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Biomedical subjects

Jens F Rehfeld

Publications and source records attributed to Jens F Rehfeld.

At least 19 recordsLinked to original sources
PubMed2007

Chloroplast membranes retard fat digestion and induce satiety: effect of biological membranes on pancreatic lipase/co-lipase.

Human obesity is a global epidemic, which causes a rapidly increased frequency of diabetes and cardiovascular disease. One reason for obesity is the ready availability of refined food products with high caloric density, an evolutionarily new event, which makes over-consumption of food inevitable. Fat is a food product with high caloric density. The mechanism for regulation of fat intake has therefore been studied to a great extent. Such studies have shown that, as long as fat stays in the intestine, satiety is promoted. This occurs through the fat-released peptide hormones, the best known being CCK (cholecystokinin), which is released by fatty acids. Hence, retarded fat digestion with prolonged time for delivery of fatty acids promotes satiety. Pancreatic lipase, together with its protein cofactor, co-lipase, is the main enzymatic system responsible for intestinal fat digestion. We found that biological membranes, isolated from plants, animals or bacteria, inhibit the lipase/co-lipase-catalysed hydrolysis of triacylglycerols even in the presence of bile salt. We propose that the inhibition is due to binding of lipase/co-lipase to the membranes and adsorption of the membranes to the aqueous/triacylglycerol interface, thereby hindering lipase/co-lipase from acting on its lipid substrate. We also found that chloroplast membranes (thylakoids), when added to refined food, suppressed food intake in rats, lowered blood lipids and raised the satiety hormones, CCK and enterostatin. Consequently, the mechanism for satiety seems to be retardation of fat digestion allowing the fat products to stay longer in the intestine.

Animals↗
PubMed2006

Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction.

AIMS: B-type natriuretic peptide (BNP) measurement in screening for left ventricular hypertrophy (LVH) and left ventricular systolic dysfunction (LVSD) has been evaluated in the general population, but corresponding information on proBNP and the N-terminal proBNP fragment is still limited. We therefore examined whether proBNP measurement is useful for LVH and LVSD screening in the general population. METHODS AND RESULTS: In the 4th Copenhagen City Heart Study, 3497 participants underwent echocardiography with assessment of left ventricular ejection fraction (LVEF) and mass. The impact of gender and age was determined and the diagnostic performance of the plasma proBNP concentration was evaluated using receiver operating characteristic (ROC) curves. Of 1502 men and 1995 women, 4.1 and 2.6% had LVSD defined as an LVEF<60% whereas only 0.4% displayed LVEF<40%. The proBNP concentration was 1.7-fold higher in women compared with men (P<0.0001) and related to age in both genders. The mean proBNP plasma concentration was two-fold higher in subjects with LVSD than without LVSD (P<0.0001). Likewise, LVH imposed a 1.9-fold increase in the proBNP concentration (P<0.0001): Both differences persisted after adjusting for ischaemic heart disease, hypertension, diabetes, gender, and age. The diagnostic performance of proBNP in detecting LVEF<40% was high with an area under the ROC curves of 0.92 (95% CI 0.79-1.00) in women and 0.85 (95% CI 0.74-0.96) in men. CONCLUSION: We have established the impact of age and gender on the proBNP concentration in a large, community-based cohort. The diagnostic performance for proBNP measurement in screening for LVH and LVSD in the general population parallels the reported data for BNP.

Echocardiography↗
PubMed2006

Appetite suppression through delayed fat digestion.

High-fat diets are often associated with greater caloric intake and weight gain. Since satiety during fat intake is induced by fat in the intestine we investigated the efficiency of a lipid compound that retards fat digestion to regulate fat intake. We found this compound to reduce high-fat food intake, body weight and blood lipids in Sprague-Dawley rats, without causing steatorrhea. The absence of steatorrhea is explained by an increased pancreatic lipase/colipase secretion, compensating the impaired lipolysis by the added compound. The animals also had an elevated CCK secretion. The satiety for fat may be the consequence of elevated CCK and procolipase/enterostatin levels. We conclude that compounds can be found that delay intestinal fat digestion and control high-fat food intake through the release of satiety signals, without causing steatorrhea. The absence of steatorrhea makes such compounds advantageous over lipase inhibitors in the treatment of obesity.

Animals↗
PubMed2006

Atrial secretion of B-type natriuretic peptide.

In the normal heart, the endocrine capacity resides in the atria. Atrial myocytes express and secrete natriuretic hormones that regulate fluid homeostasis and blood pressure. But in ventricular disease, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression is also activated in ventricular myocytes. Plasma concentrations of natriuretic peptides and their biosynthetic precursors are accordingly increased in patients with marked ventricular dysfunction. In contrast, atrial peptide secretion in ventricular disease has received less attention, and our present understanding of the endocrine atria during ventricular dysfunction is still scarce. Although ventricular disease and increased circulating concentrations are associated, it does not entail that the ventricle is the sole or even the main source in all types of heart disease. Clearly, the endocrine atria are also active in heart failure. Plasma measurement of cardiac natriuretic peptides and their molecular precursors can perhaps help us to discriminate when, where and how.

