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Biomedical subjects

B Angelin

Publications and source records attributed to B Angelin.

At least 19 recordsLinked to original sources
PubMed2006

Lipoprotein profiles in plasma and interstitial fluid analyzed with an automated gel-filtration system.

BACKGROUND: High-quality methods for lipoprotein characterization are warranted in studies on various metabolic diseases. MATERIALS AND METHODS: An automated system for size-exclusion chromatography (SEC) of lipoproteins using commercially available components is described. Cholesterol or triglyceride content in separated lipoproteins from plasma and interstitial fluid (IF) was continuously determined on-line using microlitre sample volumes. RESULTS: The lipoprotein assay showed a good concordance with the classic ultra-centrifugation/precipitation technique using fresh or frozen samples. Determination of lipoproteins in IF obtained from vacuum-induced skin blisters from 18 healthy subjects revealed that very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels were 18%, 19% and 25%, respectively, of concomitant plasma concentrations. The size-exclusion chromatography (SEC) system also allows for triglyceride determination on-line and it could be shown that the system is advantageous for an accurate determination of triglycerides in conditions when there are high levels of glycerol, e.g. in mice and in patients with hyperglycerolaemia (pseudo-hypertriglyceridaemia). CONCLUSIONS: The described system should be of value in studies where detailed lipoprotein analysis is warranted and particularly when significant sample series with small volumes are available. Our data also suggest that there is a 4-5.5-fold concentration gradient between plasma and IF for the three major plasma lipoproteins.

Animals↗
PubMed2006

Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man.

Bile acids (BAs) traversing the enterohepatic circulation exert several important metabolic effects. Their hepatic synthesis, controlled by the enzyme cholesterol 7alpha-hydroxylase (CYP7A1), has a unique diurnal variation in man. Here we provide evidence that the transintestinal flux of BAs regulates serum levels of intestinal fibroblast growth factor 19 (FGF19) that in turn modulate BA production in human liver. Basal FGF19 levels varied by 10-fold in normal subjects, and were reduced following treatment with a BA-binding resin and increased upon feeding the BA chenodeoxycholic acid. Serum FGF19 levels exhibited a pronounced diurnal rhythm with peaks occurring 90-120 min after the postprandial rise in serum BAs. The FGF19 peaks in turn preceded the declining phase of BA synthesis. The diurnal rhythm of serum FGF19 was abolished upon fasting. We conclude that, in humans, circulating FGF19 has a diurnal rhythm controlled by the transintestinal BA flux, and that FGF19 modulates hepatic BA synthesis. Through its systemic effects, circulating FGF19 may also mediate other known BA-dependent effects on lipid and carbohydrate metabolism.

Bile Acids and Salts↗
PubMed2004

Autosomal recessive hypercholesterolaemia: normalization of plasma LDL cholesterol by ezetimibe in combination with statin treatment.

BACKGROUND: Severe hereditary hypercholesterolaemia is most frequently due to familial hypercholesterolaemia (FH), caused by mutations in the LDL receptor (LDLR) gene. However, a phenotype very similar to FH may also be caused by defects in other genes like the genes for apolipoprotein (apo) B-100 or autosomal recessive hypercholesterolaemia (ARH). SUBJECT: An 8-year-old male of Lebanese origin was diagnosed with severe hypercholesterolaemia and extensive cutaneous and tendon xanthomas. Plasma LDL cholesterol before treatment was 17 mmol L(-1), whilst parents and both siblings had normal levels. DIAGNOSIS: Degradation of (125)I-labelled LDL in blood lymphocytes was reduced, but not abolished. Sequencing analysis of the LDLR and apoB-100 genes were negative, whilst a splice acceptor mutation in intron 1 (IVS 1 -1G>C) was detected in the ARH gene. The patient was homozygous for the mutation, whilst the parents were heterozygous. These findings were in agreement with a diagnosis of ARH. TREATMENT AND CLINICAL COURSE: Monthly LDL apheresis and atorvastatin 120 mg daily reduced LDL cholesterol preapheresis level to 4.8 mmol L(-1). When ezetimibe was given 10 mg day(-1) in combination with rosuvastatin 80 mg day(-1), LDL cholesterol was further lowered to 1.6 mmol L(-1), which made apheresis unnecessary. Cutaneous and tendon xanthomas disappeared completely and the intima-media thickness of the common carotid arteries decreased. At age 23 he developed a small myocardial infarction. CONCLUSION: ARH should be considered in cases of severe hypercholesterolaemia with a pattern of recessive inheritance. Combination therapy with high-dose statin and ezetimibe seems to be the treatment of choice in ARH and may reduce or eliminate the need for LDL apheresis treatment.

