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Biomedical subjects

S Ewerth

Publications and source records attributed to S Ewerth.

At least 37 records · Page 2Linked to original sources
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

Studies of the human liver insulin receptor in noninsulin-dependent diabetes mellitus.

The insulin binding characteristics and the structural components of the insulin receptor were studied in the purified liver plasma membranes from seven patients with noninsulin-dependent diabetes (NIDDM) and seven control subjects. In comparison to the controls, diabetic subjects had a 65% reduction in plasma insulin levels in response to an oral glucose load. Specific insulin binding by liver membranes from diabetic patients was, however, twofold greater than the binding activity by membranes from control subjects. This alteration resulted largely from an increase in the number of insulin receptors and a modest increase in receptor binding affinity. Holo (nonreduced) receptor species of similar molecular weights were detected by an affinity labeling technique in the two membrane preparations and sulfhydryl reduction demonstrated an insulin binding subunit of 125,000 mol wt. Overall, these results show that the hepatic insulin resistance of NIDDM cannot be explained by a deficiency in insulin binding.

Diabetes Mellitus, Type 2↗
PubMed1986

25-Hydroxylase activity in subcellular fractions from human liver. Evidence for different rates of mitochondrial hydroxylation of vitamin D2 and D3.

25-Hydroxylation of vitamin D2 and D3 was studied in subcellular fractions from human liver, using a technique based on isotope dilution-mass spectrometry. The mitochondrial fraction fortified with isocitrate catalysed 25-hydroxylation of vitamin D3 at a rate of about 10 pmol/mg protein X min. Under the same conditions, the rate of 25-hydroxylation of vitamin D2 was less than 2 pmol/mg protein X min. Crude microsomes fortified with NADPH catalysed 25-hydroxylation of vitamin D3 to a very low extent, and this activity was not linear with the amount of microsomal protein. A higher rate of conversion was obtained with a partially purified cytochrome P-450 fraction in the presence of NADPH-cytochrome P-450 reductase and NADPH. This fraction also catalysed 25-hydroxylation of 1 alpha-hydroxyvitamin D3 and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol. 25-Hydroxylation of vitamin D2 could not be detected, neither with crude microsomes, nor with the microsomal cytochrome P-450 fraction. Since the assay for 25-hydroxyvitamin D2 was less sensitive than that for 25-hydroxyvitamin D3, these experiments do not rule out the presence of some 25-hydroxylase activity towards vitamin D2 in the microsomes. The results are discussed in relation to previous work in which a lower toxicity has been reported for vitamin D2 than for vitamin D3 in some mammalian species.

Cholecalciferol↗
PubMed1986

Bile acid synthesis in man: assay of hepatic microsomal cholesterol 7 alpha-hydroxylase activity by isotope dilution-mass spectrometry.

The present work describes an accurate assay of the rate-limiting enzyme in bile acid synthesis, the cholesterol 7 alpha-hydroxylase, in human liver. The assay is based on isotope dilution-mass spectrometry, and endogenous microsomal cholesterol is used as the only substrate for the enzyme. Operative liver biopsies were obtained from patients undergoing elective cholecystectomy under highly standardized conditions. In ten gallstone patients, the enzyme activity of the microsomal fraction averaged 9.6 +/- 1.4 (mean +/- SEM) pmol X min-1 X mg protein-1 corresponding to a daily synthesis of about 0.5 mmol of bile acids. Three cholestyramine-treated patients displayed a four-fold higher enzyme activity. No evidence was obtained supporting the concept that the cholesterol 7 alpha-hydroxylase is modulated by phosphorylation-dephosphorylation.

Bile Acids and Salts↗
PubMed1985

Serum concentrations of ursodeoxycholic acid in portal venous and systemic venous blood of fasting humans as determined by isotope dilution-mass spectrometry.

