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1.
Sci Rep ; 14(1): 14732, 2024 06 26.
Article in English | MEDLINE | ID: mdl-38926604

ABSTRACT

Excess amounts of histones in the cell induce mitotic chromosome loss and genomic instability, and are therefore detrimental to cell survival. In yeast, excess histones are degraded by the proteasome mediated via the DNA damage response factor Rad53. Histone expression, therefore, is tightly regulated at the protein level. Our understanding of the transcriptional regulation of histone genes is far from complete. In this study, we found that calcineurin inhibitor treatment increased histone protein levels, and that the transcription factor NFATc1 (nuclear factor of activated T cells 1) repressed histone transcription and acts downstream of the calcineurin. We further revealed that NFATc1 binds to the promoter regions of many histone genes and that histone transcription is downregulated in a manner dependent on intracellular calcium levels. Indeed, overexpression of histone H3 markedly inhibited cell proliferation. Taken together, these findings suggest that NFATc1 prevents the detrimental effects of histone H3 accumulation by inhibiting expression of histone at the transcriptional level.


Subject(s)
Calcineurin , Histones , NFATC Transcription Factors , NFATC Transcription Factors/metabolism , NFATC Transcription Factors/genetics , Histones/metabolism , Calcineurin/metabolism , Humans , Cell Proliferation , Gene Expression Regulation , Promoter Regions, Genetic , Signal Transduction , Transcription, Genetic , Calcium/metabolism
2.
Life Sci Alliance ; 7(8)2024 Aug.
Article in English | MEDLINE | ID: mdl-38803221

ABSTRACT

FK506-binding protein 52 (FKBP52) is a member of the FKBP family of proline isomerases. FKBP52 is up-regulated in various cancers and functions as a positive regulator of steroid hormone receptors. Depletion of FKBP52 is known to inhibit cell proliferation; however, the detailed mechanism remains poorly understood. In this study, we found that FKBP52 depletion decreased MDM2 transcription, leading to stabilization of p53, and suppressed cell proliferation. We identified NFATc1 and NFATc3 as transcription factors that regulate MDM2 We also found that FKBP52 associated with NFATc3 and facilitated its nuclear translocation. In addition, calcineurin, a well-known Ca2+ phosphatase essential for activation of NFAT, plays a role in MDM2 transcription. Supporting this notion, MDM2 expression was found to be regulated by intracellular Ca2+ Taken together, these findings reveal a new role of FKBP52 in promoting cell proliferation via the NFAT-MDM2-p53 axis, and indicate that inhibition of FKBP52 could be a new therapeutic tool to activate p53 and inhibit cell proliferation.


Subject(s)
Cell Proliferation , NFATC Transcription Factors , Proto-Oncogene Proteins c-mdm2 , Tacrolimus Binding Proteins , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/metabolism , Tacrolimus Binding Proteins/metabolism , Tacrolimus Binding Proteins/genetics , Cell Proliferation/genetics , NFATC Transcription Factors/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Cell Line, Tumor , Calcium/metabolism , Calcineurin/metabolism , Gene Expression Regulation, Neoplastic , Neoplasms/metabolism , Neoplasms/genetics , Neoplasms/pathology , Signal Transduction
3.
J Biol Chem ; 300(4): 107209, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38519029

ABSTRACT

FOXO1 is a transcription factor and potential tumor suppressor that is negatively regulated downstream of PI3K-PKB/AKT signaling. Paradoxically, FOXO also promotes tumor growth, but the detailed mechanisms behind this role of FOXO are not fully understood. In this study, we revealed a molecular cascade by which the Thr24 residue of FOXO1 is phosphorylated by AKT and is dephosphorylated by calcineurin, which is a Ca2+-dependent protein phosphatase. Curiously, single nucleotide somatic mutations of FOXO1 in cancer occur frequently at and near Thr24. Using a calcineurin inhibitor and shRNA directed against calcineurin, we revealed that calcineurin-mediated dephosphorylation of Thr24 regulates FOXO1 protein stability. We also found that FOXO1 binds to the promoter region of MDM2 and activates transcription, which in turn promotes MDM2-mediated ubiquitination and degradation of p53. FOXO3a and FOXO4 are shown to control p53 activity; however, the significance of FOXO1 in p53 regulation remains largely unknown. Supporting this notion, FOXO1 depletion increased p53 and p21 protein levels in association with the inhibition of cell proliferation. Taken together, these results indicate that FOXO1 is stabilized by calcineurin-mediated dephosphorylation and that FOXO1 supports cancer cell proliferation by promoting MDM2 transcription and subsequent p53 degradation.


