Karin Salzmann

Effects of weight loss on PLTP activity and HDL particle size

OBJECTIVE: Dyslipidaemia in obesity is characterized by hypertriglyceridaemia, low HDL-C levels, small, dense HDL particles and increased phospholipid transfer protein (PLTP) activity.METHODS: In the present study, we investigated PLTP activity and HDL particle size in 16 morbidly obese, middle-aged women, who underwent Swedish Adjustable Gastric Banding surgery. Study subjects were tested within 2 months before and 1 y after surgery. PLTP activity was determined by exogenous substrate assay and HDL particle size by gradient gel electrophoresis, respectively.RESULTS: Pronounced weight loss after gastric banding surgery resulted in a significant decrease of PLTP activity from 8.42±2.04 to 7.43±2.21 μmol/ml/h (P=0.02). The size of HDL2 particles increased signficantly from 14.04±0.86 to 14.28±0.64 nm (P=0.02) after body weight reduction, while no change in HDL3 particle size was apparent.DISCUSSION: Our results suggest that dyslipidaemia in obesity is—at least partially—reversible by weight loss. We hypothesize that reduction of PLTP activity and increase of HDL particle size are important component factors in converting the atherogenic lipoprotein profile of obese subjects into a less atherogenic profile with weight loss.

Analysis of long-chain ω-3 fatty acid content in fish-oil supplements

ZusammenfassungHINTERGRUND: In zahlreichen Studien wurden die verschiedensten vorteilhaften Effekte von mehrfach ungesättigten Omega 3 Fettsäuren auf Atherosklerose, Arrhythmie und Hypertriglyzeridämie nachgewiesen, was zahlreiche Gesundheitsorganisationen dazu veranlasst hat, einen täglichen Verzehr von einem Gramm Omega 3 Fettsäuren täglich für antiatherosklerotische sowie antiarrhytmische Wirkungen oder zwei bis vier g/d Omega 3 Fettsäuren zur Senkung der Plasmatriglyzeride zu empfehlen. Es sind zahlreiche Präparate auf dem Markt erschienen, welche die ω-3 PUFA-arme westliche Ernährung in Form von Kapseln ergänzen. Da diese Präparate beträchtlichen Variationen des Gehalts an langkettigen ω-3 PUFAs unterworfen sein können, haben wir neun kommerziell erhältliche Produkte bezugnehmend auf ihre Fettsäurekomposition getestet. METHODEN: Neun kommerziell erhältliche ω-3 PUFA Nahrungsergänzungsmittel wurden mittels kapillärer Gaschromatographie auf ihren Gehalt an langkettigen ω-3 PUFA untersucht. ERGEBNISSE: Die neun von uns getesteten Präparate zeigen hinsichtlich der Konzentration an langkettigen ω-3 PUFA große Unterschiede von bis zu 63,7 ± 1,58 mol % (p = 0,002) und die Meisten scheitern daran, die empfohlene Tagesdosis von einem Gramm zu erzielen, selbst wenn sie in der höchsten vom Hersteller angegebenen Dosierung verabreicht werden. Acht der Präparate enthalten entweder gleiche oder signifikant höhere langkettige ω-3 PUFA Mengen als vom Hersteller angegeben und ein Hersteller macht keine Angabe. Die höchsten Anteile an Eicosapentaensäure (EPA) und Docosahexaensäure (DHA) wurden in Omacor® (95,80 ± 0,63%) und Percucor® (76,8 ± 7,11%) vorgefunden. KONKLUSION: Verabreichung von langkettigen ω-3 Fettsäurepräparaten kann in großen Unterschieden der tatsächlich konsumierten Menge resultieren. Daher ist es empfehlenswert, die am höchsten standardisierten und gereinigten Produkte zu verwenden.SummaryBACKGROUND: Omega-3 polyunsaturated fatty acids (long-chain ω-3 PUFA) have proved to be beneficial in atherosclerosis, arrhythmia and hypertriglyceridemia in several studies, which has led national and international societies to recommend an intake of 1 g/d long-chain ω-3 PUFA for antiatherosclerotic and antiarrhythmic purposes or 2–4 g/d for a lipid lowering effect. Numerous preparations are marketed for supplementing western diet, which is low in long-chain ω-3 PUFA. Since these preparations vary in their long-chain ω-3 PUFA content, we tested nine commercially available products for their fatty acid composition. METHODS: Nine commercially available ω-3 fatty acid supplements were analyzed using capillary gas chromatography to determine their fatty acid content. RESULTS: The nine preparations showed huge differences, up to 63.7 ± 1.58 mol% (P = 0.002), in their longchain ω-3 fatty acid content. Most of them failed to achieve the daily recommended dose of 1 g, even when administered at the highest dosage according to the manufacturers recommendations. Eight of the preparations contained either equal or significantly greater amounts of long-chain ω-3 PUFA than denoted by the manufacturer; one preparation did not provide any information. The highest percentage of DHA and EPA was detected in Omacor® (95.80 ± 0.63%) and Percucor® (76.8 ± 7.109%). CONCLUSION: Administering long-chain ω-3 fatty acid preparations may result in huge differences in terms of the actual amount ingested. It is therefore advisable to use the most standardized and purified products available.