Atrial Fibrillation↗
PubMed2006

The endoproteolytic maturation of progastrin and procholecystokinin.

The homologous brain-gut propeptides, procholecystokinin (proCCK) and progastrin, both undergo extensive posttranslational maturation in specific neuroendocrine cells. The process comprises multiple endoproteolytic cleavages at mono- and dibasic sites, in addition to exoproteolytic trimmings and amino acid derivatizations. Knockout of prohormone convertases (PCs) in mice and studies in cell lines indicate that PC1, PC2 and, to a minor extent, PC5, are responsible for most of the endoproteolytic cleavages of both prohormones. Progastrin in antral G-cells is cleaved by PC1 at two di-Arg sites, R36R37 and R73R74, whereas, PC2 only cleaves at the single di-Lys site, K53K54. Pituitary corticotrophs and intestinal TG-cells, both of which express gastrin, do not cleave K53K54 due to lack of PC2. In proCCK five monobasic (R25, R44, R50, K61 and R75) as well as a single dibasic site (R85R86) can all be cleaved by both PC1 and PC2. But the cleavage differs in a cell-specific manner in that PC1 is responsible for the entire endoproteolytic cleavage in intestinal endocrine I-cells, except for perhaps the K61 site. In contrast PC2 is responsible for most endoproteolysis of proCCK in the cerebral CCK-neurons, which do not express PC1 in significant amounts. Moreover, PC5 appears to contribute to a minor extent to the neuronal proCCK and to the antral progastrin processing. This review emphasizes that prohormone convertases play a decisive but substrate and cell-specific role in the biosynthetic maturation of gastrin and CCK.

Animals↗
PubMed2006

Characteristics of the Danish families with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is caused by autosomal dominantly inherited mutations in the MEN1 gene. Here, we report 25 MEN1 mutations - of which 12 are novel - found in 36 Danish families with MEN1 or variant MEN1 disease. Furthermore, one FIHP family was found to have an earlier reported mutation. The mutations were predominantly found in exons 9 and 10 encoding the C-terminal part of menin. Seven of the mutations were missense mutations, changing conserved residues. Furthermore screening of 93 out of 153 consecutive patients with primary hyperparathyroidism (pHPT) identified five mutation carriers. Two of these belonged to known MEN1 families, whereas the only MEN1-related disease in the other three was pHPT. Screening of 96 consecutive patients with fore-/midgut endocrine tumours revealed five mutation carries out of 28 patients with sporadic gastrinomas, whereas no mutations were found in 68 patients with other fore-/midgut endocrine tumours. Moreover, screening of 60 consecutive patients with primary prolactinoma did not identify any mutation carriers. Our data indicate that MEN1 mutation screening is efficient in patients with familial MEN1. Screening should also be offered to patients with pHPT or gastrinomas after thorough investigation into the family history. In contrast, sporadic carcinoid tumours or primary prolactinomas are rarely associated with germ-line MEN1 mutations.

Amino Acid Sequence↗
PubMed2006

Gastric inflammation, metaplasia, and tumor development in gastrin-deficient mice.

BACKGROUND & AIMS: Gastrin deficiency and proton pump inhibitor treatment cause achlorhydria, which predisposes to disease. To elucidate the underlying molecular biology, we examined the changes in gastric gene expression in both types of achlorhydria. We also explored the associated changes in the gastric microflora and the long-term consequences of gastrin-deficient achlorhydria. METHODS: Expression profiles were generated from gastric RNA from wild-type mice, gastrin knockout (KO) mice, gastrin KO mice after 1 week of gastrin infusion, and wild-type mice treated for 1 month with a proton pump inhibitor. The results were confirmed using real-time polymerase chain reaction and immunohistochemistry. Selective media were used to characterize the gastric microflora. RESULTS: The number of gastric bacteria was increased in both gastrin KO and PPI-treated mice. The expression profiles revealed activation of immune defense genes, interferon-regulated response genes, and intestinal metaplasia of the gastric mucosa. In young gastrin-deficient mice, gastrin infusions reversed the changes. Over time, the changes accumulated, became irreversible, and progressed into metaplasia and polyp development. Finally, the study showed that gastrin regulated the expression of genes encoding extracellular matrix proteins. CONCLUSIONS: Independently of gastrin, achlorhydria is associated with gastric bacterial overgrowth and intestinal gene expression patterns and is associated with predisposition to disease. Gastrin is therefore essential for prevention of gastric disease, mainly through control of acid secretion but to a lesser extent also through control of gastric gene expression. The gastrin-deficient mouse serves as a useful new model for gastric metaplasia and neoplasia.

