective cholecystectomy under highly standardized conditions. In 34 patients the enzyme activity of the microsomal fraction averaged 6.6 +/- 0.7 (mean +/- SEM) pmol.min-1.mg protein-1 in the absence of exogenous cholesterol. Freezing of the liver biopsy in liquid nitrogen increased the enzyme activity five- to sixfold. Similarly, freezing of the microsomal fraction prepared from unfrozen liver tissue increased the enzyme activity about twofold. These results may help to explain previous disparate results reported in the literature. The enhanced ACAT activity obtained by freezing was at least partly explained by a transfer of unesterified cholesterol to the microsomal fraction and possibly also by making the substrate(s) more available to the enzyme. Preincubation of the microsomal fraction, prepared from unfrozen liver tissue, with unlabeled cholesterol increased the enzyme activity about fivefold. This finding indicates that hepatic ACAT in humans can also utilize exogenous cholesterol as substrate. Addition of cholesterol to frozen microsomes prepared from unfrozen liver tissue increased the ACAT activity two- to threefold, whereas addition of cholesterol to microsomes prepared from frozen liver tissue did not further increase the enzyme activity. No evidence supporting the concept that ACAT is activated-inactivated by phosphorylation-dephosphorylation could be obtained by assaying the enzyme under conditions similar to those during which the human HMG-CoA reductase is inactivated-activated.

Acyl Coenzyme A↗
PubMed1989

Mechanism of intestinal formation of deoxycholic acid from cholic acid in humans: evidence for a 3-oxo-delta 4-steroid intermediate.

12 alpha-Hydroxy-3-oxo-4-cholenoic acid coupled to an adenosine nucleotide has been shown to be a metabolite of cholic acid in the intestinal anaerobic bacteria, Eubacterium species VPI 12708 (1987. J. Biol. Chem. 262: 4701-4707) and it has been suggested that this may be an intermediate in the conversion of cholic acid into deoxycholic acid. The possibility that the intestinal conversion of cholic acid into deoxycholic acid involves a 3-oxo-delta 4-steroid as an intermediate has been studied in the present work by use of [3 beta-3H]- and [5-3H]-labeled cholic acid. Whole cells as well as cell extracts of Eubacterium sp. VPI 12708 catalyzed conversion of [3 beta-3H] + [24-14C]cholic acid into deoxycholic acid with loss of about 50% of 3H label. When unlabeled chenodeoxycholic acid (20 microM) was added along with [3 beta-3] + [24-14C]cholic acid, then approximately 85% of the [3 beta-3H]-labeled was lost from deoxycholic acid. After administration of the same mixture to two healthy volunteers, deoxycholic acid could be isolated that had lost 81 and 84%, respectively, of the 3H label. Conversion of a mixture of [5-3H]- and [24-14C]labeled cholic acid by the above intestinal bacteria or cell extracts led to loss of 79-94 of the [5-3H] label.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effects of treatment with clofibrate, bezafibrate, and ciprofibrate on the metabolism of cholesterol in rat liver microsomes.

The effects of treatment of rats with clofibrate, bezafibrate, and ciprofibrate on the hepatic metabolism of cholesterol were studied in rat liver microsomes. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity, regulating cholesterol biosynthesis, was unaffected by clofibrate and ciprofibrate and slightly decreased (20%) by bezafibrate. Also cholesterol 7 alpha-hydroxylase activity, governing bile acid biosynthesis, was unaffected by clofibrate and was reduced by 25-30% in the two other groups of rats. A major new finding was that all three fibric acid derivatives reduced ACAT (acyl-coenzyme A:cholesterol acyltransferase) activity, catalyzing the esterification of cholesterol, by 50-70%. The hepatic content of free and esterified cholesterol was determined in the bezafibrate-treated rats. The concentration of microsomal cholesteryl ester was about 60% lower in the treated rats compared to the controls whereas the concentration of total cholesterol was unchanged.

Animals↗
PubMed1989

Evidence that vasoactive intestinal peptide induces ductular secretion of bile in humans.

