Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
J Hepatol ; 79(5): 1226-1235, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37567366

RESUMO

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), and its progressive form steatohepatitis (NASH), represent a genetically and phenotypically diverse entity for which there is no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy with early-onset NAFLD/NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NAFLD. METHODS: Using hepatic steatosis as the outcome of interest, we performed an association meta-analysis of nuclear envelope-related coding variants in three large discovery cohorts (N >120,000 participants), followed by phenotype association studies in large validation cohorts (N >600,000) and functional testing of the top steatosis-associated variant in cell culture. RESULTS: A common protein-coding variant, rs6461378 (SUN1 H118Y), was the top steatosis-associated variant in our association meta-analysis (p <0.001). In ancestrally distinct validation cohorts, rs6461378 associated with histologic NAFLD and with NAFLD-related metabolic traits including increased serum fatty acids, type 2 diabetes, hypertension, cardiovascular disease, and decreased HDL. SUN1 H118Y was subject to increased proteasomal degradation relative to wild-type SUN1 in cells, and SUN1 H118Y-expressing cells exhibited insulin resistance and increased lipid accumulation. CONCLUSIONS: Collectively, these data support a potential causal role for the common SUN1 variant rs6461378 in NAFLD and metabolic disease. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD), with an estimated global prevalence of nearly 30%, is a growing cause of morbidity and mortality for which there is no approved pharmacologic therapy. Our data provide a rationale for broadening current concepts of NAFLD genetics and pathophysiology to include the nuclear envelope, and particularly Sad1 and UNC84 domain containing 1 (SUN1), as novel contributors to this common liver disease. Furthermore, if future studies confirm causality of the common SUN1 H118Y variant, it has the potential to become a broadly relevant therapeutic target in NAFLD and metabolic disease.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fenótipo , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos , Proteínas Nucleares
2.
Am J Physiol Gastrointest Liver Physiol ; 325(2): G184-G195, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37366543

RESUMO

There is increasing evidence for the importance of the nuclear envelope in lipid metabolism, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Human mutations in LMNA, encoding A-type nuclear lamins, cause early-onset insulin resistance and NASH, while hepatocyte-specific deletion of Lmna predisposes to NASH with fibrosis in male mice. Given that variants in the gene encoding LAP2α, a nuclear protein that regulates lamin A/C, were previously identified in patients with NAFLD, we sought to determine the role of LAP2α in NAFLD using a mouse genetic model. Hepatocyte-specific Lap2α-knockout (Lap2α(ΔHep)) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 wk or 6 mo. Unexpectedly, male Lap2α(ΔHep) mice showed no increase in hepatic steatosis or NASH compared with controls. Rather, Lap2α(ΔHep) mice demonstrated reduced hepatic steatosis, with decreased NASH and fibrosis after long-term HFD. Accordingly, pro-steatotic genes including Cidea, Mogat1, and Cd36 were downregulated in Lap2α(ΔHep) mice, along with concomitant decreases in expression of pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2α deletion protects against hepatic steatosis and NASH in mice and raise the possibility that LAP2α could become a potential therapeutic target in human NASH.NEW & NOTEWORTHY The nuclear envelope and lamina regulate lipid metabolism and susceptibility to nonalcoholic steatohepatitis (NASH), but the role of the nuclear lamin-binding protein LAP2α in NASH has not been explored. Our data demonstrate that hepatocyte-specific loss of LAP2α protects against diet-induced hepatic steatosis, NASH, and fibrosis in male mice, with downregulation of pro-steatotic, pro-inflammatory, and pro-fibrotic lamin-regulated genes. These findings suggest that targeting LAP2α could have future potential as a novel therapeutic avenue in NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Masculino , Camundongos , Dieta Hiperlipídica , Modelos Animais de Doenças , Hepatócitos/metabolismo , Laminas/metabolismo , Fígado/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Cirrose Hepática/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle
3.
Proc Natl Acad Sci U S A ; 116(18): 9125-9134, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30979808

RESUMO

Carbamoyl phosphate synthetase-1 (CPS1) is the major mitochondrial urea cycle enzyme in hepatocytes. It is released into mouse and human blood during acute liver injury, where is has a short half-life. The function of CPS1 in blood and the reason for its short half-life in serum are unknown. We show that CPS1 is released normally into mouse and human bile, and pathologically into blood during acute liver injury. Other cytoplasmic and mitochondrial urea cycle enzymes are also found in normal mouse bile. Serum, bile, and purified CPS1 manifest sedimentation properties that overlap with extracellular vesicles, due to the propensity of CPS1 to aggregate despite being released primarily as a soluble protein. During liver injury, CPS1 in blood is rapidly sequestered by monocytes, leading to monocyte M2-polarization and homing to the liver independent of its enzyme activity. Recombinant CPS1 (rCPS1), but not control r-transferrin, increases hepatic macrophage numbers and phagocytic activity. Notably, rCPS1 does not activate hepatic macrophages directly; rather, it activates bone marrow and circulating monocytes that then home to the liver. rCPS1 administration prevents mouse liver damage induced by Fas ligand or acetaminophen, but this protection is absent in macrophage-deficient mice. Moreover, rCPS1 protects from acetaminophen-induced liver injury even when given therapeutically after injury induction. In summary, CPS1 is normally found in bile but is released by hepatocytes into blood upon liver damage. We demonstrate a nonenzymatic function of CPS1 as an antiinflammatory protective cytokine during acute liver injury.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Ácidos e Sais Biliares/metabolismo , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Acetaminofen/metabolismo , Lesão Pulmonar Aguda/enzimologia , Adulto , Animais , Bile/metabolismo , Citocinas/metabolismo , Proteína Ligante Fas/metabolismo , Feminino , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Hepatopatias , Macrófagos/metabolismo , Masculino , Camundongos , Mitocôndrias/metabolismo
4.
FASEB J ; 34(7): 9051-9073, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32413188