Animals↗
PubMed2005

Apelin: a new plasma marker of cardiopulmonary disease.

OBJECTIVES: Dyspnea is a major symptom of both parenchymal lung disease and chronic heart failure. Underlying cardiac dysfunction can be assessed by measurement of cardiac-derived B-type natriuretic peptide or its precursor in plasma. However, no specific endocrine marker of the lung parenchyma has so far been identified. We therefore examined whether plasma concentrations of apelin, a novel inotropic hormone, is affected in patients with chronic parenchymal lung disease without cardiac dysfunction. METHODS AND RESULTS: Patients with severe chronic parenchymal lung disease and normal cardiac function (n=53), idiopathic pulmonary hypertension with increased right ventricular pressure (n=10), and patients with severe left ventricular systolic dysfunction (n=22) were enrolled. Plasma apelin-36 and proBNP concentrations were measured with radioimmunoassays. While proBNP plasma concentrations were unaffected in chronic parenchymal lung disease patients compared to normal subjects, the apelin-36 concentration was reduced 3.3-fold (median 35 pmol/l (0-162 pmol/l) vs. 117 pmol/l (55-232 pmol/l), P<0.001). Moreover, the apelin-36 concentration was decreased in chronic heart failure patients (2.1-fold, P<0.01) and in patients with idiopathic pulmonary hypertension (4.0-fold, P<0.001). In contrast, the proBNP concentration was highly increased in both chronic heart failure and idiopathic pulmonary hypertension patients. CONCLUSION: Plasma concentrations of apelin-36, a novel inotropic peptide, are decreased in patients with chronic parenchymal lung disease and preserved cardiac function. Combined measurement of apelin-36 and proBNP may be a new diagnostic approach in distinguishing pulmonary from cardiovascular causes of dyspnea.

Aged↗
PubMed2005

Antral content, secretion and peripheral metabolism of N-terminal progastrin fragments.

OBJECTIVES: In addition to the acid-stimulatory gastrins, progastrin also release N-terminal fragments. In order to examine the cellular content, secretion and peripheral metabolism of these fragments, we developed an immunoassay specific for the N-terminal sequence of human progastrin. RESULTS: The concentration of N-terminal progastrin fragments in human antral tissue was 6.7 nmol/g tissue (n=5), which was only half of that of acid-stimulatory gastrins (12 nmol/g tissue). Gel chromatography of antral extracts showed that the progastrin fragment 1-35 and 1-19 constitute the major part of the N-terminal progastrin fragments. The basal concentration of N-terminal fragments in normal human plasma was almost 30-fold higher than that of the amidated, acid-stimulatory gastrins (286 pmol/l versus 9.8 pmol/l, n=26, P<0.001). In contrast, the concentration of N-terminal fragments in hypergastrinemic plasma was only 2.7-fold higher than the concentration of amidated gastrins (540 pmol vs. 198 pmol/l, P=0.02). During meal stimulation, the plasma concentrations of N-terminal progastrin fragments and amidated gastrins increased in a correlated manner (r=0.97, P=0.005). The half life for progastrin 1-35 in circulation was 30 min, and a pig model revealed the kidneys and the vasculature to the head as the primary sites of degradation. CONCLUSION: The cellular and circulatory concentration profiles of N-terminal progastrin fragments differ markedly from those of the acid-stimulatory gastrins. The high basal plasma concentrations of N-terminal progastrin fragments cannot be explained by differences in elimination.

Animals↗
PubMed2005

Reduced ghrelin, islet amyloid polypeptide, and peptide YY expression in the stomach of gastrin-cholecystokinin knockout mice.

The antral hormone gastrin and its intestinal relative, cholecystokinin (CCK), are pivotal in the regulation of gastric functions. Other gastric hormones like ghrelin, peptide YY (PYY), and islet amyloid polypeptide (IAPP), however, also contribute to the regulation of acid secretion, motility, and feeding. Because gastrin and CCK are crucial for gastric homeostasis, we examined how loss of gastrin alone and gastrin plus CCK affected the expression of ghrelin, IAPP, and PYY and ghrelin secretion. The expression of ghrelin, IAPP, and PYY and the CCK-A receptor genes were examined in both gastrin and gastrin-CCK double-knockout (KO) mice using immunocytochemistry and quantitative RT-PCR. Ghrelin concentrations in plasma were measured using RIA. Gastrin and CCK were infused in gastrin-CCK KO mice using osmotic minipumps. The number of ghrelin cells and ghrelin gene expression were unaffected, albeit the ghrelin cells were located closer to the base of the glands in both KO mouse strains when freely fed. However, lack of both gastrin and CCK attenuated fasting-induced ghrelin expression and secretion. Fundic ghrelin cells expressed the CCK-A receptor, and ghrelin expression increased after CCK infusion. Furthermore, gastric IAPP and PYY expression as well as the number of IAPP- and PYY-containing cells were reduced in both gastrin and gastrin-CCK KO mice. Gastrin infusion increased gastric IAPP but not PYY expression. In conclusion, lack of gastrin plus CCK but not gastrin alone reduced ghrelin secretion in response to fasting through both direct and indirect mechanisms. Both gastrin and combined gastrin-CCK deficiency reduced the gastric IAPP and PYY expression.