The effect of intravenously administered vasoactive intestinal polypeptide on bile secretion was studied in 11 patients with complete biliary drainage. After infusion of vasoactive intestinal polypeptide, bile volume increased by 65%. In the 2 patients investigated, the output of bicarbonate increased by approximately 250% and the concentration by 50%-70%. Vasoactive intestinal polypeptide thus caused a bicarbonate-rich choleresis. The output of biliary lipids was not affected by infusion of vasoactive intestinal polypeptide, whereas the concentration decreased by approximately 40%. The canalicular bile flow, measured by the clearance of [14C]erythritol, was not affected by infusion of vasoactive intestinal polypeptide. The choleretic effect of vasoactive intestinal polypeptide thus seems to occur only at the ductular level. The ductular bile flow was calculated to be stimulated threefold to fourfold.

Bicarbonates↗
PubMed1988

Plasma cholesterol esterification rate in hyperlipoproteinaemia: relation to cholesterol elimination.

The present study was undertaken to determine the relationship between plasma lecithin: cholesterol acyl transfer (LCAT) rate and cholesterol and bile acid turnover in hyperlipidaemia. Nineteen healthy controls, 19 patients with hyperlipoproteinaemia (HLP) type IIa and 12 patients with HLP type IV were studied under standardized dietary conditions. Bile acid kinetics was determined with the aid of [14C]labelled cholic acid and chenodeoxycholic acid. In the hyperlipidaemic patients, cholesterol balance was calculated as the sum of bile acid synthesis plus daily faecal excretion of neutral C27 steroids minus dietary intake of cholesterol. The plasma LCAT rate was determined simultaneously. The mean values of bile acid formation, cholesterol balance, and LCAT rate in HLP type IV patients exceeded those in HLP type IIa patients or in the controls. An increased plasma LCAT rate was found among HLP type IV patients with and without evidence of cardiovascular disease. Plasma LCAT rate correlated positively with bile acid formation (Rs = +0.78, p less than 0.01) and cholesterol balance (Rs = +0.88, p less than 0.002) in HLP type IV. No such relationships were obtained in the controls or in HLP type IIa. It is suggested that an increased production and/or flux of VLDL in HLP type IV is linked to an enhanced plasma LCAT rate and to an increased formation and metabolism of cholesterol in the liver.

Bile Acids and Salts↗
PubMed1988

Occurrence of cholesterol monohydrate crystals in gallbladder and hepatic bile in man: influence of bile acid treatment.

The occurrence of cholesterol monohydrate crystals was examined and related to the degree of cholesterol saturation in gallbladder bile and hepatic bile of gallstone (GS) patients (n = 34), gallstone-free (GSF) subjects (n = 33) and GS patients treated with chenodeoxycholic acid (CDCA (n = 7) or ursodeoxycholic acid (UDCA) (n = 11) for 3 weeks prior to cholecystectomy. Twenty-five untreated GS patients (74%) and four UDCA-treated patients (40%) displayed cholesterol crystals in the gallbladder bile. Only two GSF subjects (6%) and none of the CDCA-treated patients had crystals. Half of the patients with crystals in the gallbladder bile had crystals also in the hepatic bile. Cholesterol saturation of the gallbladder bile was higher in GS (142 +/- 15%, mean +/- SEM) than in GSF patients (74 +/- 5%). Saturation was also higher in GS patients with crystals (157 +/- 20%) than in those without crystals (99 +/- 12%). Gallbladder bile was unsaturated in all CDCA- and UDCA-treated patients. The results underline the importance of the degree of cholesterol saturation for the formation of cholesterol crystals. The data also give further support to the concept that the mechanism for inducing gallstone dissolution is different for CDCA and UDCA.

Adult↗
PubMed1988

Mucin in gall bladder bile of gall stone patients: influence of treatment with chenodeoxycholic acid and ursodeoxycholic acid.

The concentration of hexosamine, a marker for mucin, was determined and related to the degree of cholesterol saturation and to the occurrence of cholesterol crystals in gall bladder bile of gall stone patients (n = 40) and gall stone free subjects (n = 25). Ten of the gall stone patients had been treated with chenodeoxycholic acid (CDCA) and eight with ursodeoxycholic acid (UDCA) three to four weeks before cholecystectomy. The hexosamine content was significantly higher in gall stone patients (137 (19) ng/ml, mean (SE) than in gall stone free subjects (83 (9) ng/ml, p less than 0.02). Treatment with CDCA or UDCA decreased cholesterol saturation, but did not significantly affect the hexosamine concentration. There was no difference in hexosamine concentration between gall stone patients with and without cholesterol crystals. The results do not support the hypothesis that the degree of cholesterol saturation is important for the mucin content of gall bladder bile in man. Neither do the data indicate that the formation and occurrence of cholesterol crystals in gall bladder bile from gall stone patients is caused by an increased concentration of mucin. As the studies were conducted on patients who had already had gall stones for several years, however, an effect of mucin in the very early stage of gall stone formation cannot be completely excluded.

