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Human Adipocytes: Proteomic Approaches
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Type 2 diabetes is characterized by increased levels of glucose in the blood originating from insulin resistance in insulin sensitive tissues and from reduced pancreatic insulin production. Around 400 million people in the world are diagnosed with type 2 diabetes and the correlation with obesity is strong. In addition to life style induction of obesity and type 2 diabetes, there are indications of genetic and epigenetic influences. This thesis has focused on the characterization of primary human adipocytes, who play a crucial role in the development of type 2 diabetes.

Histones are important proteins in chromatin dynamics and may be one of the factors behind epigenetic inheritance. In paper I, we characterized histone variants and posttranslational modifications in human adipocytes. Several of the specific posttranslational histone modifications we identified have been characterized in other cell types, but the majority was not previously known. Moreover, we identified a variant of histone H4 on protein level for the first time.

In paper II, we studied specific histone H3 methylations in the adipocytes. We found that overweight is correlated with a reduction of H3K4me2 while type 2 diabetes is associated with an increase of H3K4me3. This shows a genome-wide difference in important chromatin modifications that could help explain the epidemiologically shown association between epigenetics and metabolic health.

Caveolae is a plasma membrane structure involved in the initial and important steps of insulin signaling. In paper III we characterized the IQGAP1 interactome in human adipocytes and suggest that IQGAP1 is a link between caveolae and the cytoskeleton. Moreover, the amount of IQGAP1 is drastically lower in adipocytes from type 2 diabetic subjects compared with controls implying a potential role for IQGAP1 in insulin resistance.

In conclusion, this thesis provides new insights into the insulin signaling frameworks and the histone variants and modifications of human adipocytes.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2016. , s. 50
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1494
Nationell ämneskategori
Endokrinologi och diabetes Cellbiologi Cell- och molekylärbiologi Medicinsk genetik Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
URN: urn:nbn:se:liu:diva-125907DOI: 10.3384/diss.diva-125907ISBN: 978-91-7685-889-9 (tryckt)OAI: oai:DiVA.org:liu-125907DiVA, id: diva2:909978
Disputation
2016-03-23, Berzeliussalen, Campus US, Linköping, 09:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2016-03-08 Skapad: 2016-03-08 Senast uppdaterad: 2019-10-29Bibliografiskt granskad
Delarbeten
1. Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells
Öppna denna publikation i ny flik eller fönster >>Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells
2011 (Engelska)Ingår i: PLOS ONE, ISSN 1932-6203, Vol. 6, nr 1Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Epigenetic changes related to human disease cannot be fully addressed by studies of cells from cultures or from other mammals. We isolated human fat cells from subcutaneous abdominal fat tissue of female subjects and extracted histones from either purified nuclei or intact cells. Direct acid extraction of whole adipocytes was more efficient, yielding about 100 mu g of protein with histone content of 60%-70% from 10 mL of fat cells. Differential proteolysis of the protein extracts by trypsin or ArgC-protease followed by nanoLC/MS/MS with alternating CID/ETD peptide sequencing identified 19 histone variants. Four variants were found at the protein level for the first time; particularly HIST2H4B was identified besides the only H4 isoform earlier known to be expressed in humans. Three of the found H2A potentially organize small nucleosomes in transcriptionally active chromatin, while two H2AFY variants inactivate X chromosome in female cells. HIST1H2BA and three of the identified H1 variants had earlier been described only as oocyte or testis specific histones. H2AFX and H2AFY revealed differential and variable N-terminal processing. Out of 78 histone modifications by acetylation/trimethylation, methylation, dimethylation, phosphorylation and ubiquitination, identified from six subjects, 68 were found for the first time. Only 23 of these modifications were detected in two or more subjects, while all the others were individual specific. The direct acid extraction of adipocytes allows for personal epigenetic analyses of human fat tissue, for profiling of histone modifications related to obesity, diabetes and metabolic syndrome, as well as for selection of individual medical treatments.

Ort, förlag, år, upplaga, sidor
Public Library of Science (PLoS), 2011
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-65933 (URN)10.1371/journal.pone.0015960 (DOI)000286512900014 ()
Anmärkning

Original Publication: Asa Jufvas, Peter Strålfors and Alexander Vener, Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells, 2011, PLOS ONE, (6), 1. http://dx.doi.org/10.1371/journal.pone.0015960 Licensee: Public Library of Science (PLoS) http://www.plos.org/

Tillgänglig från: 2011-02-28 Skapad: 2011-02-28 Senast uppdaterad: 2016-03-08
2. Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes.
Öppna denna publikation i ny flik eller fönster >>Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes.
Visa övriga...
2013 (Engelska)Ingår i: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 5, nr 1, artikel-id 15Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies.

RESULTS: The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation compared with cells from normal-weight subjects. In contrast, trimethylation at lysine 4 was 40% higher in adipocytes from overweight diabetic subjects compared with normal-weight and overweight non-diabetic subjects. There was no association between level of modification and age of subjects.

CONCLUSIONS: The findings define genome-wide molecular modifications of histones in adipocytes that are directly associated with overweight and diabetes, and thus suggest a molecular basis for existing epidemiological evidence of epigenetic inheritance.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2013
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:liu:diva-99450 (URN)10.1186/1868-7083-5-15 (DOI)000329455000001 ()24004477 (PubMedID)
Tillgänglig från: 2013-10-18 Skapad: 2013-10-18 Senast uppdaterad: 2017-12-06Bibliografiskt granskad

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