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Lindquist, Susanne
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Publications (10 of 16) Show all publications
Lindquist, S., Alenius, G.-M., Berntson, L., Rantapää-Dahlqvist, S., Lundberg, L., Wang, Y. & Hernell, O. (2019). A novel target for treatment of inflammatory joint diseases. Paper presented at Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019. Annals of the Rheumatic Diseases, 78, 1525-1526
Open this publication in new window or tab >>A novel target for treatment of inflammatory joint diseases
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2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, p. 1525-1526Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: The bile salt-stimulated lipase (BSSL) is a hitherto unrecognized player in inflammation. Animals devoid of BSSL (knockout mice) are protected from developing collagen induced arthritis (CIA) and collagen antibody induced arthritis (CAIA), and antibodies directed towards BSSL has been proven to prevent or mitigate arthritis in mouse and rat arthritis models1. In humans, BSSL is present in blood2 and accumulate at sites of inflammation. Patients with acute pancreatitis have significantly increased plasma BSSL levels compared to healthy controls. Whether BSSL in blood originates from pancreas, inflammatory cells, or both remains to be elucidated.

Objectives: To determine BSSL concentration in blood samples from patients with inflammatory joint disorders and to evaluate possible relationships between circulating BSSL levels and disease-activity variables.

Methods: BSSL concentrations in plasma or serum were determined in patients with rheumatoid arthritis (RA), psoriasis arthritis (PsA), and juvenile idiopathic arthritis (JIA) by a sandwich enzyme-linked immunosorbent assay (ELISA). Correlations between BSSL concentrations and disease activity score, erythrocyte sedimentation rate (ESR), blood levels of C-reactive protein (CRP), S100A8/9, leukocyte- and neutrophil counts, proinflammatory cytokines and chemokines were analyzed using Spearman rank-order correlation.

Results: Significant correlations between BSSL concentration in plasma and disease activity score (DAS28, rS=0.31, p=0.007), ESR (rS=0.58, p<0.000), CRP (rS=0.42, p=0.012), leukocytes (rS=0.66, p<0.000), and neutrophils (rS=0.71, p<0.000) were found in RA. The BSSL plasma concentration decreased with duration of treatment with the TNFα inhibitor infliximab, in parallel with decreasing DAS28 score.

BSSL concentration was significantly higher in sera from PsA patients with both oligo- and polyarthritis compared with healthy controls. Moreover, BSSL concentration in serum correlated significantly with S100A8/A9 and CRP concentrations (rS=0.54, p<0.001 and rS=0.49, p<0.001, respectively). No correlation between levels of BSSL and cytokines or chemokines were found in RA or PsA plasma or serum, respectively.

In JIA, levels of BSSL in serum correlated significantly with JIA disease activity score (JADAS27) (rS=0.26, p=0.007), ESR (rS=0.47, p<0.000), and leukocytes (rS=0.32, p<0.000).

Conclusion: BSSL concentration in serum and plasma correlated with disease activity in patients with inflammatory joint disorders, i.e. RA, PsA and JIA. These data in humans support the relevance of our previous studies in rodents and therefore also our hypothesis 1 that BSSL is a novel target for treatment of inflammatory diseases.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-161720 (URN)10.1136/annrheumdis-2019-eular.2165 (DOI)000472207104460 ()
Conference
Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019
Available from: 2019-07-26 Created: 2019-07-26 Last updated: 2019-07-26Bibliographically approved
Wang, Y., Ding, F., Wang, T., Liu, W., Lindquist, S., Hernell, O., . . . Li, N. (2017). Purification and characterization of recombinant human bile salt-stimulated lipase expressed in milk of transgenic cloned cows. PLoS ONE, 12(5), Article ID e0176864.
Open this publication in new window or tab >>Purification and characterization of recombinant human bile salt-stimulated lipase expressed in milk of transgenic cloned cows
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176864Article in journal (Refereed) Published
Abstract [en]