Adult↗
PubMed1987

Altered action of glucagon on human liver in type 2 (non-insulin-dependent) diabetes mellitus.

Glucagon may play a role in the metabolic derangements of overt Type 2 (non-insulin-dependent) diabetes mellitus. We therefore have evaluated the early steps in glucagon action by investigating the hormone-sensitive adenylyl cyclase system in liver membranes from seven Type 2 diabetic patients with fasting hyperglycaemia and two-fold elevations in plasma glucagon. The comparison was made with seven control subjects matched for age, sex and body weight. Glucagon receptor binding was almost identical in the two groups. There were, however, marked alterations in the adenylyl cyclase activity in membranes from the diabetic patients. This activity was reduced by 35-50% when compared to control activity. Basal cyclase activity, as well as the activity after stimulation with glucagon or with agents (i.e., sodium fluoride and forskolin) that act beyond the glucagon receptor, was significantly decreased (p less than 0.05, p less than 0.001 respectively). In conclusion, uncontrolled Type 2 diabetes in associated with an over-all loss of responsiveness of the hormone-sensitive adenylyl cyclase in human liver, which apparently results from post-receptor alterations. This change may provide a mechanism for reducing the effect of hyperglycagonaemia in Type 2 diabetes mellitus.

Adenylyl Cyclases↗
PubMed1987

In vitro studies of lipid metabolism in human liver.

To study the regulation of lipid metabolism in human liver, we have developed assay systems for three rate-determining microsomal enzymes of hepatic cholesterol metabolism: 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (regulating cholesterol biosynthesis), cholesterol 7 alpha-hydroxylase (governing bile acid formation), and acyl-CoA:cholesterol acyltransferase (ACAT; rate limiting for cholesterol esterification). In addition, we have obtained an assay for low-density lipoprotein binding to its specific receptor in human liver, and we have studied a possible rate-determining enzymatic step in triglyceride biosynthesis, cytosolic phosphatidic acid phosphatase. These assays allow us to study the effects of metabolic perturbations on hepatic lipid metabolism in humans and thus to evaluate the important role of the liver in lipoprotein synthesis and degradation.

Cholesterol↗
PubMed1987

Spontaneous regression of Budd-Chiari syndrome (hepatic venous occlusion) in a young female.

A case of occlusion of the hepatic veins in an 18-year-old girl is presented. The onset was sudden with massive ascites and markedly impaired general condition. The diagnosis was based on liver biopsy and angiograms of the caval and hepatic veins as well as of the celiac artery. No predisposing factors could be found. The patient was treated conservatively with laparocentesis and diuretics. Clear improvement was seen after two weeks, and after four weeks she had no ascites and could be discharged. All liver function tests were then normalized. After three months, all diuretics could be withdrawn, and in the following 11 years she has remained completely recovered. The case illustrates that also widespread thrombi of the hepatic veins may sometimes rapidly dissolve spontaneously, with apparent total reconstitution of hepatic function. This case is unusual since previously reported cases have had high mortality rates and, in surviving cases, operative procedures or large doses of diuretics have been required to control the ascites.

Adolescent↗
PubMed1987

Biliary lipid metabolism in chronic pancreatitis: influence of steatorrhoea.

Kinetics of [24-14C] cholic acid and [24-14C] chenodeoxycholic acid and biliary lipid composition were determined in patients with chronic alcoholic pancreatitis with (n = 8) and without (n = 8) steatorrhoea. Pool sizes, syntheses and fractional catabolic rates of the two bile acids were not significantly different from corresponding values in healthy controls. Biliary lipid composition was normal in patients without steatorrhoea. Patients with steatorrhoea, on the other hand, had lower cholesterol saturation of bile than corresponding controls. This is probably because of malabsorption of cholesterol.

Adult↗
PubMed1987

The pool of free cholesterol is not of major importance for regulation of the cholesterol 7 alpha-hydroxylase activity in rat liver microsomes.

