Lucia Rohrer - Academia.edu (original) (raw)

Papers by Lucia Rohrer

Circulation, Nov 25, 2014

Introduction: Roux-en-Y gastric bypass (RYGB) reduces body weight (BW) and cardiovascular (CV) mo... more Introduction: Roux-en-Y gastric bypass (RYGB) reduces body weight (BW) and cardiovascular (CV) mortality in morbidly obese patients (pts). We showed in rats that glucagon-like peptide-1 (GLP-1) contributes to improve endothelial vasorelaxation early after RYGB in a BW loss-independent manner. Hypothesis: Here, we investigated in rats and patients whether obesity-induced HDL dysfunction improves after RYGB by a GLP-1-dependent mechanism. Methods: Diet induced obese male Wistar rats undergoing RYGB received vehicle (RYv); sham-operated ad libitum fed rats received vehicle (ALv) or the GLP-1 analog liraglutide (AL-lira; 0.2 mg/kg BID). HDL was isolated after 8 days. In parallel, HDL was also isolated from 28 healthy subjects and 28 morbidly obese pts (BMI >40) before, 14 days and 12 weeks after RYGB. In endothelial cells stimulated with HDL, we assessed nitric oxide (NO) production by DAF-2 fluorescence and endothelial NO synthase (eNOS) protein dimerization. Moreover, we measured paraoxonase-1 (PON-1) antio...

High-density lipoprotein (HDL) is a mixture of complex particles mediating reverse cholesterol tr... more High-density lipoprotein (HDL) is a mixture of complex particles mediating reverse cholesterol transport in the human body and several cytoprotective activities. Despite its relevance for human health, many aspects of HDL-mediated lipid trafficking and cellular signaling remain elusive at the molecular level. During HDL's journey throughout the body, its function is mediated through interactions with cell surface receptors on different cell types. Using four different cellular model systems HDL is interacting with, we comparatively analyzed their surfaceomes to define the HDL receptome. Surfaceome analysis of EA.hy926, HEPG2, foam cells, and human aortic endothelial cells (HAEC) revealed the main currently known HDL-receptor scavenger receptor B1 (SCRB1), as well as 154 shared cell surface receptors representing potential HDL interaction receptor candidates. Since vascular endothelial growth factor A (VEGF-A) was recently found as a regulatory factor of transendothelial transpor...

Circulation Research, 2022

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of ... more Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. ...

Circulation, 2014

Journal of Biological Chemistry, 1991

Several vasoprotective functions of high-density lipoproteins (HDL) on the endothelium have been ... more Several vasoprotective functions of high-density lipoproteins (HDL) on the endothelium have been shown to depend on the presence of sphingosine-1-phosphate (S1P) receptors (S1PRs) as well as scavenger receptor class B type 1 (SR-B1). Interference with the presence of S1P or the activity of S1PR1 or S1PR3 mimics many effects seen by the interference with SR-B1. This raises the question on interactions between S1P receptors and SR-B1. We investigated the influence of S1PRs on SR-B1 expression in human aortic endothelial cells. Silencing or pharmacological inhibition of S1PR1 or S1PR3 down-regulated SCARB1 mRNA expression as well as SR-B1 protein abundance. RNA interference with S1PR1 or S1PR3 also decreased cellular association of 125I-HDL with HAECs. Further mechanistic studies showed that knockdown of S1PR1 or S1PR3 reduced SR-B1 protein by inducing its degradation through deceasing Akt activity. Moreover, silencing of S1PR1 or S1PR3 suppressed SCARB1 mRNA expression by decreasing c...

Journal of Lipid Research, 2020

Loss of pancreatic β-cell mass and function as a result of sustained ER stress is a core step in ... more Loss of pancreatic β-cell mass and function as a result of sustained ER stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog (Hh) signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca2+-ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the Hh signaling receptor Smoothened (SMO) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced β-cell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (OHC). Supplementation...