Subject(s)
Calcineurin , Cell Proliferation , Forkhead Box Protein O1 , Proteolysis , Proto-Oncogene Proteins c-mdm2 , Tumor Suppressor Protein p53 , Proto-Oncogene Proteins c-mdm2/metabolism , Proto-Oncogene Proteins c-mdm2/genetics , Humans , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Forkhead Box Protein O1/metabolism , Forkhead Box Protein O1/genetics , Calcineurin/metabolism , Calcineurin/genetics , Phosphorylation , Ubiquitination , Cell Line, Tumor , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/genetics , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Protein Stability
4.
J Biochem ; 175(3): 235-244, 2024 Mar 04.
Article in English | MEDLINE | ID: mdl-38030387

ABSTRACT

The transcription factor NFAT plays key roles in multiple biological activities, such as immune responses, tissue development and malignant transformation. NFAT is dephosphorylated by calcineurin, which is activated by intracellular calcium levels, and translocated into the nucleus, resulting in transcriptional activation. Calcineurin dephosphorylates various target proteins and regulates their functions. However, the regulation of NFAT degradation is largely unknown, and it is unclear whether calcineurin contributes to the stability of NFAT. We investigated the effect of calcineurin inhibition on NFAT protein stability and found that the dephosphorylation of NFAT by calcineurin promotes the NFAT stabilization, whereas calcineurin mutant that is defective in phosphatase activity was unable to stabilize NFAT. Increased intracellular calcium ion concentration, which is essential for calcineurin activation, also induced NFAT stability. In addition, we identified S-phase kinase associated protein 2 (Skp2), an F-box protein of the SCF ubiquitin ligase complex, as a factor mediating degradation of NFAT when calcineurin was depleted. In summary, these findings revealed that the dephosphorylation of NFAT by calcineurin protects NFAT from degradation by Skp2 and promotes its protein stability.


Subject(s)
Calcineurin , NFATC Transcription Factors , Calcineurin/metabolism , NFATC Transcription Factors/metabolism , Calcium/metabolism , S-Phase Kinase-Associated Proteins , Proteins/metabolism
5.
Sci Rep ; 13(1): 13116, 2023 08 12.
Article in English | MEDLINE | ID: mdl-37573463

ABSTRACT

c-Myc, a transcription factor, induces cell proliferation and is often aberrantly or highly expressed in cancers. However, molecular mechanisms underlying this aberrantly high expression remain unclear. Here, we found that intracellular Ca2+ concentration regulates c-Myc oncoprotein stability. We identified that calcineurin, a Ca2+-dependent protein phosphatase, is a positive regulator of c-Myc expression. Calcineurin depletion suppresses c-Myc targeted gene expression and c-Myc degradation. Calcineurin directly dephosphorylates Thr58 and Ser62 in c-Myc, which inhibit binding to the ubiquitin ligase Fbxw7. Mutations within the autoinhibitory domain of calcineurin, most frequently observed in cancer, may increase phosphatase activity, increasing c-Myc transcriptional activity in turn. Notably, calcineurin inhibition with FK506 decreased c-Myc expression with enhanced Thr58 and Ser62 phosphorylation in a mouse xenograft model. Thus, calcineurin can stabilize c-Myc, promoting tumor progression. Therefore, we propose that Ca2+ signaling dysfunction affects cancer-cell proliferation via increased c-Myc stability and that calcineurin inhibition could be a new therapeutic target of c-Myc-overexpressing cancers.