Amyloid↗
PubMed2005

Antral G-cell in gastrin and gastrin-cholecystokinin knockout animals.

The antral hormone gastrin is the key regulator of gastric acid secretion, mucosal growth and differentiation. Gastrin is synthesized in the endocrine G-cells in the antroduodenal mucosa. We have now examined the way in which the loss of gastrin alone or gastrin plus cholecystokinin (CCK) affects the antral G-cell. Immunohistochemistry, radioimmunoassay and quantitative real-time polymerase chain reaction techniques were employed to examine the expression of genes belonging to the G-cell secretory pathway in gastrin and gastrin-CCK knockout mice. Transmission electron microscopy was used to examine the ultrastructure of the G-cells. The number of G-cells increased but the secretory granules were few and abnormally small in the G-cells of both mouse models compared with wildtypes. Thus, gastrin is not necessary for the formation of G-cells as such but the lack of gastrin reduces the number and size of their secretory granules suggesting that gastrin is vital for the formation and/or maintenance of secretory granules in G-cells.

Animals↗
PubMed2005

Small gallstones, preserved gallbladder motility, and fast crystallization are associated with pancreatitis.

Acute pancreatitis is a severe complication of gallstones with considerable mortality. We sought to explore the potential risk factors for biliary pancreatitis. We compared postprandial gallbladder motility (via ultrasonography) and, after subsequent cholecystectomy, numbers, sizes, and types of gallstones; gallbladder bile composition; and cholesterol crystallization in 21 gallstone patients with previous pancreatitis and 30 patients with uncomplicated symptomatic gallstones. Gallbladder motility was stronger in pancreatitis patients than in patients with uncomplicated symptomatic gallstones (minimum postprandial gallbladder volumes: 5.8 +/- 1.0 vs. 8.1 +/- 0.7 mL; P = .005). Pancreatitis patients had more often sludge (41% vs. 13%; P = .03) and smaller and more gallstones than patients with symptomatic gallstones (smallest stone diameters: 2 +/- 1 vs. 8 +/- 2 mm; P = .001). Also, crystallization occurred much faster in the bile of pancreatitis patients (1.0 +/- 0.0 vs. 2.5 +/- 0.4 days; P < .001), possibly because of higher mucin concentrations (3.3 +/- 1.9 vs. 0.8 +/- 0.2 mg/mL; P = .04). No significant differences were found in types of gallstones, relative biliary lipid contents, cholesterol saturation indexes, bile salt species composition, phospholipid classes, total protein or immunoglobulin (G, M, and A), haptoglobin, and alpha-1 acid glycoprotein concentrations. In conclusion, patients with small gallbladder stones and/or preserved gallbladder motility are at increased risk of pancreatitis. The potential benefit of prophylactic cholecystectomy in this patient category has yet to be explored.

Bile↗
PubMed2005

B-type natriuretic peptide and its precursor in cardiac venous blood from failing hearts.

BACKGROUND: Plasma concentrations of B-type natriuretic peptide (BNP-32) and its precursor (proBNP) are increased in chronic heart failure. Accordingly, BNP-32 and proBNP are both being implemented as clinical markers. AIM: To determine the molar relation of BNP-32 and proBNP in different cardiovascular regions. METHODS AND RESULTS: Blood samples were obtained from different cardiovascular regions during right heart catheterization in heart failure patients, and from normal subjects. Plasma BNP-32 and proBNP concentrations were measured using sequence-specific radioimmunoassays. Patients with severe left ventricular dysfunction (n=21) displayed increased peripheral plasma concentrations of both BNP-32 (four-fold, P=0.0008) and proBNP (seven-fold, P=0.0002) compared with normal subjects. Moreover, the peripheral concentrations were highly correlated with the corresponding concentrations in the coronary sinus (BNP-32: r=0.97, P<0.0001; proBNP: r=0.94, P<0.0001). Despite comparable peripheral concentrations of BNP-32 and proBNP, the BNP-32 concentration was higher than the proBNP concentration in the coronary sinus (median 126 pmol/l (21-993) vs. 103 pmol/l (16-691), P=0.035). CONCLUSIONS: The BNP-32 and proBNP concentrations are closely related in venous cardiac blood. The findings suggest an overall constitutive secretion of processed proBNP, i.e. an N-terminal precursor fragment and BNP-32, in chronic heart failure.

Adult↗