Bile salt-stimulated lipase (BSSL) is a lipolytic digestive enzyme with broad substrate specificity secreted from exocrine pancreas into the intestinal lumen in all species and from the lactating mammary gland into the milk of some species, notably humans but not cows. BSSL in breast milk facilitates digestion and absorption of milk fat and promotes growth of small for gestational age preterm infants. Thus, purified recombinant human BSSL (rhBSSL) can be used for treatment of patients with fat malabsorption and expressing rhBSSL in the milk of transgenic cloned cows would therefore be a mean to meet a medical need. In the present study, a vector pBAC-hLF-hBSSL was constructed, which efficiently expressed active rhBSSL in milk of transgenic cloned cows to a concentration of 9.8 mg/ml. The rhBSSL purified from cow milk had the same enzymatic activity, N-terminal amino acid sequence, amino acid composition and isoelectric point and similar physicochemical characteristics as human native BSSL. Our study supports the use of transgenic cattle for the cost-competitive, large-scale production of therapeutic rhBSSL.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-136186 (URN)10.1371/journal.pone.0176864 (DOI)000400649500022 ()28475629 (PubMedID)
Available from: 2017-07-07 Created: 2017-07-07 Last updated: 2018-06-09Bibliographically approved
Vahid, H. M., Susanne, L., Shrikant, S. K., Thomas, B. & Jing-Xia, L. (2014). Analysis of Neurotrophic Factors in Limb and Extraocular Muscles of Mouse Model of Amyotrophic Lateral Sclerosis. PLoS ONE, 9(10), Article ID e109833.
Open this publication in new window or tab >>Analysis of Neurotrophic Factors in Limb and Extraocular Muscles of Mouse Model of Amyotrophic Lateral Sclerosis
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, article id e109833Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is currently an incurable fatal motor neuron syndrome characterized by progressive weakness, muscle wasting and death ensuing 3–5 years after diagnosis. Neurotrophic factors (NTFs) are known to be important in both nervous system development and maintenance. However, the attempt to translate the potential of NTFs into the therapeutic options remains limited despite substantial number of approaches, which have been tested clinically. Using quantitative RT-PCR (qRT-PCR) technique, the present study investigated mRNA expression of four different NTFs: brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4) and glial cell line-derived neurotrophic factor (GDNF) in limb muscles and extraocular muscles (EOMs) from SOD1G93A transgenic mice at early and terminal stages of ALS. General morphological examination revealed that muscle fibres were well preserved in both limb muscles and EOMs in early stage ALS mice. However, in terminal ALS mice, most muscle fibres were either atrophied or hypertrophied in limb muscles but unaffected in EOMs. qRT-PCR analysis showed that in early stage ALS mice, NT-4 was significantly down-regulated in limb muscles whereas NT-3 and GDNF were markedly up-regulated in EOMs. In terminal ALS mice, only GDNF was significantly up-regulated in limb muscles. We concluded that the early down-regulation of NT-4 in limb muscles is closely associated with muscle dystrophy and dysfunction at late stage, whereas the early up-regulations of GDNF and NT-3 in EOMs are closely associated with the relatively well-preserved muscle morphology at late stage. Collectively, the data suggested that comparing NTFs expression between limb muscles and EOMs from different stages of ALS animal models is a useful method in revealing the patho-physiology and progression of ALS, and eventually rescuing motor neuron in ALS patients.