Subject(s)
Calcineurin , Transcription Factors , Humans , Mice , Animals , Calcineurin/genetics , Calcineurin/metabolism , Transcriptional Activation , Transcription Factors/metabolism , Gene Expression Regulation , Protein Processing, Post-Translational
6.
Biochem Biophys Res Commun ; 641: 84-92, 2023 01 22.
Article in English | MEDLINE | ID: mdl-36525928

ABSTRACT

The epidermal growth factor receptor (EGFR) is highly expressed or abnormally activated in several types of cancers, such as lung and colorectal cancers. Inhibitors that suppress the tyrosine kinase activity of EGFR have been used in the treatment of lung cancer. However, resistance to these inhibitors has become an issue in cancer treatment, and the development of new therapies that inhibit EGFR is desired. We found that calcineurin, a Ca2+/calmodulin-activated serine/threonine phosphatase, is a novel regulator of EGFR. Inhibition of calcineurin by FK506 treatment or calcineurin depletion promoted EGFR degradation in cancer cells. In addition, we found that calcineurin dephosphorylates EGFR at serine (S)1046/1047, which in turn stabilizes EGFR. Furthermore, in human colon cancer cells transplanted into mice, the inhibition of calcineurin by FK506 decreased EGFR expression. These results indicate that calcineurin stabilizes EGFR by dephosphorylating S1046/1047 and promotes tumor growth. These findings suggest that calcineurin may be a new therapeutic target for cancers with high EGFR expression or activation.


Subject(s)
Calcineurin , Tacrolimus , Humans , Animals , Mice , Calcineurin/metabolism , Tacrolimus/pharmacology , Serine/metabolism , ErbB Receptors/metabolism , Phosphorylation
7.
Bioessays ; 44(12): e2200148, 2022 12.
Article in English | MEDLINE | ID: mdl-36192154

ABSTRACT

Estrogen receptor α (ERα) is a ligand-dependent transcription factor that regulates the expression of estrogen-responsive genes. Approximately 70% of patients with breast cancer are ERα positive. Estrogen stimulates cancer cell proliferation and contributes to tumor progression. Endocrine therapies, which suppress the ERα signaling pathway, significantly improve the prognosis of patients with breast cancer. However, the development of de novo or acquired endocrine therapy resistance remains a barrier to breast cancer treatment. Therefore, understanding the regulatory mechanisms of ERα is essential to overcome the resistance to treatment. This review focuses on the regulation of ERα expression, including copy number variation, epigenetic regulation, transcriptional regulation, and stability, as well as functions from the point of view post-translational modifications.


Subject(s)
Breast Neoplasms , Estrogen Receptor alpha , Humans , Female , Estrogen Receptor alpha/genetics , DNA Copy Number Variations , Epigenesis, Genetic , Breast Neoplasms/genetics , Estrogens
8.
Proc Natl Acad Sci U S A ; 119(15): e2110256119, 2022 04 12.
Article in English | MEDLINE | ID: mdl-35394865

ABSTRACT

Estrogen receptor α (ERα) is a transcription factor that induces cell proliferation and exhibits increased expression in a large subset of breast cancers. The molecular mechanisms underlying the up-regulation of ERα activity, however, remain poorly understood. We identified FK506-binding protein 52 (FKBP52) as a factor associated with poor prognosis of individuals with ERα-positive breast cancer. We found that FKBP52 interacts with breast cancer susceptibility gene 1 and stabilizes ERα, and is essential for breast cancer cell proliferation. FKBP52 depletion resulted in decreased ERα expression and proliferation in breast cancer cell lines, including MCF7-derived fulvestrant resistance (MFR) cells, suggesting that inhibiting FKBP52 may provide a therapeutic effect for endocrine therapy­resistant breast cancer. In contrast, FKBP51, a closely related molecule to FKBP52, reduced the stability of ERα. Consistent with these findings, FKBP51 was more abundantly expressed in normal tissues than in cancer cells, suggesting that these FKBPs may function in the opposite direction. Collectively, our study shows that FKBP52 and FKBP51 regulate ERα stability in a reciprocal manner and reveals a regulatory mechanism by which the expression of ERα is controlled.