The fasting concentrations of ursodeoxycholic acid were determined in peripheral and portal venous serum of untreated (n = 12) and ursodeoxycholic acid-treated (n = 7) patients undergoing cholecystectomy. The levels of ursodeoxycholic acid were also determined in peripheral venous serum of 9 healthy subjects before and during treatment with ursodeoxycholic acid. Ursodeoxycholic acid, as well as cholic, chenodeoxycholic, and deoxycholic acids, were analyzed by a highly specific method based on isotope dilution-mass spectrometry. The fasting peripheral venous serum concentration of total (unconjugated plus conjugated) ursodeoxycholic acid averaged 0.14 mumol/L in the untreated gallstone patients and 0.19 mumol/L in the healthy subjects. The corresponding value in portal venous serum was 0.44 mumol/L. Treatment with ursodeoxycholic acid raised the level of this bile acid about 25-fold in portal as well as in peripheral venous serum. The proportion of unconjugated ursodeoxycholic acid was 34% in portal and 49% in peripheral venous serum of treated subjects. The mean hepatic uptake of ursodeoxycholic acid was calculated to be about 60% both in untreated and treated subjects. This uptake was significantly lower than that of cholic acid (83%). The hepatic uptake of ursodeoxycholic acid also tended to be lower than that of chenodeoxycholic acid (68%). This was mainly due to a lower hepatic uptake of unconjugated ursodeoxycholic acid (34%) compared with unconjugated chenodeoxycholic acid (49%). The relatively low hepatic uptake of unconjugated ursodeoxycholic acid explains why serum levels of the administered bile acid are higher during treatment with ursodeoxycholic acid than during treatment with chenodeoxycholic acid. Our results also give evidence that the hepatic uptake of ursodeoxycholic acid cannot be saturated under physiologic conditions.

Adult↗
PubMed1985

Glucagon receptor of human liver. Studies of its molecular weight and binding properties, and its ability to activate hepatic adenylyl cyclase of non-obese and obese subjects.

The glucagon receptor and the adenylyl cyclase system of human liver membranes were studied in six non-obese and six obese subjects who had elevated insulin and plasma glucagon levels. Analysis of specific glucagon binding by the method of Scatchard demonstrated a linear (monocomponent) plot with a dissociation constant of 2-3 nM, and the binding at low hormone concentrations was sensitive to guanosine triphosphate (GTP). The molecular weight of the glucagon receptor was 63,000 D as determined by an affinity labeling procedure and sodium dodecyl sulfate gel electrophoresis. Affinity labeling of this structure was specific for glucagon and inhibited by GTP. Glucagon stimulated the production of cyclic adenosine monophosphate (cAMP) by human membranes with half-maximal activation elicited by 6 nM hormone. The human cyclase system required GTP to facilitate an optimal glucagon response. NaF (10 mM) also activated the cyclase system and produced the same magnitude of response as maximum glucagon activation. A comparison of the liver adenylyl cyclase system of non-obese and obese subjects was made using glucagon (5 nM and 1 microM) and NaF (10 mM). No significant differences in cAMP production were noted between the two groups, regardless of the agent used to activate the enzyme. These findings agree with the glucagon binding studies that showed similar amounts of binding activity in the membranes from the two groups. Also, there was no influence of either age or sex of the subjects on the adenylyl cyclase response. In conclusion, human liver membranes contain a glucagon receptor and an adenylyl cyclase system that correspond closely to the well-studied system in animal liver. This system in human obesity is not altered by the approximately twofold elevation in plasma glucagon that occurs in this metabolic disorder.

Adenylyl Cyclases↗
PubMed1984

Effect of glucose on beta-adrenergic induced downregulation of insulin receptor binding in human fat cells.

The effect of beta-adrenergic stimulation on specific insulin binding to isolated human fat cells was investigated at 24 degrees C and 37 degrees C. In the absence of glucose isoprenaline caused a 40% decrease in high affinity insulin binding at both temperatures. At 37 degrees C the reduction in binding was completely offset by the addition of glucose to the medium. A maximum effect of glucose occurred at 5 mmol/l. At 24 degrees C, however, there was no effect of glucose on insulin binding. The effects of glucose and isoprenaline on insulin binding were not related to the lipolytic activities these two agents. In conclusion, low amounts of glucose prevent catecholamine induced down-regulation of insulin receptor binding in human fat cells at physiological temperature.

Adipose Tissue↗
PubMed1984

Effect of ursodeoxycholic acid treatment on intestinal absorption of triglycerides in man.

The aim of the present study was to evaluate whether treatment with ursodeoxycholic acid (UDCA) may affect the absorption of dietary fat in man. Fifteen healthy subjects volunteered for the study. They were treated with UDCA in a daily dose of 15 mg/kg body weight for 4 weeks. Before and during treatment fat absorption was measured with a 14C-triolein breath test. In addition, fasting serum bile acids were measured in 11 of the subjects. The maximum specific activity of 14CO2 was not significantly changed during the treatment period. However, the cumulative output of 14CO2 during a 6-h period was decreased by about 25% (p less than 0.03). Several subjects with decreased outputs also lost 1-2 kg of body weight during the study period. UDCA treatment raised the serum level of this bile acid from 0.18 +/- 0.11 mumol/l to 5.98 +/- 1.08 mumol/l. The concentrations of the other bile acids were not significantly changed. It is suggested that UDCA treatment may in some patients be associated with an impaired fat absorption. Whether this effect is of any clinical importance remains to be elucidated.