Adult↗
PubMed2002

Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene.

Familial hypercholesterolemia (FH) is an autosomal codominant disease, caused by mutations in the LDL receptor gene. To characterize the distribution of genetic aberrations in Swedish FH-patients fulfilling the clinical criteria of FH, we have investigated 150 unrelated Swedish patients for mutations in the LDL receptor gene and for the most common mutation causing familial ligand defective apo B-100 (FDB). Of the patients, 77 were recruited from Huddinge University Hospital in Stockholm and 73 from Sahlgren's University Hospital in Göteborg. Screening was carried out using SSCP and Southern blotting techniques, combined with DNA sequence analysis. In total, mutations regarded as cause for disease were identified in 55 patients (37%), representing 32 different types of mutations. In the LDL receptor gene we detected four nonsense mutations, 13 missense mutations, seven splice junction mutations, and four major rearrangements. In addition, two small deletions were identified and one base exchange in the promoter region. The most common mutation (apo B3500) causing FDB was found in three patients. The most frequent mutation was FH-Helsinki, reflecting the admixture of Finnish immigrants. We further identified 15 point mutations which were not considered to affect the function of the gene, and thus were regarded as polymorphic changes. This multitude of mutations reflects a heterogeneous genetic background in our series of Swedish FH-patients and differs from the situation in the other Scandinavian countries. Future studies should aim at characterizing the importance of other genes for the development of the FH phenotype.

Adult↗
PubMed2001

[Blood lipid derangement common in peripheral artery disease. Lipid-lowering agents may alleviate symptoms and slow the atherosclerotic process].

In the new guidelines from the Swedish Medical Products Agency, an aggressive approach is recommended for the treatment of hyperlipidemia in all patients with manifest atherosclerotic disease. Patients with intermittent claudication should therefore receive lipid-lowering treatment on the same indications as patients with coronary artery disease. The present article reviews our knowledge of hyperlipidemia as a risk factor for the development of peripheral artery disease. Hyperlipidemia is frequently found in these patients and the most common lipid derangements are low levels of HDL-cholesterol and hypertriglyceridemia. Hard end-point data concerning morbidity and mortality during lipid-lowering treatment in this specific population is largely lacking, although previous studies indicate that lipid-lowering treatment slows the atherosclerotic process and induces pain relief.

Adult↗
PubMed2001

Growth hormone reduces plasma cholesterol in LDL receptor-deficient mice.

Growth hormone (GH) has pleiotropic effects on cholesterol and lipoprotein metabolism. Pituitary GH is important for the normal regulation of hepatic LDL receptors (LDLR), for the enzymatic activity of bile acid regulatory cholesterol 7alpha-hydroxylase (C7alphaOH), and for the maintenance of resistance to dietary cholesterol. The present study aimed to determine whether GH has beneficial effects on plasma lipids and hepatic cholesterol metabolism in mice devoid of LDLR. Compared with wild-type controls, LDLR-deficient mice had approximately 250% elevated plasma total cholesterol and approximately 50% increased hepatic cholesterol levels; hepatic HMG CoA reductase activity was reduced by 70%, whereas C7alphaOH activity was increased by 40%. In LDLR mice, GH infusion reduced plasma cholesterol and triglycerides up to 40%, whereas HMG CoA reductase and C7alphaOH activities were stimulated by approximately 50% and 110% respectively. GH also stimulated HMG CoA reductase and C7alphaOH activities in control mice, whereas hepatic LDLR and plasma lipoproteins were unchanged. The effects of cholestyramine and atorvastatin on C7alphaOH in LDLR-deficient mice were potentiated by GH, and this was associated with a further reduction in plasma cholesterol. GH treatment reduces plasma cholesterol and triglycerides and stimulates C7alphaOH activity in mice devoid of LDLR, particularly in combination with resin or statin treatment. The potential of GH therapy in patients with homozygous familial hypercholesterolemia should be evaluated.

Animals↗
PubMed2001

Analysis of the ileal bile acid transporter gene, SLC10A2, in subjects with familial hypertriglyceridemia.