Subject(s)
Breast Neoplasms , Estrogen Receptor alpha , Tacrolimus Binding Proteins , Breast Neoplasms/metabolism , Cell Line, Tumor , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Protein Stability , Tacrolimus Binding Proteins/metabolism
9.
Mol Oncol ; 16(4): 940-956, 2022 02.
Article in English | MEDLINE | ID: mdl-34057812

ABSTRACT

The growth of prostate cancer is dependent on the androgen receptor (AR), which serves as a ligand-specific transcription factor. Although two immunophilins, FKBP51 and FKBP52, are known to regulate AR activity, the precise mechanism remains unclear. We found that depletion of either FKBP51 or FKBP52 reduced AR dimer formation, chromatin binding, and phosphorylation, suggesting defective AR signaling. Furthermore, the peptidyl-prolyl cis/trans isomerase activity of FKBP51 was found to be required for AR dimer formation and cancer cell growth. Treatment of prostate cancer cells with FK506, which binds to the FK1 domain of FKBPs, or with MJC13, an inhibitor of FKBP52-AR signaling, also inhibited AR dimer formation. Finally, elevated expression of FKBP52 was associated with a higher rate of prostate-specific antigen recurrence in patients with prostate cancer. Collectively, these results suggest that FKBP51 and FKBP52 might be promising targets for prostate cancer treatment through the inhibition of AR dimer formation.


Subject(s)
Prostatic Neoplasms , Receptors, Androgen , Cell Proliferation , Dimerization , Humans , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Tacrolimus Binding Proteins/genetics , Tacrolimus Binding Proteins/metabolism
10.
Proc Natl Acad Sci U S A ; 118(44)2021 11 02.
Article in English | MEDLINE | ID: mdl-34711683

ABSTRACT

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to ß-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118 Finally, the expression of the calcineurin A-α gene (PPP3CA) was associated with poor prognosis in ER-α-positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α-positive breast cancer.


Subject(s)
Breast Neoplasms/metabolism , Calcineurin/metabolism , Estrogen Receptor alpha/metabolism , Calcineurin/physiology , Cell Line, Tumor , Estradiol/pharmacology , Estrogen Receptor alpha/drug effects , Estrogens/metabolism , Female , Gene Expression/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Proteasome Endopeptidase Complex/metabolism , Protein Processing, Post-Translational/drug effects , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination/drug effects
11.
Cancer Sci ; 112(7): 2739-2752, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33939241

ABSTRACT

DNA damage induces transcriptional repression of E2F1 target genes and a reduction in histone H3-Thr11 phosphorylation (H3-pThr11 ) at E2F1 target gene promoters. Dephosphorylation of H3-pThr11 is partly mediated by Chk1 kinase and protein phosphatase 1γ (PP1γ) phosphatase. Here, we isolated NIPP1 as a regulator of PP1γ-mediated H3-pThr11 by surveying nearly 200 PP1 interactor proteins. We found that NIPP1 inhibits PP1γ-mediated dephosphorylation of H3-pThr11 both in vivo and in vitro. By generating NIPP1-depleted cells, we showed that NIPP1 is required for cell proliferation and the expression of E2F1 target genes. Upon DNA damage, activated protein kinase A (PKA) phosphorylated the NIPP1-Ser199 residue, adjacent to the PP1 binding motif (RVxF), and triggered the dissociation of NIPP1 from PP1γ, leading to the activation of PP1γ. Furthermore, the inhibition of PKA activity led to the activation of E2F target genes. Statistical analysis confirmed that the expression of NIPP1 was positively correlated with E2F target genes. Taken together, these findings demonstrate that the PP1 regulatory subunit NIPP1 modulates E2F1 target genes by linking PKA and PP1γ during DNA damage.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , DNA Damage , E2F1 Transcription Factor/genetics , Endoribonucleases/metabolism , Histones/metabolism , Phosphoprotein Phosphatases/metabolism , Protein Phosphatase 1/metabolism , RNA-Binding Proteins/metabolism , CRISPR-Cas Systems , Cell Proliferation , Cells, Cultured , Checkpoint Kinase 1/metabolism , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Endoribonucleases/deficiency , Endoribonucleases/isolation & purification , Epigenetic Repression , Gene Expression Regulation , Humans , Phosphoprotein Phosphatases/deficiency , Phosphoprotein Phosphatases/isolation & purification , Phosphorylation , Promoter Regions, Genetic , Protein Processing, Post-Translational , RNA, Messenger/metabolism , RNA-Binding Proteins/isolation & purification , Receptors, Neuropeptide Y/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , Ultraviolet Rays
12.
Genes Cells ; 26(6): 447-454, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33848395