Journal of Lipid Research, 2018

Clear cell renal cell carcinomas (ccRCC) are characterized by inactivation of von Hippel-Lindau (... more Clear cell renal cell carcinomas (ccRCC) are characterized by inactivation of von Hippel-Lindau (VHL) gene and intracellular lipid accumulation by unknown pathomechanism. The immunochemical analysis of 356 RCCs revealed high abundance of apolipoproteins apoA-I and apoB as well as scavenger receptor BI (SR-BI) in the clear cell RCC subtype. Given the characteristic loss of VHL function in ccRCC, we used VHL-defective and VHL-proficient cells to study the potential influence of VHL on lipoprotein uptake. VHL-defective patient-derived ccRCC cells and cell lines (786O and RCC4) showed enhanced uptake as well as less re-secretion and degradation of radio-iodinated high and low density lipoproteins (125I-HDL and 125I-LDL) compared to the VHL-proficient cells. The ccRCC cells showed enhanced VEGF and SR-BI expression compared to normal kidney epithelial cells. Uptake of 125I-HDL and 125I-LDL by patient-derived normal kidney epithelial cells as well as VHL-re-expressing ccRCC cell lines 786-O-VHL and RCC4-O-VHL cells was strongly enhanced by VEGF treatment. The knock-down of VEGF co-receptor neuropilin (NRP1) as well as blocking of SR-BI significantly reduced the uptake of lipoproteins into ccRCC cells in vitro. LDL stimulated proliferation of 786-O cells more potently than 786-O-VHL cells in a NRP1-and SR-BI-dependent manner. In conclusion, enhanced lipoprotein uptake due to increased activities of VEGF/NRP1 and SR-BI promotes lipid accumulation and proliferation of VHL-defective ccRCC cells.

Proceedings of the National Academy of Sciences, 1993

We have isolated a gene coding for a fourth human somatostatin (somatotropin release-inhibiting f... more We have isolated a gene coding for a fourth human somatostatin (somatotropin release-inhibiting factor) receptor. This additional somatostatin receptor (hSSTR4) is specifically expressed in human fetal and adult brain and lung tissue. The deduced amino acid sequence of the receptor displays both sequence and structural homology to three cloned somatostatin receptors as well as to other members of the family of GTP-binding-protein-coupled seven-helix transmembrane-spanning receptors. Pharmacological characterization of the expressed receptor reveals specific, high-affinity binding of somatostatin 14 and somatostatin 28. Surprisingly, several well-characterized synthetic somatostatin analogs fail to exhibit high-affinity binding to hSSTR4, indicating the existence of pharmacologically different receptor subtypes. Our data suggest that the diverse biological effects exerted by somatostatin are mediated by a family of receptors with discrete patterns of expression and different pharmaco...

Arteriosclerosis, thrombosis, and vascular biology, May 1, 2017

Low- and high-density lipoproteins (LDL and HDL) must pass the endothelial layer to exert pro- an... more Low- and high-density lipoproteins (LDL and HDL) must pass the endothelial layer to exert pro- and antiatherogenic activities, respectively, within the vascular wall. However, the rate-limiting factors that mediate transendothelial transport of lipoproteins are yet little known. Therefore, we performed a high-throughput screen with kinase drug inhibitors to identify modulators of transendothelial LDL and HDL transport. Microscopy-based high-content screening was performed by incubating human aortic endothelial cells with 141 kinase-inhibiting drugs and fluorescent-labeled LDL or HDL. Inhibitors of vascular endothelial growth factor (VEGF) receptors (VEGFR) significantly decreased the uptake of HDL but not LDL. Silencing of VEGF receptor 2 significantly decreased cellular binding, association, and transendothelial transport of (125)I-HDL but not (125)I-LDL. RNA interference with VEGF receptor 1 or VEGF receptor 3 had no effect. Binding, uptake, and transport of HDL but not LDL were s...

Atherosclerosis, 2015

5.1.3 Co-localization of ApoA-I and HDL with markers of endocytosis 35 5.1.4 HDL is trafficking t... more 5.1.3 Co-localization of ApoA-I and HDL with markers of endocytosis 35 5.1.4 HDL is trafficking through different compartments over a period of 4 hours 42 5.1.5 HDL is passing the endothelial monolayer faster than it accumulates inside the vesicles identified 44 5.1.6 Colocalization of HDL with organelles 44 5.1.7 Role of the cytoskeleton on HDL trafficking 50 5.2 Volume enhancement of 1.4 nm Nanogold-HDL for visualization in EM 50 5.2.1 Increased detection sensitivity of volume silver enhancement of 1.4 nm nanogold HDL after HPF and FSF compared to classical on-section silver enhancement 51 5.2.2 1.4 nm nanogold LDL and 1.4 nm nanogold Albumin 52 5.2.3 High background on badly frozen samples, very low on well-frozen samples 52 5.3 Cellular localization of ABCA1, ABCG1, SR-BI and EL in endothelial cells and in bovine endothelium 54

