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Retinol-binding protein 4 (RBP4) is the major transport protein for retinol in blood. Recent evidence from genetic mouse models shows that circulating RBP4 derives exclusively from hepatocytes. Because RBP4 is elevated in obesity and associates with the development of glucose intolerance and insulin resistance, we tested whether a liver-specific overexpression of RBP4 in mice impairs glucose homeostasis. We used adeno-associated viruses (AAV) that contain a highly liver-specific promoter to drive expression of murine RBP4 in livers of adult mice. The resulting increase in serum RBP4 levels in these mice was comparable with elevated levels that were reported in obesity. Surprisingly, we found that increasing circulating RBP4 had no effect on glucose homeostasis. Also during a high-fat diet challenge, elevated levels of RBP4 in the circulation failed to aggravate the worsening of systemic parameters of glucose and energy homeostasis. These findings show that liver-secreted RBP4 does not impair glucose homeostasis. We conclude that a modest increase of its circulating levels in mice, as observed in the obese, insulin-resistant state, is unlikely to be a causative factor for impaired glucose homeostasis.
Metabolic footprint and intestinal microbial changes in response to dietary proteins in a pig model
(2019)
Epidemiological studies revealed that dietary proteins can contribute to the modulation of the cardiovascular disease risk. Still, direct effects of dietary proteins on serum metabolites and other health-modulating factors have not been fully explored. Here, we compared the effects of dietary lupin protein with the effects of beef protein and casein on the serum metabolite profile, cardiovascular risk markers and the fecal microbiome. Pigs were fed diets containing 15% of the respective proteins for 4 weeks. A classification analysis of the serum metabolites revealed six biomarker sets of two metabolites each that discriminated between the intake of lupin protein, lean beef or casein. These biomarker sets included 1- and 3-methylhistidine, betaine, carnitine, homoarginine and methionine. The study revealed differences in the serum levels of the metabolites 1- and 3- methylhistidine, homoarginine, methionine and homocysteine, which are involved in the one-carbon cycle. However, these changes were not associated with differences in the methylation capacity or the histone methylation pattern. With the exception of serum homocysteine and homoarginine levels, other cardiovascular risk markers, such as the homeostatic model assessment index, trimethylamine-N-oxide and lipids, were not influenced by the dietary protein source. However, the composition of the fecal microorganisms was markedly changed by the dietary protein source. Lupin-protein-fed pigs exhibited more species from the phyla Bacteroidetes and Firmicutes than the other two groups. In conclusion, different dietary protein sources induce distinct serum metabolic fingerprints, have an impact on the cardiovascular risk and modulate the composition of the fecal microbiome. (C) 2019 Elsevier Inc. All rights reserved.
Oxidative posttranslationale Modifikationen endogener Proteine werden v. a. durch reaktive Sauerstoff- und Stickstoffspezies (engl:. Reactive Oxygen Species, ROS, reactive nitrogen species, RNS) hervorgerufen und können sowohl reversibel (z. B. Disulfidbindungen) als auch irreversibel (z. B. Proteincarbonyle) erfolgen [1–3]. Lange wurde angenommen, dass oxidative posttranslationale Proteinmodifikationen (oxPTPM) nur von untergeordneter Bedeutung für den Metabolismus sind. Tatsächlich handelt es sich jedoch um einen physiologischen Prozess, der über die Modulation der Proteinstruktur auch die Proteinfunktion (z. B. Enzymaktivität, Stabilität) und somit zahlreiche Stoffwechselwege wie den Energiestoffwechsel, die Immunfunktion, die vaskuläre Funktion sowie Apoptose und Genexpression beeinflussen kann. Die Bildung von oxPTPM ist dabei hochreguliert und hängt u. a. von der Proteinstruktur, der Verfügbarkeit von ROS und RNS sowie dem lokalen Mikromilieu der Zelle ab [2, 4].
Obesity is a key component of equine metabolic syndrome, which is highly associated with laminitis. Feed restriction and/or exercise are known to alleviate the detrimental effects of insulin resistance in obese ponies. However, little is known about changes in the serum lipid patterns due to weight reduction and its association with disease outcomes. Therefore, the lipid patterns in the serum of 14 mature ponies before and after a 14-week body weight reduction program (BWRP) were investigated by multi-one-dimensional thin-layer chromatography (MOD-TLC). Additionally, sensitivity to insulin (SI), body condition scores (BCS) and cresty neck scores (CNS) were measured. A BWRP resulted in a significant loss of body weight (P < 0.001), which was associated with beneficial decreases in BCS and CNS (both, P < 0.001). Serum lipid compositions revealed significantly increased free fatty acid (FFA), sphingomyelin (SM; both P < 0.001), total cholesterol (C) and cholesterol ester (CE) (both P < 0.01) and triacylglycerol (TG; P < 0.05) densities. Improvement of SI after the BWRP was associated with increases in neutral lipids (C, CE and TG, all P < 0.01), FFA and the phospholipid SM (both, P < 0.001). The results show that a BWRP in obese ponies was effective and associated with changes in the concentrations of neutral lipids and the phospholipid SM, indicating that SM may play a role in insulin signaling pathways and thus in the pathogenesis of insulin resistance and the progression of metabolic syndrome in obese ponies.