Adult↗
PubMed1983

Metabolic effects of four intravenous nutritional regimens after elective surgery. I. Clinical data and biochemistry.

Biochemical variables have been determined in 28 patients before and after resection of carcinoma of colon or rectum. A synthetic oral diet was given for four days before operation, (0.1 gN.kg/day and 165 kJ.kg/day) and four isocaloric intravenous regimens with different amounts and proportions of amino acids were given for six days after operation. During the preoperative diet the serum urea, glucose, urate, inorganic phosphate and cholesterol concentration decreased while those of triglyceride, iron and alanine amino-transferase increased. After operation the serum triglyceride, protein, albumin, iron, TIBC and urate concentrations decreased. The serum calcium fell in all groups receiving amino acids after operation while magnesium increased in all groups except the one receiving the highest amount of amino acids. The urea concentration decreased when no amino acids were given but increased when amino acids were administered whereas the reverse situation occurred with cholesterol. The highest increase in glucose level was observed when the highest amount of amino acids were given.

Journal Article↗
PubMed1983

Ursodeoxycholic acid treatment in cholesterol gallstone disease: effects on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, biliary lipid composition, and plasma lipid levels.

The present study was undertaken to characterize the effects of ursodeoxycholic acid on biliary lipid metabolism in man. Fifteen gallstone patients were treated with ursodeoxycholic acid at a daily dosage of 15 mg per kg body weight for about 4 weeks before cholecystectomy. At operation a liver biopsy, together with gallbladder and hepatic bile, were obtained. Eighteen untreated gallstone patients undergoing cholecystectomy served as controls. During treatment with ursodeoxycholic acid, hepatic bile became unsaturated with cholesterol in all patients investigated. The total biliary lipid concentration remained unchanged. The hepatic cholesterol concentration decreased by about 20%. No significant change in the microsomal HMG CoA reductase activity was observed (38.5 +/- 6.7 pmol . min-1 . mg protein-1 vs 38.3 +/- 4.7 pmol . min-1 . mg protein-1 in the controls; means +/- SEM). Plasma concentrations of total cholesterol were reduced by about 10%, and those of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by about 15%. Plasma triglyceride levels remained essentially unchanged during treatment. We conclude that, similar to chenodeoxycholic acid therapy, ursodeoxycholic acid treatment results in unsaturation of fasting hepatic bile. In contrast to the changes seen during chenodeoxycholic acid feeding, however, the unsaturation of hepatic bile during ursodeoxycholic acid treatment is not primarily related to a decreased hepatic HMG CoA reductase activity. Furthermore, while chenodeoxycholic acid tends to increase plasma LDL levels, such changes are not seen during ursodeoxycholic acid treatment.

Adult↗
PubMed1982

Hepatic uptake of bile acids in man. Fasting and postprandial concentrations of individual bile acids in portal venous and systemic blood serum.

This investigation was undertaken in order to (a) characterize the postprandial inflow of individual bile acids to the liver and (b) determine if peripheral venous bile acid levels always adequately reflect the portal venous concentration, or if saturation of hepatic bile acid uptake can occur under physiological conditions. In five patients with uncomplicated cholesterol gallstone disease, the umbilical cord was cannulated during cholecystectomy, and a catheter was left in the left portal branch for 5 to 7 d. The serum concentrations of cholic acid, chenodeoxycholic acid, and deoxycholic acid in portal venous and systemic circulation were then determined at intervals of 15 to 30 min before and after a standardized meal. A highly accurate and specific gas chromatographic/mass spectrometric technique was used. The sum of the fasting concentrations of the three bile acids averaged 14.04+/-4.13 mumol/liter in portal venous serum, and 2.44+/-0.31 mumol/liter in peripheral venous serum. The estimated hepatic fractional uptake of cholic acid was approximately 90%, and those of chenodeoxycholic acid and deoxycholic acid were 70-80%. This resulted in an enrichment of systemic bile acids in the dihydroxy bile acid species. In response to a standardized meal, portal venous bile acid concentrations increased two- to sixfold, with a peak seen 15-60 min after the meal. The maximum postprandial portal venous bile acid concentration averaged 43.04+/-6.12 mumol/liter, and the corresponding concentration in peripheral serum was 5.22+/-0.74 mumol/liter. The estimated fractional uptakes of the individual bile acids were not affected by the increased inflow to the liver. The peripheral venous concentrations of individual as well as total bile acids were well correlated with those in portal venous serum. The results (a) give a quantitation of postprandial bile acid inflow to the liver and (b) indicate that the hepatic uptake system for bile acids in healthy man cannot be saturated during maximal inflow of endogenous bile acids. Measurement of peripheral serum bile acids can thus give important information on the status of the enterohepatic circulation.