Keywords
neurotrophins, neurotrophic factor, limb muscles, extraocular muscles, ALS
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:umu:diva-96545 (URN)10.1371/journal.pone.0109833 (DOI)000346766200057 ()
Available from: 2014-11-21 Created: 2014-11-21 Last updated: 2018-06-07Bibliographically approved
Lindquist, S., Andersson, E.-L., Lundberg, L. & Hernell, O. (2012). Bile salt-stimulated lipase plays an unexpected role in arthritis development in rodents. PLoS ONE, 7(10), e47006
Open this publication in new window or tab >>Bile salt-stimulated lipase plays an unexpected role in arthritis development in rodents
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47006-Article in journal (Refereed) Published
Abstract [en]

Objective: The present study aimed to explore the hypothesis that bile salt-stimulated lipase (BSSL), in addition to being a key enzyme in dietary fat digestion during early infancy, plays an important role in inflammation, notably arthritis. Methods: Collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rodents are commonly used experimental models that reproduce many of the pathogenic mechanisms of human rheumatoid arthritis, i.e. increased cellular infiltration, synovial hyperplasia, pannus formation, and erosion of cartilage and bone in the distal joints. We used the CIA model to compare the response in BSSL wild type (BSSL-WT) mice with BSSL-deficient 'knock-out' (BSSL-KO) and BSSL-heterozygous (BSSL-HET) littermates. We also investigated if intraperitoneal injection of BSSL-neutralizing antibodies affected the development or severity of CIA and PIA in mice and rats, respectively. Results: In two consecutive studies, we found that BSSL-KO male mice, in contrast to BSSL-WT littermates, were significantly protected from developing arthritis. We also found that BSSL-HET mice were less prone to develop disease compared to BSSL-WT mice, but not as resistant as BSSL-KO mice, suggesting a gene-dose effect. Moreover, we found that BSSL-neutralizing antibody injection reduced both the incidence and severity of CIA and PIA in rodents. Conclusion: Our data strongly support BSSL as a key player in the inflammatory process, at least in rodents. It also suggests the possibility that BSSL-neutralizing agents could serve as a therapeutic model to reduce the inflammatory response in humans.

Place, publisher, year, edition, pages
San Fransisco, USA: Public Library Science, 2012
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-61775 (URN)10.1371/journal.pone.0047006 (DOI)000309807700046 ()
Available from: 2012-11-27 Created: 2012-11-26 Last updated: 2018-06-08Bibliographically approved
Andersson, E.-L., Hernell, O., Bläckberg, L., Fält, H. & Lindquist, S. (2011). Bile salt-stimulated lipase and pancreatic lipase-related protein 2: key enzymes for lipid digestion in the newborn examined using the Caco-2 cell line. Journal of Lipid Research, 52(11), 1949-1956
Open this publication in new window or tab >>Bile salt-stimulated lipase and pancreatic lipase-related protein 2: key enzymes for lipid digestion in the newborn examined using the Caco-2 cell line
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2011 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, no 11, p. 1949-1956Article in journal (Refereed) Published
Abstract [en]

In rodents, bile salt-stimulated lipase (BSSL) and pancreatic lipase-related protein 2 (PLRP2) are the dominant lipases expressed in the exocrine pancreas in early life, when milk is the main food. The aim of the present study was to evaluate if BSSL and PLRP2 are also key enzymes in neonatal intestinal fat digestion. Using Caco-2 cells as a model for the small intestinal epithelium, purified human enzymes were incubated in the apical chamber with substrates and bile salt concentrations resembling the milieu of the small intestine of newborn infants. BSSL and PLRP2 hydrolyzed triglycerides (TG) to free fatty acids (FA) and glycerol. The cells took up the FA, which were reesterfied to TG. Together, BSSL and PLRP2 have a synergistic effect, increasing cellular uptake 4-fold compared to the sum of each lipase alone. A synergistic effect was also observed with retinyl ester as a substrate. PLRP2 hydrolyzed cholesteryl ester but not as efficiently as BSSL, and the two had an additive rather than synergistic effect. We conclude the key enzymes in intestinal fat digestion are different in newborns than later in life. Further studies are needed to fully understand this difference and its implication for designing optimal neonatal nutrition.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2011
Keywords
Bile acids and salts, Digestion, Fatty acid, Lipase, Nutrition, Triglycerides, Caco-2 cells, Fat, Newborn
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-46582 (URN)10.1194/jlr.M015685 (DOI)21865348 (PubMedID)
Available from: 2011-09-06 Created: 2011-09-06 Last updated: 2018-06-08Bibliographically approved
Stax, M. J., Naarding, M. A., Tanck, M. W., Lindquist, S., Hernell, O., Lyle, R., . . . Paxton, W. A. (2011). Binding of human milk to pathogen receptor DC-SIGN varies with bile salt-stimulated lipase (BSSL) gene polymorphism. PloS one, 6(2), e17316
Open this publication in new window or tab >>Binding of human milk to pathogen receptor DC-SIGN varies with bile salt-stimulated lipase (BSSL) gene polymorphism
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2011 (English)In: PloS one, ISSN 1932-6203, Vol. 6, no 2, p. e17316-Article in journal (Refereed) Published
Abstract [en]

