APOH is increased in the plasma and liver of type 2 diabetic patients with metabolic syndrome

Castro, Antoni; Lázaro, Iolanda; Selva, David M.; Céspedes, Ela; Girona, Josefa; NúriaPlana,; Guardiola, Montse; Cabré, Anna; Simó, Rafael; Masana, Luís

doi:10.1016/j.atherosclerosis.2009.09.072

Cited by 45 publications

(38 citation statements)

References 21 publications

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“…In the same study, SNPs within the ApoC3 locus have been linked with patients with metabolic syndrome (38). Likewise, elevated circulating ApoH levels have been associated with metabolic syndrome and type II diabetes mellitus (39). Taken together, these findings extend the potential importance of LRH-1 as a key factor in metabolic syndrome.…”

Section: Antiproliferative Mechanism Of Lrh-1 Inhibition Is Conservedsupporting

confidence: 61%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Colorectal cancers (CRCs) account for nearly 10% of all cancer deaths in industrialized countries. Recent evidence points to a central role for the nuclear receptor liver receptor homolog-1 (LRH-1) in intestinal tumorigenesis. Interaction of LRH-1 with the Wnt/β-catenin pathway, highly active in a critical subpopulation of CRC cells, underscores the importance of elucidating LRH-1's role in this disease. Reduction of LRH-1 diminishes tumor burden in murine models of CRC; however, it is not known whether LRH-1 is required for tumorigenesis, for proliferation, or for both. In this work, we address this question through shRNA-mediated silencing of LRH-1 in established CRC cell lines. LRH-1 mRNA knockdown results in significantly impaired proliferation in a cell line highly expressing the receptor and more modest impairment in a cell line with moderate LRH-1 expression. Cell-cycle analysis shows prolongation of G0/G1 with LRH-1 silencing, consistent with LRH-1 cellcycle influences in other tissues. Cluster analysis of microarray gene expression demonstrates significant genome wide alterations with major effects in cell-cycle regulation, signal transduction, bile acid and cholesterol metabolism, and control of apoptosis. This study demonstrates a critical proproliferative role for LRH-1 in established colon cancer cell lines. LRH-1 exerts its effects via multiple signaling networks. Our results suggest that selected CRC patients could benefit from LRH-1 inhibitors.C olorectal cancer (CRC) accounts for nearly 10% of all cancer deaths in the United States. Much is understood about maintenance, but little is known about molecules driving initiation or metastasis of CRCs. Recent discoveries in animal and cellular models of CRC suggest a role for the nuclear receptor liver receptor homolog-1 (LRH-1, also known as NR5A2) (1).LRH-1, previously thought to be constitutively active, has a functional hormone-binding pocket that binds phosphatidylcholines (2, 3). The structure of the hormone-binding domain of LRH-1 has been determined with four different phospholipids in the binding pocket (4-6).LRH-1 is vital; knockout mouse embryos fail to undergo gastrulation (7). LRH-1 is expressed in the adult in the gastrointestinal tract, including liver and pancreas, and is also present in ovaries, where it regulates steroidogenesis (8). It is highly expressed in intestinal crypts where it is believed to play a role in intestinal epithelial cell renewal (9). LRH-1 has prominent roles in development, metabolism, stem-cell pluripotency, and tumorigenesis (10-14).LRH-1 figures prominently in WNT signaling in the intestine (9, 13). The WNT gene family is a large, conserved signaling pathway with roles in development, cellular homeostasis, and tumorigenesis (15). WNT signaling activates β-catenin, an important transcriptional coactivator that is active in over 80% of CRCs (16). LRH-1 physically binds to β-catenin and functions synergistically in the regulation of certain target genes, including cyclin E1 (9).LRH-1 and β-catenin contribute to ...

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Section: Antiproliferative Mechanism Of Lrh-1 Inhibition Is Conservedsupporting

confidence: 61%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The signal peptide [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] is underlined in the figure. The protein was further subjected to PROSITE and ASC analyses (see "Bioinformatic analysis"), which indicated that the following cysteine residues are likely to be involved in disulfide bond formation and to be responsible for the Sushi domain secondary structure: C23-C66, C51-C79, C84-C124, C110-C137, C142-C188, C174-C200, C205-C248, and C234-C260.…”

Section: Resultsmentioning

confidence: 99%

“…2 ␤ 2 GPI plasma concentrations are strongly associated with the metabolic syndrome and cardiovascular disease in type 2 diabetic patients and could be considered as a clinical marker of cardiovascular risk. 3 This glycoprotein is also the most common target for antiphospholipid antibodies frequently associated with vascular cell dysfunction, 4 thrombotic events, and pro-atherogenic mechanisms. [5][6][7][8] In chronic disorders related to endothelial cell dysfunction, such as systemic lupus erythematosus, antiphospholipid antibody syndrome (APS), and atherosclerosis, ␤ 2 GPI plays a role as a target antigen for an immune-mediated attack, possibly influencing the progression of disease.…”