ABSTRACT

UHRF1 (Ubiquitin-like with PHD and ring finger domains 1) regulates DNA methylation and histone modifications and plays a key role in cell proliferation and the DNA damage response. However, the function of UHRF2, a paralog of UHRF1, in the DNA damage response remains largely unknown. Here, we show that UHRF2 is essential for maintaining cell viability after UV irradiation, as well as for the proliferation of cancer cells. UHRF2 was found to physically interact with ATR in a DNA damage-dependent manner through UHRF2's TTD domain. In addition, phosphorylation of threonine at position 1989, which is required for UV-induced activation of ATR, was impaired in cells depleted of UHRF2, suggesting that UHRF2 is essential in ATR activation. In conclusion, these results suggest a new regulatory mechanism of ATR activation mediated by UHRF2.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Ultraviolet Rays , Cell Death/radiation effects , Cell Line, Tumor , Cell Proliferation/radiation effects , Checkpoint Kinase 1/metabolism , DNA Damage , Humans , Protein Binding/radiation effects
13.
Sci Rep ; 9(1): 12779, 2019 09 04.
Article in English | MEDLINE | ID: mdl-31484966

ABSTRACT

The Calcineurin/NFAT (nuclear factor of activated T cells) pathway plays an essential role in the tumorigenic and metastatic properties in breast cancer. The molecular mechanism of the antiproliferative effect of calcineurin inhibition, however, is poorly understood. We found that calcineurin inhibition delayed cell cycle progression at G1/S, and promoted cyclin D1 degradation by inhibiting dephosphorylation at T286. Importantly, overexpression of cyclin D1 partially rescued delayed G1/S progression, thereby revealing cyclin D1 as a key factor downstream of calcineurin inhibition. Cyclin D1 upregulation is observed in human invasive breast cancers, and our findings indicate that dysregulation of T286 phosphorylation could play a role in this phenomenon. We therefore propose that targeting site specific phosphorylation of cyclin D1 could be a potential strategy for clinical intervention of invasive breast cancer.


Subject(s)
Breast Neoplasms/metabolism , Calcineurin/metabolism , Cyclin D1/metabolism , G1 Phase , S Phase , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Calcineurin/genetics , Cell Line, Tumor , Cyclin D1/genetics , Female , Humans , Neoplasm Invasiveness , Phosphorylation
14.
Gen Comp Endocrinol ; 261: 31-39, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29360464

ABSTRACT

Melanocortin 4 receptor (MC4R), which is a member of the G protein-coupled receptor (GPCR) family, mediates regulation of energy homeostasis upon the binding of α-melanocyte-stimulating hormone (α-MSH) in the central nervous system (CNS). Melanocortin 2 receptor accessory protein 2 (MRAP2) modulates the function of MC4R. We performed cDNA cloning of cat MC4R and MRAP2 and characterized their amino acid sequences, mRNA expression patterns in cat tissues, protein-protein interactions, and functions. We found high sequence homology (>88%) with other mammalian MC4R and MRAP2 encoding 332 and 206 amino acid residues, respectively. Reverse transcription-polymerase chain reaction analysis revealed that cat MC4R and MRAP2 mRNA were expressed highly in the CNS. In CHO-K1 cells transfected with cat MC4R, stimulation with α-MSH increased intracellular cyclic adenosine monophosphate (cAMP) concentration in a dose-dependent manner. Furthermore, the presence of MRAP2 enhanced the cat MC4R-mediated cAMP production. These results suggested that cat MC4R acts as a neuronal mediator in the CNS and that its function is modulated by MRAP2. In addition, our NanoBiT study showed the dynamics of their interactions in living cells; stimulation with α-MSH slightly affected the interaction between MC4R and MRAP2, and did not affect MC4R homodimerization, suggesting that they interact in the basal state and that structural change of MC4R by activation may affect the interaction between MC4R and MRAP2.