Aged↗
PubMed1982

Postprandial serum concentration of individual bile acids in man. Influence of ileal resection.

For the purpose of characterizing the importance of intestinal function in the maintenance of the enterohepatic circulation of individual bile acids, the serum concentrations of cholic acid (C), chenodeoxycholic acid (CD), and deoxycholic acid (D) were determined after a standardized meal. Two groups of subjects were included: 10 healthy controls and 7 patients with ileal resections 20-80 cm long. The bile acid concentrations were determined using a highly specific and accurate gas chromatographic-mass spectrometric technique with the aid of deuterium-labelled internal standards. In patients with ileal resections, only a moderate and early increase was seen in C concentration after a meal, whereas the CD elevation was more pronounced and prolonged. The D concentrations were reduced both after fasting and postprandially. The data indicate that ileal resection results in essentially complete absence of active bile acid resorption and that intestinal uptake via nonionic diffusion is probably dominant, resulting in postprandial rise of mainly CD in serum.

Adult↗
PubMed1982

On the enterohepatic circulation of bile acids in man.

1. Fasting concentrations of C, CD and D were determined in systemic and portal venous serum in gallstone patients and controls (patients with adenomyoma of the gallbladder) undergoing cholecystectomy. No differences were observed between the two groups either in systemic or portal serum concentrations of the bile acids or in their hepatic uptake. Ketonic bile acid concentrations amounted to 9% and 8% of the non-oxidized bile acids in the systemic and portal circulation, respectively. 2. Fasting systemic and portal venous serum concentrations of bile acids were measured in gallstone patients fed with C and CD prior to cholecystectomy. Treatment with CD increased the total portal inflow of bile acids by 60%, whereas C treatment did not alter this total inflow compared with controls. This difference may partly explain why hepatic bile is unsaturated during treatment with CD, but not with C. 3. The postprandial concentrations of bile acids were determined in the systemic and portal venous circulation in cholecystectomized patients. The systemic venous bile acid level reflected the portal venous level. The estimated hepatic uptake of the individual bile acids was highly efficient and could not be saturated during maximal physiological portal inflow to the liver. The existence of a lymphatic transport of bile acids, calculated to correspond to about 0.2% of the portal transport, was demonstrated in four patients undergoing renal transplantation. 4. Cholestyramine treatment was shown to reduce the plasma cholesterol level in patients with familial hypercholesterolaemia without lowering the fasting systemic level of total bile acids. Nor did this treatment reduce the fasting portal inflow of total bile acids. The total bile acid concentration in healthy volunteers during treatment showed a 40% reduction postprandially, but not in the fasting state, indicating that the effect of cholestyramine on hepatic cholesterol metabolism is the consequence of a reduced postprandial inflow of portal bile acids. The effects of the loss of the active site of bile acid absorption on the postprandial serum bile acid pattern were studied in patients with ileal resections. In general, the postprandial response of C was reduced whereas that of CD remained less affected.

Bile Acids and Salts↗
PubMed1982

Cholestyramine treatment reduces postprandial but not fasting serum bile acid levels in humans.

Fasting serum concentrations of cholic acid, chenodeoxycholic acid, and deoxycholic acid were determined in healthy subjects and in patients with familial hypercholesterolemia before and during treatment with cholestyramine. The bile acids were analyzed by a specific isotope-dilution technique by using gas chromatography-mass spectrometry. Cholestyramine treatment did not change the fasting concentration of total bile acids, but the contribution of cholic acid was increased; those of chenodeoxycholic acid and deoxycholic acid were decreased. No decrease of fasting bile-acid concentrations in portal venous serum was seen in 2 cholestyramine-treated gallstone patients. The postprandial total bile-acid concentration was about 40% lower during cholestyramine treatment in healthy subjects, reflecting a reduced postprandial inflow of bile acids to the liver. This degree of interruption of the postprandial enterohepatic circulation may be sufficient to produce a near maximal bile-acid biosynthesis rate and to promote lowering of plasma cholesterol also in the fasting state. It is concluded that the postprandial bile-acid inflow to the liver may be more important as a regulator of bile-acid biosynthesis than is the fasting level of bile acids.