Familial hypertriglyceridemia (FHTG), a disease characterized by elevated plasma very low density lipoprotein triglyceride levels, has been associated with impaired intestinal absorption of bile acids. The aim of this study was to test the hypothesis that defects in the active ileal absorption of bile acids are a primary cause of FHTG. Single-stranded conformation polymorphism analysis was used to screen the ileal Na(+)/bile acid cotransporter gene (SLC10A2) for FHTG-associated mutations. Analysis of 20 hypertriglyceridemic patients with abnormal bile acid metabolism revealed 3 missense mutations (V98I, V159I, and A171S), a frame-shift mutation (646insG) at codon 216, and 4 polymorphisms in the 5' flanking sequence of SLC10A2. The SLC10A2 missense mutations and 5' flanking sequence polymorphisms were not correlated with bile acid production or turnover in the hypertriglyceridemic patients and were equally prevalent in the unaffected control subjects. In transfected COS cells, the V98I, V159I, and A171S isoforms all transported bile acids similar to the wild-type SLC10A2. The 646insG frame-shift mutation abolished bile acid transport activity in transfected COS cells but was found in only a single FHTG patient. These findings indicate that the decreased intestinal bile acid absorption in FHTG patients is not commonly associated with inherited defects in SLC10A2.

Adult↗
PubMed2001

Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice.

The nuclear oxysterol-receptor paralogues LXRalpha and LXRbeta share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXRalpha has been established as an important regulator of cholesterol catabolism in cholesterol-fed mice, little is known about the function of LXRbeta in vivo. We have generated mouse lines with targeted disruptions of each of these LXR receptors and have compared their responses to dietary cholesterol. Serum and hepatic cholesterol levels and lipoprotein profiles of cholesterol-fed animals revealed no significant differences between LXRbeta(-/-) and wild-type mice. Steady-state mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphate synthase, and squalene synthase were increased in LXRbeta(-/-) mice compared with LXRbeta(+/+) mice, when fed standard chow. The mRNA levels for cholesterol 7alpha-hydroxylase, oxysterol 7alpha-hydroxylase, sterol 12alpha-hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indicate that LXRbeta(-/-) mice - in contrast to LXRalpha(-/-) mice - maintain their resistance to dietary cholesterol, despite subtle effects on the expression of genes coding for enzymes involved in lipid metabolism. Thus, our data indicate that LXRbeta has no complete overlapping function compared with LXRalpha in the liver.

Alanine Transaminase↗
PubMed2000

Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice.

Clinical case reports have documented disturbances of carbohydrate and lipid metabolism in aromatase deficient and estrogen resistant males. The aim of the present study was to explore the metabolic functions of estrogens in male mice and to dissect the estrogen receptor (ER) specificity of such effects. Total body fat content and serum levels of leptin were followed in ERalpha knockout (ERKO), ERbeta knockout (BERKO), and ERalpha/beta double knockout (DERKO) mice. Neither the total body fat nor serum leptin levels were altered in any group before or during sexual maturation. However, after sexual maturation ERKO and DERKO, but not BERKO, demonstrated a clear increase in total body fat and enhanced serum leptin levels. Serum cholesterol was increased and a qualitative change in the lipoprotein profile, including smaller LDL particles, was observed in ERKO and DERKO mice. In conclusion, ERalpha but not ERbeta-inactivated male mice develop obesity after sexual maturation.

Adipose Tissue↗
PubMed2000

LDL-apheresis in patients with nephrotic syndrome: effects on serum albumin and urinary albumin excretion.

BACKGROUND: Hyperlipidemia is a common feature of the nephrotic syndrome (NS). From retrospective studies, it has been suggested that aggressive lipid-lowering with low-density lipoprotein apheresis (LDL-A) may not only improve dyslipidemia but also decrease urinary albumin excretion and increase serum levels of albumin in patients with focal segmental sclerosis. METHODS: Seven patients (6 males) aged 44 +/-7 years (SEM) with NS (duration 29+/-11 months) of diverse etiologies were investigated in a prospective study. A fixed protocol of LDL-A was designed for treatment twice-a-week for 3 weeks and then once a week for 7 weeks. The effects of LDL-A on lipid parameters (cholesterol, triglycerides, HDL, Lp(a), apo A-I, apo B) and renal parameters (iohexol clearance, serum albumin and 24-h urinary albumin excretion) were evaluated. RESULTS: Following treatment by LDL-A a remission in the severity of the NS was observed in two patients whereas a clear improvement was observed in four of the patients. A small, but significant (P<0.05), increase in serum albumin levels from 20+/-2 to 24+/-2 g L(-1) was noted after LDL-A. As expected, serum lipid parameters improved during LDL-A, and significant decreases in serum cholesterol, apo B and plasma Lp(a) were observed at different time-points of LDL-A. Conversely, no significant changes in either triglyceride, HDL or apo A-I levels were observed during LDL-A. CONCLUSIONS: The present uncontrolled prospective study shows that LDL-A causes a rapid 30-40% decrease in serum cholesterol and plasma Lp(a) levels in patients with NS. The present prospective study also suggests that short-term LDL-A treatment may increase serum albumin levels in nephrotic patients.