Section: Introductionmentioning

confidence: 99%

Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs

Buttari

Profumo

Capozzi

et al. 2011

Blood

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In chronic disorders related to endothelial cell dysfunction, plasma ␤ 2 glycoprotein I (␤ 2 GPI) plays a role as a target antigen of pathogenetic autoimmune responses. However, information is still lacking to clarify why ␤ 2 GPI triggers autoimmunity. It is possible that posttranslational modification of the protein, such as nonenzymatic glycosylation, leads to the formation of advanced glycation end products (AGEs). The aim of our study was to explore whether glucose-modified ␤ 2 GPI is able to interact and activate monocytederived immature dendritic cells (iDCs) from healthy human donors. SDS-PAGE and spectrofluorometric analyses indicated that ␤ 2 GPI incubated with glucose was sugar modified, and that this modification likely consisted of AGE formation, resulting in AGE-␤ 2 GPI. AGE-␤ 2 GPI caused phenotypical and functional maturation of iDCs involving the activation of p38 MAPK, ERK, and NF-B. It also induced on DCs a significant up-regulation of RAGE, the receptor for AGEs. Evidence for RAGE involvement comes from blocking experiments with an anti-RAGE mAb, confocal analysis, and coimmunoprecipitation experiments. AGE-␤ 2 GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes toward a Th2 polarization. These findings might explain in part the interactive role of ␤ 2 GPI, AGEs, and DCs in chronic disorders related to endothelial cell dysfunction. (Blood. 2011;117(23):6152-6161) Introduction ␤ 2 Glycoprotein I (␤ 2 GPI) or apolipoprotein H is an abundant plasma glycoprotein that binds to negatively charged phospholipids and is involved in clotting mechanisms and lipid pathways. 1 Studies performed in healthy individuals have shown a correlation between plasma ␤ 2 GPI and fasting glucose, lipids, and lipoprotein levels. 2 ␤ 2 GPI plasma concentrations are strongly associated with the metabolic syndrome and cardiovascular disease in type 2 diabetic patients and could be considered as a clinical marker of cardiovascular risk. 3 This glycoprotein is also the most common target for antiphospholipid antibodies frequently associated with vascular cell dysfunction, 4 thrombotic events, and pro-atherogenic mechanisms. [5][6][7][8] In chronic disorders related to endothelial cell dysfunction, such as systemic lupus erythematosus, antiphospholipid antibody syndrome (APS), and atherosclerosis, ␤ 2 GPI plays a role as a target antigen for an immune-mediated attack, possibly influencing the progression of disease. 9-13 ␤ 2 GPI stimulates a vigorous adaptive humoral response, but also a cellular immune response. 14-15 Cellular immunity to ␤ 2 GPI exists in patients with APS 14 and in healthy individuals. 16 Recently, we showed that ␤ 2 GPI is a T-cell target in patients with advanced carotid atherosclerotic plaques. 17 Although much is known about ␤ 2 GPI as a cofactor in autoimmune diseases, crucial information is still lacking to clarify why this abundant self-plasma protein is the target of autoimmune responses.The molecular structure and location of the major epitopic region(s) on the...

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“…However, another study showed that the level of β 2 GP I was not different between diabetic and non-diabetic patients matched for age, sex and body mass index. These results indicated that β 2 GP I levels rose in diabetic patients with obesity and metabolic syndromes [15]. …”

Section: Discussionmentioning

confidence: 99%

Effects of reduced β2-glycoprotein I on the expression of aortic matrix metalloproteinases and tissue inhibitor matrix metalloproteinases in diabetic mice

Wang

et al. 2014

BMC Cardiovasc Disord

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BackgroundReduced β2-glycoprotein I (reduced β2GP I), which has free sulfhydryl groups, is present in plasma and serum; it can protect vascular endothelial cells from damage due to oxidative stress in vitro. We investigated the effects of reduced β2GP I on the expression of various matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the aortas of diabetic mice.MethodsWe provided 120 female 8-week-old Balb/c mice with a high sugar, high fat diet. After 8 weeks they were injected with streptozotocin to induce diabetes. We treated mice in the mono dose groups with β2GP I, reduced β2GP I, or phosphate-buffered saline (PBS) on day 1 and fed them for 3 weeks. The mice in the complex dose groups were treated with β2GP I, reduced β2GP I, or PBS on days 1 and 22 and fed for 6 weeks. Control mice were given a standard chow diet. Blood lipids were measured at the end of 3 or 6 weeks, and aortas removed to observe morphological and molecular biological changes.ResultsThe low-density lipoprotein cholesterol levels in mice of the reduced β2GP I group were lower than those in the diabetic group. Aortic lipid deposition in the reduced β2GP I group was significantly less than in the diabetic control group. In the aortas, reduced β2GP I decreased MMP2/TIMP2 mRNA and protein expression levels, and MMP9/TIMP1 expression levels compared with those in diabetic controls. Reduced β2GP I down-regulated p38 mitogen-activated protein kinase (p38MAPK) mRNA expression and phosphorylated p38MAPK protein expression compared with those in diabetic controls of the complex dose group.ConclusionsReduced β2GP I plays a role in diabetic mice related to vascular protection, inhibiting vascular lipid deposition, and plaque formation by reducing MMPs/TIMPs expression through down-regulation of the p38MAPK signaling pathway.

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APOH is increased in the plasma and liver of type 2 diabetic patients with metabolic syndrome

Cited by 45 publications

References 21 publications

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs

Effects of reduced β2-glycoprotein I on the expression of aortic matrix metalloproteinases and tissue inhibitor matrix metalloproteinases in diabetic mice

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