European Heart Journal, 2013

Lipids and inflammation 767 plaque inflammation precedes the neovascular disease process has not ... more Lipids and inflammation 767 plaque inflammation precedes the neovascular disease process has not been fully elucidated. Contrast-enhanced ultrasound (CEUS) has been introduced as a technique to assess the presence of plaque neovascularization. Microwave radiometry (MR) allows in vivo non-invasive measurement of temperature of tissues, reflecting inflammatory activation. We assessed in intermediate carotid lesions the coincidence of carotid plaque inflammation assessed by MR, with plaque neovascularization measured by CEUS. Methods: Consecutive patients with coronary artery disease and carotid atherosclerosis underwent carotid ultrasound imaging, CEUS and MR. Plaque texture, plaque surface and plaque echogenicity were analysed. Contrast enhancement (CE) by CEUS was defined as the % percentage of signal intensity difference, prior and post contrast infusion. Thermal heterogeneity (T) was assigned as maximal temperature along the carotid artery minus minimum. Results: Eighty-six carotid arteries of 48 patients were included. Fatty plaques had higher CE% compared with mixed and calcified (21.44±2.70 vs 17.11±5.23 vs 8.55±2.42 p<0.01 for all comparisons). Heterogeneous plaques had higher CE% compared with homogenous (21.44±2.7 vs 14.66±6.02, p<0.01). Plaques with irregular surface had higher CE% compared with plaques with regular (18.29±5.09 vs 13.64±6.06 p<0.01). Fatty plaques had higher T compared with mixed and calcified (1.13±0.27 vs 0.95±0.34 vs 0.53±0.26°C, p<0.01 for all comparisons). Heterogeneous plaques had higher T compared with homogenous (1.13±0.27 vs 0.83±0.37°C p<0.01). Plaques with irregular surface had higher T compared with plaques with regular (1.05±0.32 vs 0.75±0.32°C p<0.01). There was a good correlation between T and CE (R=0.60, p<0.001). Increased CE% coincided with increased T in the majority of plaques (85.8%). Conclusions: Neovascularisation and inflammation coincide in carotid atheromatous plaques in mild lesions, as indicated by two noninvasive methods.

Proceedings of the National Academy of Sciences, 1991

Type I and type II scavenger receptors, which have been implicated in the development of atherosc... more Type I and type II scavenger receptors, which have been implicated in the development of atherosclerosis and other macrophage-associated functions, differ only by the presence in the type I receptor of an extracellular cysteine-rich C-terminal domain. Stable Chinese hamster ovary (CHO) cell transfectants expressing high levels of either the type I or type II bovine scavenger receptors have been generated. Type I and type II receptors in these cells mediated high-affinity saturable endocytosis of both 125I-labeled acetylated low density lipoprotein (LDL) and 125I-labeled oxidized LDL with the distinctive broad ligand specificity characteristic of scavenger receptors. After incubation for 2 days with acetylated LDL, the transfected cells accumulated oil red O-staining lipid droplets reminiscent of those in macrophage foam cells, whereas untransfected CHO cells did not. Thus, macrophage-specific gene products other than the scavenger receptor are not required for modified-LDL-induced i...

Nephrology Dialysis Transplantation, 2013

Introduction and Aims: Malnutrition and protein-energy wasting, as assessed by a combination of s... more Introduction and Aims: Malnutrition and protein-energy wasting, as assessed by a combination of several nutritional parameters, are associated with increased morbidity and mortality in hemodialysis (HD) patients. "Nutritional resilience" refers to the maintenance of an adequate nutritional status in the face of stressors such as intercurrent illness and hospitalization. We conducted a retrospective cohort study in incident HD patients with the aims of identifying changes in nutritional parameters around the time of hospitalization, and assessing predictors of nutritional resilience. Methods: The patient cohort was derived from the Fresenius Medical Care North America database, and included incident patients who 1) started HD between 2007 and 2012, 2) were hospitalized for 7-14 days during this period and 3) started HD >60 days prior to hospitalization and survived >60 days after hospitalization. Only data from the first hospitalization per patient during 2007-2012 were used. To assess temporal patterns of nutritional parameters, serum albumin (Alb), creatinine (Crea), phosphate (P), equilibrated normalized protein catabolic rate (enPCR) and interdialytic weight gain (IDWG) were plotted over 3 months prior to and after hospitalization. Change in albumin (the percent difference between serum albumin within 30 days before admission and within 30 days of discharge) was analyzed by hospitalization diagnosis groupings. Logistic regression was performed to assess factors associated with a decline in albumin >5% after hospitalization. Results: 31,632 patients were included in the analysis. Prior to hospitalization, most nutritional parameters declined, although there was an increase in enPCR, likely reflecting increased tissue catabolism (Figure).The greatest declines in albumin were observed in hospitalizations for injuries resulting in amputation or fracture (-9.3%) or other musculoskeletal injuries (-8.6%). Statistically significant factors that were "protective" against a >5% decline in albumin were higher creatinine, higher body mass index, lower IDWG, female gender, younger age, non-white race, shorter hospitalization, and cardiovascular disease as a comorbidity. Conclusions: Worsening of nutritional parameters is observed with hospitalization in the HD population, and the degree of albumin decline varies with type of hospitalization. These results will aid in developing a risk score for nutritional decline during hospitalization in HD patients and assist in identifying those who will benefit most from nutritional interventions.