Adult↗
PubMed2000

Biphasic effects of the natural estrogen 17beta-estradiol on hepatic cholesterol metabolism in intact female rats.

The protective influence of estrogens in cardiovascular disease is believed to be partly due to beneficial effects on cholesterol metabolism. Much of the experimental data are based on models in which synthetic estrogens have been used in pharmacological doses, and therefore, the physiological role of estrogens in cholesterol metabolism is uncertain. To evaluate this important issue, we performed experiments in intact female rats with use of the natural estrogen 17beta-estradiol (E2) administered either subcutaneously or orally. After physiological doses of E2 (< or =0.04 mg. kg(-1). d(-1)) were administered, plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I were increased. In the liver, 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7alpha-hydroxylase activities were increased, as well as cholesterol 7alpha-hydroxylase mRNA levels. These effects were abolished during treatment with higher doses of E2, whereas apo A-I mRNA increased in a dose-dependent way. After treatment with pharmacological doses of E2 (> or =0.2 mg. kg(-1). d(-1)), the number of hepatic low density lipoprotein receptors increased and plasma cholesterol was reduced. These effects were similar after both oral and subcutaneous administration of E2. Our results show that the responses to E2 are biphasic: plasma HDL, apo A-I, and hepatic enzyme activities governing bile acid and cholesterol synthesis increased only at physiological doses of E2. At pharmacological doses of E2, hepatic low density lipoprotein receptors are stimulated and plasma cholesterol is reduced. Therefore, under physiological conditions, E2 exerts its major effects on hepatic cholesterol metabolism through mechanisms other than stimulation of low density lipoprotein receptor expression.

Administration, Oral↗
PubMed2000

Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol.

Thyroid hormone (T3) influences hepatic cholesterol metabolism, and previous studies have established an important role of this hormone in the regulation of cholesterol 7alpha-hydroxylase (CYP7A), the rate-limiting enzyme in the synthesis of bile acids. To evaluate the respective contribution of thyroid hormone receptors (TR) alpha1 and beta in this regulation, the responses to 2% dietary cholesterol and T3 were studied in TRalpha1 and TRbeta knockout mice under hypo- and hyperthyroid conditions. Our experiments show that the normal stimulation in CYP7A activity and mRNA level by T3 is lost in TRbeta-/- but not in TRalpha1-/-mice, identifying TRbeta as the mediator of T3 action on CYP7A and, consequently, as a major regulator of cholesterol metabolism in vivo. Somewhat unexpectedly, T3-deficient TRbeta-/- mice showed an augmented CYP7A response after challenge with dietary cholesterol, and these animals did not develop hypercholesterolemia to the extent as did wild-type (wt) controls. The latter results lend strong support to the concept that TRs may exert regulatory effects in vivo independent of T3.

Animals↗
PubMed1999

Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans.

BACKGROUND: Apolipoprotein (apo) A-I is the major protein component of HDL, a cholesterol transport particle that protects against atherosclerosis. Apo A-I is believed to promote reverse cholesterol transport, transferring cholesterol from peripheral cells to the liver for subsequent elimination. To test this hypothesis in humans, we measured fecal steroid excretion before and after the intravenous infusion of human proapo A-I (precursor of apo A-I) liposome complexes. METHODS AND RESULTS: Four subjects with heterozygous familial hypercholesterolemia w re studied under standardized conditions. The fecal excretion of bile acids and neutral sterols was determined for 9 days before and 9 days after an intravenous infusion of recombinant human proapo A-I (4 g protein) liposome complexes. Plasma apoA-I and HDL cholesterol levels increased transiently (mean peak concentrations were 64% and 35% above baseline, respectively) during the first 24 hours. Mean lipoprotein lipid and apolipoprotein levels were not different during the 2 collecting periods, however. Serum lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, was also unchanged. The fecal excretion of cholesterol (neutral sterols and bile acids) increased in all subjects (mean increase, +39% and +30%, respectively), corresponding to the removal of approximately 500 mg/d excess cholesterol after infusion. Control infusions with only liposomes in 2 of the patients did not influence lipoprotein pattern or cholesterol excretion. CONCLUSIONS: Infusion of proapoA-I liposomes in humans promotes net cholesterol excretion from the body, implying a stimulation of reverse cholesterol transport. This mechanism may prove useful in the treatment of atherosclerosis.

Adult↗