Subject(s)
Receptor Activity-Modifying Proteins/genetics , Receptor, Melanocortin, Type 4/genetics , Amino Acid Sequence , Animals , Base Sequence , CHO Cells , Cats , Cricetinae , Cricetulus , Cyclic AMP/metabolism , DNA, Complementary/genetics , Gene Expression Profiling , Glycosylation , Homeostasis , Protein Binding , Protein Multimerization , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor Activity-Modifying Proteins/chemistry , Receptor Activity-Modifying Proteins/metabolism , Receptor, Melanocortin, Type 4/chemistry , alpha-MSH/metabolism
15.
J Vet Med Sci ; 77(12): 1681-4, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26165138

ABSTRACT

Nuclear factor κB (NF-κB) is a key factor in the development of chronic inflammation and is deeply involved in age-related and metabolic diseases development. These diseases have become a serious problem in cats. Sirtuin 1 (SIRT1) is associated with aging and metabolism through maintaining inflammation via NF-κB. In addition, fibroblasts are considered an important factor in the development of chronic inflammation. Therefore, we aimed to examine the effect of cat SIRT1 (cSIRT1) on NF-κB in cat fibroblast cells. The up-regulation of NF-κB transcriptional activity and pro-inflammatory cytokine mRNA expression by p65 subunit of NF-κB and lipopolysaccharide was suppressed by cSIRT1 in cat fibroblast cells. Our findings show that cSIRT1 is involved in the suppression of inflammation in cat fibroblast cells.


Subject(s)
Cats , Fibroblasts/drug effects , NF-kappa B/metabolism , Sirtuin 1/pharmacology , Animals , Cells, Cultured , Cytokines , Fibroblasts/metabolism , Gene Expression Regulation/drug effects , Inflammation , NF-kappa B/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription, Genetic , Up-Regulation
16.
Front Vet Sci ; 2: 34, 2015.
Article in English | MEDLINE | ID: mdl-26664963

ABSTRACT

Oxidized low-density lipoprotein (LDL) is thought to play an important role in the inflammatory response associated with human obesity. The purpose of this preliminary study was to determine oxidized LDL concentrations in healthy dogs and cats, and to evaluate whether obesity affects oxidized LDL concentration, using 39 cats and 19 dogs that had visited two different veterinary clinics in Japan. We hypothesized that oxidized LDL concentrations measured against body condition score (BCS) may have a potential value in evaluating the qualities of accumulated or circulating lipids in obese dogs and cats that do not show signs of metabolic diseases. The mean oxidized LDL value in BCS3 dogs (2.4 ± 0.9 µg/dl) was very similar to that of BCS5 dogs (2.2 ± 0.3 µg/dl). The mean oxidized LDL value of BCS4 dogs was 7.2 ± 10.3 µg/dl and the highest among three groups. BCS4 dogs included two dogs whose oxidized LDL values were higher than the mean oxidized LDL value of healthy humans (11.2 ± 0.3 µg/dl). On the other hand, the mean oxidized LDL value of BCS3 cats was 2.5 ± 0.9 µg/dl, and those of BCS4 and 5 cats were higher than that of BCS3, but there was no significant difference. The BCS4 cat group included one cat with a higher oxidized LDL value, and the BCS5 group also included two cats with oxidized LDL values higher than the mean oxidized LDL value of healthy humans. Interestingly, the oxidized LDL values in two obese dogs and three obese cats were indeed higher than the mean oxidized LDL value of humans with coronary artery disease (20.1 ± 1.1 µg/dl). In conclusion, this preliminary study showed reference ranges of oxidized dogs and cats against BCS. Obesity alone does not appear to have any direct effect on serum oxidized LDL values in healthy dogs and cats.

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