The relationship between the cholesterol 7 alpha-hydroxylase activity and the pool of free cholesterol in rat liver microsomes was studied under experimental conditions aimed to stimulate (biliary drainage, cholestyramine treatment, and lymphatic drainage) as well as inhibit (chenodeoxycholic acid treatment) bile acid synthesis. Highly accurate methods based on isotope dilution-mass spectrometry were used both for assay of the cholesterol 7 alpha-hydroxylase activity and the concentration of free cholesterol in the microsomes. In the assay of the cholesterol 7 alpha-hydroxylase, only endogenous cholesterol was used as substrate for the enzyme. Under the experimental conditions employed, the concentration of microsomal free cholesterol remained essentially unchanged in spite of a more than 20-fold variation in enzyme activity. It is concluded that the total pool of free cholesterol in the microsomes is not of major regulatory importance for the cholesterol 7 alpha-hydroxylase in rats.

Animals↗
PubMed1987

On the possible use of the serum level of 7 alpha-hydroxycholesterol as a marker for increased activity of the cholesterol 7 alpha-hydroxylase in humans.

The possibility was investigated that the serum level of 7 alpha-hydroxycholesterol can be used as a marker for cholesterol 7 alpha-hydroxylase activity. Six patients with gallstone disease were found to have a mean level of 7 alpha-hydroxycholesterol in serum of 30 +/- 4 ng/ml (mean +/- SEM) as measured by isotope dilution-mass spectrometry, using deuterated 7 alpha-hydroxycholesterol as internal standard. After treatment with cholestyramine in a dose of 8 g twice daily for 2-3 weeks preoperatively, the serum level increased to 128 +/- 20 ng/ml (P less than 0.001). Eight other patients with gallstone disease had a mean level of 7 alpha-hydroxycholesterol in serum of 29 +/- 7 ng/ml. Treatment with chenodeoxycholic acid, 15 mg per kg body weight per day for 3-4 weeks before surgery, decreased the mean level to 20 +/- 7 ng/ml (P greater than 0.05). The activity of the cholesterol 7 alpha-hydroxylase in liver biopsies taken during operation was found to be 38 +/- 5 pmol/min per mg of protein in the group of patients treated with cholestyramine and 1.3 +/- 0.5 pmol/min per mg in the group of patients treated with chenodeoxycholic acid. Liver biopsies from a group of untreated patients (n = 13) had a mean cholesterol 7 alpha-hydroxylase activity of 7.6 +/- 1.5 pmol/min per mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Correlation between serum levels of some cholesterol precursors and activity of HMG-CoA reductase in human liver.

The possibility that the serum concentrations of various cholesterol precursors may reflect the activity of the hepatic HMG-CoA reductase was investigated in humans under different conditions. The serum levels of squalene, free and esterified lanosterol, (4 alpha, 4 beta, 14 alpha-trimethyl-5 alpha-cholest-8, 24-dien-3 beta-ol), two dimethylsterols (4 alpha, 4 beta-dimethyl-5 beta-cholest-8-en-3 beta-ol and 4 alpha, 4 beta-dimethyl-5 alpha-cholest-8, 24-dien-3 beta-ol), two methostenols (4 alpha-methyl-5 alpha-cholest-7-en-3 beta-ol and 4 alpha-methyl-5 alpha-cholest-8-en-3 beta-ol), two lathosterols (5 alpha-cholest-7-en-3 beta-ol and 5 alpha-cholest-8-en-3 beta-ol) and desmosterol (cholest-5, 24-dien-3 beta-ol) were measured in untreated patients (n = 7) and patients treated with cholestyramine (QuestranR, 8 g twice daily for 2-3 weeks, n = 5) or chenodeoxycholic acid (15 mg/kg body weight daily for 3-4 weeks, n = 8) prior to elective cholecystectomy. The activity of the hepatic microsomal HMG-CoA reductase was measured in liver biopsies taken in connection with the operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Combined treatment with cholestyramine and nicotinic acid in heterozygous familial hypercholesterolaemia: effects on biliary lipid composition.

In ten patients with heterozygous familial hypercholesterolaemia, combination therapy with cholestyramine and nicotinic acid was instituted for a minimum of 2 months. During therapy, plasma low-density lipoprotein levels were reduced by 32%, and low-density lipoprotein to high-density lipoprotein ratios by 40%. The cholesterol saturation of fasting gall-bladder bile was reduced by 33% during treatment. We conclude that long-term combination therapy with cholestyramine and nicotinic acid is practically feasible in heterozygous familial hypercholesterolaemia, normalizes plasma cholesterol and low-density lipoprotein levels in many patients, and does not result in unwanted side-effects on biliary lipids. It should therefore be considered as the therapy of choice in this condition.

Adult↗