To study the role of the TTR-RBP4-ROH complex components (transthyretin, serum retinol binding protein, retinol) and of angiogenic factors PlGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1) in pregnancies complicated by small for gestational age infants (SGA). Case control study conducted on maternal serum collected between 11 + 0 to 13 + 6 weeks of gestation. TTR, RBP4, ROH, PlGF and sFlt-1 were measured in SGA patients (birth weight < 10%) who delivered at term (n = 37) and before 37 weeks of gestation (n = 17) and in a matched control group with uneventful pregnancies (n = 37). We found decreased RBP4 in SGA patients that delivered fetuses < 3% and in fetuses delivered after the 37 weeks of gestation compared to controls [1.50 (95% CI 1.40-1.75) vs 1.62 (95% CI 1.47-1.98), p < 0.05]. Further, we found lower PlGF and sFlt-1 concentrations in SGA that delivered before 37 weeks of gestation compared to controls (respectively, PIGF and sFlt-1: 39.7 pg/ml (95% CI 32.3-66.3) vs 62.9 pg/ml (95% CI 45.2-78.4) and 906 pg/ml (95% CI 727-1626) vs 1610 pg/ml (95% CI 1088-212), p < 0.05). First trimester maternal serum RBP4 and angiogenic factors PlGF and sFlt-1 can differently predict the timing of delivery of pregnancies complicated by SGA fetuses.
Background
The kidneys are essential for the metabolism of vitamin A (retinol) and its transport proteins retinol-binding protein 4 (RBP4) and transthyretin. Little is known about changes in serum concentration after living donor kidney transplantation (LDKT) as a consequence of unilateral nephrectomy; although an association of these parameters with the risk of cardiovascular diseases and insulin resistance has been suggested. Therefore we analyzed the concentration of retinol, RBP4, apoRBP4 and transthyretin in serum of 20 living-kidney donors and respective recipients at baseline as well as 6 weeks and 6 months after LDKT.
Results
As a consequence of LDKT, the kidney function of recipients was improved while the kidney function of donors was moderately reduced within 6 weeks after LDKT. With regard to vitamin A metabolism, the recipients revealed higher levels of retinol, RBP4, transthyretin and apoRBP4 before LDKT in comparison to donors. After LDKT, the levels of all four parameters decreased in serum of the recipients, while retinol, RBP4 as well as apoRBP4 serum levels of donors increased and remained increased during the follow-up period of 6 months.
Conclusion
LDKT is generally regarded as beneficial for allograft recipients and not particularly detrimental for the donors. However, it could be demonstrated in this study that a moderate reduction of kidney function by unilateral nephrectomy, resulted in an imbalance of components of vitamin A metabolism with a significant increase of retinol and RBP4 and apoRBP4 concentration in serum of donors.
In sub-Saharan Africa, infectious diseases and malnutrition constitute the main health problems in children, while adolescents and adults are increasingly facing cardio-metabolic conditions. Among adolescents as the largest population group in this region, we investigated the co-occurrence of infectious diseases, malnutrition and cardio-metabolic risk factors (CRFs), and evaluated demographic, socio-economic and medical risk factors for these entities. In a cross-sectional study among 188 adolescents in rural Ghana, malarial infection, common infectious diseases and Body Mass Index were assessed. We measured ferritin, C-reactive protein, retinol, fasting glucose and blood pressure. Socio-demographic data were documented. We analyzed the proportions (95% confidence interval, CI) and the cooccurrence of infectious diseases (malaria, other common diseases), malnutrition (underweight, stunting, iron deficiency, vitamin A deficiency [VAD]), and CRFs (overweight, obesity, impaired fasting glucose, hypertension). In logistic regression, odds ratios (OR) and 95% CIs were calculated for the associations with socio-demographic factors. In this Ghanaian population (age range, 14.4-15.5 years; males, 50%), the proportions were for infectious diseases 45% (95% CI: 38-52%), for malnutrition 50% (43-57%) and for CRFs 16% (11- 21%). Infectious diseases and malnutrition frequently co-existed (28%; 21-34%). Specifically, VAD increased the odds of non-malarial infectious diseases 3-fold (95% CI: 1.03, 10.19). Overlap of CRFs with infectious diseases (6%; 2-9%) or with malnutrition (7%; 3-11%) was also present. Male gender and low socio-economic status increased the odds of infectious diseases and malnutrition, respectively. Malarial infection, chronic malnutrition and VAD remain the predominant health problems among these Ghanaian adolescents. Investigating the relationships with evolving CRFs is warranted.
The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time-and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.