The Journal of Immunology, 2012

Vascular endothelial cells (EC) are an exposed tissue with intimate contact with circulating Ag-s... more Vascular endothelial cells (EC) are an exposed tissue with intimate contact with circulating Ag-specific CTL. Experimental in vitro and clinical data suggested that endothelial cells present a different repertoire of MHC class I-restricted peptides compared with syngeneic leukocytes or epithelial cells. This endothelial-specific peptide repertoire might protect EC from CTL-mediated cell death. The HLA-A*02-restricted peptide profile of human EC and syngeneic B lymphoblastoid cells was biochemically analyzed and compared. For EC selective peptides, source protein expression, peptide binding affinity, and peptide–HLA-A*02 turnover were measured. The significance of abundant peptide presentation for target cell recognition by immunodominant CTL was tested by small interfering RNA treatment of EC to knock down the source proteins. High amounts of two peptides, PTRF56–64 and CD59106–114, were consistently detected in EC. This predominance of two endothelial peptides was explained by cell...

The Journal of Experimental Medicine, 2007

Environmental factors, including diet, play a central role in influencing the balance of normal i... more Environmental factors, including diet, play a central role in influencing the balance of normal immune homeostasis; however, many of the cellular mechanisms maintaining this balance remain to be elucidated. Using mouse models of genetic and high-fat/cholesterol diet–induced dyslipidemia, we examined the influence of dyslipidemia on T cell and dendritic cell (DC) responses in vivo and in vitro. We show that dyslipidemia inhibited Toll-like receptor (TLR)–induced production of proinflammatory cytokines, including interleukin (IL)-12, IL-6, and tumor necrosis factor-α, as well as up-regulation of costimulatory molecules by CD8α− DCs, but not by CD8α+ DCs, in vivo. Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses. As a consequence of this immune modulation, host resistance to Leishmania major was compromised. We found that oxidized low-density lipoprotein (oxLDL) was the key active component responsible for th...

European Respiratory Journal, 2013

Bilirubin is a strong antioxidant. Increased serum levels have been associated with lower respira... more Bilirubin is a strong antioxidant. Increased serum levels have been associated with lower respiratory disease and mortality risk. We studied the association of bilirubin with lung function in the Swiss study on Air Pollution and Lung Disease in adults (SAPALDIA) cohort. Associations between natural logarithmised bilirubin and forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and mean forced expiratory flow between 25%-75% of FVC (FEF25-75%) were tested using multiple linear regression in the whole study population (n54195) and strata of eversmoking and high body mass index (BMI, defined by the highest distribution quartile). Associations were retested with single nucleotide polymorphism rs6742078, a genetic determinant of bilirubin. High bilirubin levels were significantly associated with higher FEV1/FVC and FEF25-75% overall. Upon stratification, significant associations persisted in ever-smokers, amounting to 1.1% (95% CI 0.1-2.2%) increase in FEV1/FVC, and 116.2 mL?s-1 (95% CI-15.9-248.4 mL?s-1) in FEF25-75% per interquartile range of bilirubin exposure in smokers with high BMI. Associations were positive but nonsignificant in neversmokers with high BMI. Similarly, rs6742078 genotype TT was associated with increased FEV1/FVC and FEF25-75%. Our results suggest a possible protective role of bilirubin on lung tissue, which could be important for prevention and therapy. @ERSpublications Serum bilirubin is associated with lung function in subjects with low-grade inflammation from the general population http://ow.ly/tD3FP

Endocrinology, 2009

A low high-density lipoprotein (HDL) plasma concentration and the abundance of small dense low-de... more A low high-density lipoprotein (HDL) plasma concentration and the abundance of small dense low-density lipoproteins (LDL) are risk factors for developing type 2 diabetes. We therefore investigated whether HDL and LDL play a role in the regulation of pancreatic islet cell apoptosis, proliferation, and secretory function. Isolated mouse and human islets were exposed to plasma lipoproteins of healthy human donors. In murine and human β-cells, LDL decreased both proliferation and maximal glucose-stimulated insulin secretion. The comparative analysis of β-cells from wild-type and LDL receptor-deficient mice revealed that the inhibitory effect of LDL on insulin secretion but not proliferation requires the LDL receptor. HDL was found to modulate the survival of both human and murine islets by decreasing basal as well as IL-1β and glucose-induced apoptosis. IL-1β-induced β-cell apoptosis was also inhibited in the presence of either the delipidated protein or the deproteinated lipid moieties...