Bile Acids and Salts↗
PubMed1982

Hepatic cholesterol metabolism in obesity: activity of microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase.

Obesity is often associated with an elevated total body cholesterol synthesis. In order to evaluate the role of hepatic cholesterogenesis in this phenomenon, we assayed the rate-limiting step in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in the microsomal fraction of liver biopsies obtained operatively from ten morbidly obese (relative body weight greater than 155%) subjects. Eighteen normal-weight patients (relative body weight less than 120%) with cholesterol gallstones served as controls. Hepatic HMG CoA reductase activity, expressed as pmol X min-1 X mg protein-1, was 60% higher in the obese subjects compared to the gallstone patients (P less than 0.05). Microsomal protein concentration was lower in the obese patients, so that enzyme activity calculated per gram liver was not significantly different between the two groups. However, mevalonate formation, expressed in terms of total organ activity, was higher in the obese than in the nonobese group. The results suggest that the liver is a major contributor to the increased cholesterol production seen in obesity.

Adult↗
PubMed1982

Fasting levels of monoketonic bile acids in human peripheral and portal circulation.

It has been suggested that large amounts of ketonic bile acids may be present in portal venous blood. We have therefore determined the approximate concentration of 3-oxo-, 7-oxo-, and 12-oxo-bile acids (monoketonic bile acids) in human peripheral and portal circulation. These compounds were converted into the corresponding 3alpha-, 7alpha-, and 12alpha-hydroxy bile acids by treatment with sodium borodeuteride, thus increasing the molecular weight of each bile acid formed by one mass unit. The ratio between deuterated and nondeuterated bile acid was determined by combined gas-liquid chromatography-mass spectrometry with use of selected ion monitoring. From the ratio obtained and from the concentration of unlabeled bile acid, determined by isotope dilution-mass spectrometry, the approximate concentration of the different ketonic bile acids could be calculated. This method underestimates 3-oxygenated bile acids by 4-8%, 7-oxygenated bile acids by 2-3%, and 12-oxygenated bile acids by about 25%. The approximate concentration of monoketonic 3,7-oxygenated bile acids was found to be 0.08 +/- 0.02 and 0.37 +/- 0.25 micro mol/l in the peripheral venous serum and the portal venous serum, respectively. The approximate concentration of monoketonic 3,12-oxygenated bile acids was found to be 0.07 +/- 0.02 and 0.32 +/- 0.12 micro mol/l in the peripheral venous serum and the portal venous serum, respectively. The approximate concentration of monoketonic 3,7,12-oxygenated bile acids was found to be 0.03 +/- 0.01 and 0.14 +/- 0.05 micro mol/l in the peripheral venous serum and in the portal venous serum, respectively. The total concentration of the ketonic bile acids constituted only 9 +/- 1% and 8 +/- 3% of the nonoxidized bile acids in the peripheral venous serum and in the portal venous serum, respectively. Thus it seems less likely that the portal inflow of ketonic bile acids is of significant physiological importance under normal conditions.-Björkhem, I., B. Angelin, K. Einarsson, and S. Ewerth. Fasting levels of monoketonic bile acids in human peripheral and portal circulation.

Adult↗
PubMed1982

Lymphatic transport of bile acids in man.

The possibility of a lymphatic transport of bile acids in man was investigated. Four patients were studied 2-4 weeks after renal transplantation. As a part of the postoperative immunosuppressive treatment they all had a thoracic duct fistula for lymphatic drainage. After a standardized meal, lymph and peripheral blood samples were simultaneously collected at 30-minute intervals for 210 minutes. The bile acids, cholic acid, chenodeoxycholic acid, and deoxycholic acid were assayed by a gas-liquid chromatography-mass spectrometry method using deuterium-labeled internal standards. The concentration of cholic acid was about the same in lymph and serum. The concentrations of chenodeoxycholic and deoxycholic acids were 2-3 times higher in lymph than in serum, both in the fasting state and postprandially. These results are explained by a more efficient passive absorption of the less polar dihydroxy bile acids. The transport of bile acids in the lymph was calculated to be only about 0.2% of that in the portal vein.

Adult↗