LRP1b shows restricted expression in human tissues and binds to several extracellular ligands, including fibrinogen and apoE ― carrying lipoproteins

Objective To investigate low-density lipoprotein receptor-related protein 1b (LRP1b) expression in human tissues and to identify circulating ligands of LRP1b. Methods and results Using two independent RT-PCR assays, LRP1b mRNA was detected in human brain, thyroid gland, skeletal muscle, and to a lesser amount in testis but absent in other tissues, including heart, kidney, liver, lung, and placenta. Circulating ligands were purified from human plasma by affinity chromatography using FLAG-tagged recombinant LRP1b ectodomains and identified by mass spectrometry. Using this technique, several potential ligands (fibrinogen, clusterin, vitronectin, histidine rich glycoprotein, serum amyloid P-component, and immunoglobulins) were identified. Direct binding of LRP1b ectodomains to fibrinogen was verified by co-immunoprecipitation. ApoE – carrying lipoproteins were shown to bind to LRP1b ectodomains in a lipoprotein binding assay. Furthermore, binding as well as internalization of very low density lipoproteins by cells expressing an LRP1b minireceptor was demonstrated. Discussion LRP1b expression in humans appears to be confined to few tissues, which could point out to specialized functions of LRP1b in certain organs. Most of the newly identified LRP1b ligands are well-known factors in blood coagulation and lipoprotein metabolism, suggesting a possible role of LRP1b in atherosclerosis.

Serum prolactin in advanced chronic liver disease.

Hyperprolactinemia is a frequent endocrine disorder with well known harmful effects on the reproductive system and bone metabolism. Besides prolactinomas several drugs and disorders such as renal failure and hypothyroidism have been shown to cause hyperprolactinemia. Based on former studies, liver cirrhosis has also been suggested to cause hyperprolactinemia, while mechanisms have not been identified yet. In this study, we set out to investigate the prevalence and predictors of hyperprolactinemia in 178 patients with liver cirrhosis of different etio-logies. Eighteen out of 178 patients - 7 females and 11 males - displayed elevated serum pro-lactin levels. When patients were excluded who suffered from co-morbidities or took medication that are discussed to potentially interfere with prolactin metabolism, only 3 males displayed increased serum prolactin levels. Prolactin levels were similar in patients with liver cirrhosis of different etiologies. Our data suggest that hyperprolactinemia is not commonly found in patients with liver cirrhosis, but is mostly associated with intake of drugs or presence of comorbidites which are known to potentially cause hyperprolactinemia. We thus hypothesize that in contrast to former studies liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of co-morbidities or drugs that are known to potentially increase prolactin levels, marked hyperprolactinemia needs further investigation in patients with liver cirrhosis.

Dynamics of Bile Acid Profiles, GLP-1 and FGF19 after Laparoscopic Gastric Banding.