The observed variation in DC-SIGN binding properties among milk samples may have implications for the risk of mucosal transmission of pathogens during breastfeeding.

Identifiers
urn:nbn:se:umu:diva-42898 (URN)10.1371/journal.pone.0017316 (DOI)21386960 (PubMedID)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
Johansson, B. B., Torsvik, J., Gundersen, L., Vesterhus, M., Ragvin, A., Tjora, E., . . . Njolstad, P. R. (2011). Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase gene (CEL-MODY): a protein misfolding disease. Journal of Biological Chemistry, 286(40), 34593-34605
Open this publication in new window or tab >>Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase gene (CEL-MODY): a protein misfolding disease
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2011 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 40, p. 34593-34605Article in journal (Refereed) Published
Abstract [en]

CEL-MODY, diabetes with pancreatic lipomatosis and exocrine dysfunction, is due to dominant frame-shift mutations in the acinar cell carboxyl-ester lipase gene (CEL). As Cel knock-out mice do not express the phenotype and the mutant protein has an altered, intrinsically disordered tandem repeat domain, we hypothesized that the disease mechanism might involve a negative effect of the mutant protein. In silico analysis showed that the pI of the tandem repeat was markedly increased from pH 3.3 in wild-type (WT) to 11.8 in mutant (MUT) human CEL. By stably over-expressing CEL-WT and CEL-MUT in HEK293 cells, we found similar glycosylation, ubiquitination, constitutive secretion and quality control of the two proteins. The CEL-MUT protein demonstrated, however, a high propensity to form aggregates found intracellularly and extracellularly. Different physico-chemical properties of the intrinsically disordered tandem repeat domains of WT and MUT proteins may contribute to different short-range and long-range interactions with the globular core domain and other macromolecules, including cell membranes. Thus, we propose that CEL-MODY is a protein misfolding disease caused by a negative gain-of-function effect of the mutant proteins in pancreatic tissues.

Place, publisher, year, edition, pages
Bethesda, Md.: American Society for Biochemistry and Molecular Biology, 2011
Keywords
Diabetes, ER stress, Genetic diseases, Metabolic diseases, Protein secretion, Protein stability, MODY, aggregation, carboxyl-ester lipase, proteopathy
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-45846 (URN)10.1074/jbc.M111.222679 (DOI)21784842 (PubMedID)
Available from: 2011-08-18 Created: 2011-08-18 Last updated: 2018-06-08Bibliographically approved
Lindquist, S. & Hernell, O. (2010). Lipid digestion and absorption in early life: an update.. Current opinion in clinical nutrition and metabolic care, 13(3), 314-20
Open this publication in new window or tab >>Lipid digestion and absorption in early life: an update.
2010 (English)In: Current opinion in clinical nutrition and metabolic care, ISSN 1363-1950, E-ISSN 1473-6519, Vol. 13, no 3, p. 314-20Article in journal (Refereed) Published
Abstract [en]