Context An increase of bile acids (BAs), fibroblast growth factor 19 (FGF19), and glucagon-like peptide 1 (GLP-1) has been implicated in metabolic improvements after Roux-en-Y gastric bypass and vertical sleeve gastrectomy. However, data are still conflicting regarding their role after laparoscopic adjustable gastric banding (LAGB). Objective To assess the fasting BA, FGF19, and GLP-1 concentrations in plasma before and after LAGB and to test for correlations with immunometabolic parameters. Furthermore, hepatic farnesoid X receptor (FXR) expression and regulation of FXR-dependent genes were analyzed. Design and Setting Observational study at the University Hospital Innsbruck. Patients Twenty obese patients. Interventions Fasting plasma samples were taken before, 3, 6, and 12 months after LAGB. Liver biopsies were obtained at surgery and after 6 months postoperatively. Main Outcome Measures BA profiles, GLP-1 and FGF19 levels, hepatic FXR expression and regulation of FXR target genes were determined. Results Total, conjugated, and secondary BAs transiently increased 3 months after LAGB (P < 0.01). Only one BA, glycolithocholic acid sulfate, remained significantly elevated throughout the whole follow-up period (P < 0.05). GLP-1 had increased transiently 3 months after surgery (P < 0.01), whereas FGF19 levels increased continuously (P < 0.05). Insulin, homeostasis model assessment index, C-reactive protein, FGF19, and GLP-1 correlated positively with different BAs. No differences were seen in hepatic FXR expression and FXR-regulated genes. Conclusions Our study results, not only identified LAGB-induced changes in BAs and BA-induced hormones, but also revealed associations between changes in BA profile with GLP-1 and FGF19.

Postprandial lipemia induces pancreatic α cell dysfunction characteristic of type 2 diabetes: studies in healthy subjects, mouse pancreatic islets, and cultured pancreatic α cells

BACKGROUND Type 2 diabetes is associated with pancreatic α cell dysfunction, characterized by elevated fasting plasma glucagon concentrations and inadequate postprandial glucose- and insulin-induced suppression of glucagon secretion. The cause and the underlying mechanisms of α cell dysfunction are unknown. OBJECTIVE Because Western dietary habits cause postprandial lipemia for a major part of a day and, moreover, increase the risk of developing type 2 diabetes, we tested the hypothesis that postprandial lipemia with its characteristic elevation of triglyceride-rich lipoproteins (TGRLs) might cause pancreatic α cell dysfunction. DESIGN In a crossover study with 7 healthy volunteers, 2 experiments using 2 fat-enriched meals were performed on each volunteer; meal 1 was designed to increase plasma concentrations of both TGRLs and nonesterified fatty acids and meal 2 to increase TGRLs only. Intravenous glucose boli were injected at 0800 after an overnight fast and postprandially at 1300, 3 h after ingestion of a fat-enriched meal. Glucagon concentrations were measured throughout the days of the experiments. In addition to the study in humans, in vitro experiments were performed with mouse pancreatic islets and cultured pancreatic alpha TC 1 clone 9 (αTC1c9) cells, which were incubated with highly purified TGRLs. RESULTS In humans, postprandial lipemia increased plasma glucagon concentrations and led to an inadequate glucose- and insulin-induced suppression of glucagon. There was no difference between the 2 meal types. In mouse pancreatic islets and cultured pancreatic αTC1c9 cells, purified postprandial TGRLs induced abnormalities in glucagon kinetics comparable with those observed in humans. The TGRL-induced α cell dysfunction was due to reduced γ-aminobutyric acid A receptor activation in pancreatic α cells. CONCLUSION We concluded that postprandial lipemia induces pancreatic α cell dysfunction characteristic of type 2 diabetes and, therefore, propose that pancreatic α cell dysfunction could be viewed, at least partly, as a postprandial phenomenon.

Fat-enriched rather than high-fructose diets promote whitening of adipose tissue in a sex-dependent manner

Adipose tissue is a critical regulator of energy metabolism and an effector organ of excessive caloric intake. We studied the effects of high-fructose (HFruD), high-fat (HFD) and mixed high-sucrose and high-fat diet (HFHSD) on adipocyte morphology and biology and consecutive metabolic effects in male and female C57BL/6 mice. Forty male and 40 female mice were randomly assigned to one of four dietary groups and fed for 10 weeks ad libitum. After 10 weeks of feeding, mice were analyzed in regard to glucose metabolism, insulin sensitivity and alteration in adipocyte morphology and function. Weight gain and diminished insulin sensitivity in HFD- and HFHSD-fed mice were accompanied by increased adipocyte size and a shift in size distribution towards larger adipocytes in all mice. The latter effect was also found but less pronounced in HFruD-fed mice, while insulin sensitivity and body weight remained unaffected. In male mice, expansion of white adipocytes along with decreased uncoupling protein 1 (UCP-1) expression and alterations of mitochondrial biogenesis was found after HFD and HFHSD feeding, while in female mice, UCP-1 expression was also reduced in the HFruD dietary group. Diet-induced cellular alterations were less pronounced in female mice. Our data demonstrate that high-fat rather than high fructose consumption drives metabolically disadvantageous alterations of adipocyte differentiation involving whitening and insulin resistance in a sex-dependent manner with most deleterious effects seen upon administration of combined sucrose and fat-enriched diet in male mice.

Metabolic effects of reduced growth hormone action in fatty liver disease

BackgroundAdult growth hormone (GH) deficiency is associated with fatty liver disease and shows several features of the metabolic syndrome. Vice versa obesity is characterized as a state of low GH function. Here, we aimed to define the role of hepatic GH signaling and its metabolic consequences in non-alcoholic fatty liver disease.MethodsIn humans, GHR and IGF-1 levels were determined in liver samples of 29 obese patients with non-alcoholic steatohepatitis (NASH) or simple steatosis. Cellular effects of GH on insulin signaling were investigated in GH receptor (GHR) knockdown HepG2 cells.ResultsHepatic IGF-1 expression levels reflecting GH action were significantly lower and fasting glucose concentrations higher in patients with NASH than in patients with simple steatosis. GHR knockdown in hepatocytes resulted in a scenario of high glucose output displayed by reduced glycogen content, increased gluconeogenesis and diminished insulin signaling.ConclusionsOur data suggest that GH signaling in the liver is diminished in patients with NASH and associated with deteriorated hepatic insulin sensitivity and metabolic activity. Reduced hepatic GH action might contribute to insulin resistance in obese patients with NASH.

Circulating Wnt inhibitory factor 1 levels are associated with development of cardiovascular disease

BACKGROUND AND AIMS Wnt signaling is involved in atherosclerotic plaque formation directly and indirectly by modulating cardiovascular risk factors. We investigated whether circulating concentrations of Wnt inhibitors are associated with cardiovascular events in subjects with intermediate cardiovascular risk. METHODS 904 non-diabetic subjects participating in the SAPHIR study were assessed. In the SAPHIR study, middle-aged women without overt atherosclerotic disease at study entry were followed up for 10 years. 88 patients of our study cohort developed cardiovascular disease at follow-up (CVD group). Subjects of the CVD group were 1:2 case-control matched for age, sex, BMI and smoking behavior with subjects without overt cardiovascular disease after a 10 year-follow-up (control group). 18 patients of the CVD group and 19 subjects of the control group were retrospectively excluded due to fulfilling exclusion criteria. Baseline circulating sclerostin, dickkopf (DKK)-1, secreted frizzled-related protein (SFRP)-1 and Wnt inhibitory factor (WIF)-1 levels were assessed by ELISA. RESULTS Baseline systemic SFRP-1 and WIF-1 levels were significantly higher in patients with cardiovascular events (n = 70) when compared to healthy controls (n = 157) while DKK-1 and sclerostin levels were similar in both groups. Logistic regression analysis revealed WIF-1 as a significant predictor of future cardiovascular events. CONCLUSIONS Our data suggest that increased SFRP-1 and WIF-1 levels precede the development of symptomatic atherosclerotic disease. Assessment of systemic WIF-1 levels, which turned out to be independently associated with CVD, might help to early identify patients at intermediate cardiovascular risk.