PURPOSE OF REVIEW: To highlight our understanding of digestion and absorption of dietary lipids in newborn infants, and specifically how these processes differ from those in children and adults. RECENT FINDINGS: The intestinal concentration of pancreatic triglyceride lipase (PTL) and bile salts is lower in newborns compared to later in life. Instead the PTL-related protein 2 and bile salt-stimulated lipase (BSSL) are the key enzymes secreted from pancreas, which in concerted action with gastric lipase operate to achieve efficient fat absorption during infancy. BSSL is also present in human milk which affects fat absorption and growth in breast-fed preterm infants. Under conditions of low luminal bile salt concentrations fat absorption is likely to occur from liquid crystalline product phases, which may result in absorption from an extended part of the small intestinal mucosal surfaces compared to adults. Chylomicron assembly and secretion also seem to adapt to the specific situation of the newborn. SUMMARY: Both fat digestion and product absorption are different in newborn infants compared to adults; other lipases are used for digestion and different physical-chemical phases may be used for product absorption. Why these differences occur is still an unsolved question of considerable importance to neonatal nutrition.

Keywords
human milk, lipases, lipid absorption, neonatology, nutrition
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-35025 (URN)10.1097/MCO.0b013e328337bbf0 (DOI)000277281500016 ()20179589 (PubMedID)
Available from: 2010-07-02 Created: 2010-07-02 Last updated: 2018-06-08Bibliographically approved
Li, X., Lindquist, S., Angsten, G., Yi, J., Olsson, T. & Hernell, O. (2008). Adiponectin and peroxisome proliferator-activated receptor gamma expression in subcutaneous and omental adipose tissue in children.. Acta Paediatr, 97(5), 630-5
Open this publication in new window or tab >>Adiponectin and peroxisome proliferator-activated receptor gamma expression in subcutaneous and omental adipose tissue in children.
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2008 (English)In: Acta Paediatr, ISSN 0803-5253, Vol. 97, no 5, p. 630-5Article in journal (Other academic) Published
Identifiers
urn:nbn:se:umu:diva-10171 (URN)18373719 (PubMedID)
Available from: 2008-06-26 Created: 2008-06-26 Last updated: 2018-06-09Bibliographically approved
Li, X., Lindquist, S., Lowe, M., Noppa, L. & Hernell, O. (2007). Bile Salt-Stimulated Lipase and Pancreatic Lipase-Related Protein 2 Are the Dominating Lipases in Neonatal Fat Digestion in Mice and Rats.. Pediatr Res
Open this publication in new window or tab >>Bile Salt-Stimulated Lipase and Pancreatic Lipase-Related Protein 2 Are the Dominating Lipases in Neonatal Fat Digestion in Mice and Rats.
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2007 (English)In: Pediatr Res, ISSN 0031-3998Article in journal (Refereed) Published
Abstract [en]

During infancy, the basic conditions for digestion of dietary fat differ from later in life. The bile salt-stimulated lipase (BSSL) is an enzyme expressed in the exocrine pancreas and in some species (including human) also in the lactating mammary gland and secreted with the milk. The aim of this study was to compare the ontogeny of four pancreatic lipases [BSSL, pancreatic triglyceride lipase (PL), pancreatic lipase-related protein 2 (PLRP2), and phospholipase A2 (PLA2)] in one species that supplies BSSL with milk (the mouse) and one that does not (the rat). We followed expression of the four pancreatic lipases from postnatal d 1 until after weaning in both species. We found that BSSL and PLRP2, two lipases with broad substrate specificity, dominated. It was not until weaning that significant expression of PL and PLA2 were induced. Thus, BSSL and PLRP2 seem to be responsible for fat digestion as long as milk is the main food. Moreover, the early temporal pattern of BSSL expression differed between species. We speculate that the milk-borne BSSL is able to compensate for a slower ontogeny of pancreatic BSSL expression in the mouse.

PMID: 17805199 [PubMed - as supplied by publisher]

Keywords
Fat, BSSL, infancy
Identifiers
urn:nbn:se:umu:diva-18038 (URN)17805199 (PubMedID)
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2018-06-09Bibliographically approved
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