RESUMO

Laminopathies are rare diseases associated with mutations in LMNA, which encodes nuclear lamin A/C. LMNA variants lead to diverse tissue-specific phenotypes including cardiomyopathy, lipodystrophy, myopathy, neuropathy, progeria, bone/skin disorders, and overlap syndromes. The mechanisms underlying these heterogeneous phenotypes remain poorly understood, although post-translational modifications, including phosphorylation, are postulated as regulators of lamin function. We catalogued all known lamin A/C human mutations and their associated phenotypes, and systematically examined the putative role of phosphorylation in laminopathies. In silico prediction of specific LMNA mutant-driven changes to lamin A phosphorylation and protein structure was performed using machine learning methods. Some of the predictions we generated were validated via assessment of ectopically expressed wild-type and mutant LMNA. Our findings indicate phenotype- and mutant-specific alterations in lamin phosphorylation, and that some changes in phosphorylation may occur independently of predicted changes in lamin protein structure. Therefore, therapeutic targeting of phosphorylation in the context of laminopathies will likely require mutant- and kinase-specific approaches.


Assuntos
Estudos de Associação Genética , Genótipo , Lamina Tipo A/genética , Laminopatias/patologia , Mutação , Fenótipo , Feminino , Humanos , Lamina Tipo A/metabolismo , Laminopatias/classificação , Laminopatias/genética , Laminopatias/metabolismo , Masculino , Fosforilação
5.
Gastroenterology ; 154(6): 1602-1619.e1, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29549040

RESUMO

The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes. Studies of patients and mouse genetic models have pointed to important roles for lamins and their associated proteins in the function of gastrointestinal organs, including liver and pancreas. We review the interactions and functions of the lamina in relation to the nuclear envelope and genome, the ways in which its dysfunction is thought to contribute to human disease, and possible avenues for targeted therapies.


Assuntos
Gastroenteropatias/genética , Laminas/fisiologia , Lâmina Nuclear/fisiologia , Animais , Citoesqueleto/metabolismo , Genoma , Humanos , Laminas/química , Fígado/citologia , Camundongos , Pâncreas/citologia
6.
Hepatology ; 67(5): 1710-1725, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28902428

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial, but twin and familial studies indicate significant heritability, which is not fully explained by currently known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina-associated proteins predispose to NAFLD and used a candidate gene-sequencing approach to test for variants in 10 nuclear lamina-related genes in a cohort of 37 twin and sibling pairs: 21 individuals with and 53 without NAFLD. Twelve heterozygous sequence variants were identified in four lamina-related genes (ZMPSTE24, TMPO, SREBF1, SREBF2). The majority of NAFLD patients (>90%) had at least one variant compared to <40% of controls (P < 0.0001). When only insertions/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (>80% versus <25%; P < 0.0001). Presence of a lamina variant segregated with NAFLD independently of the PNPLA3 I148M polymorphism. Several variants were found in TMPO, which encodes the lamina-associated polypeptide-2 (LAP2) that has not been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin-LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin-binding protein p62/SQSTM1. CONCLUSION: Several variants in nuclear lamina-related genes were identified in a cohort of twins and siblings with NAFLD; one such variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents an association of TMPO/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. (Hepatology 2018;67:1710-1725).


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/genética , Lâmina Nuclear/genética , Adulto , Feminino , Imunofluorescência/métodos , Predisposição Genética para Doença , Variação Genética , Técnicas de Genotipagem/métodos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Immunoblotting/métodos , Imunoprecipitação/métodos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Irmãos , Espectrometria de Massas em Tandem/métodos , Gêmeos
7.
Clin Endocrinol (Oxf) ; 86(5): 698-707, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28199729

RESUMO

CONTEXT: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. OBJECTIVE: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. RESULTS: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. CONCLUSIONS: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.


Assuntos
Composição Corporal , Lipodistrofia Parcial Familiar/diagnóstico , Lipodistrofia/diagnóstico , Adolescente , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Lipodistrofia/genética , Lipodistrofia/metabolismo , Lipodistrofia/fisiopatologia , Lipodistrofia Parcial Familiar/genética , Lipodistrofia Parcial Familiar/metabolismo , Lipodistrofia Parcial Familiar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Mol Cell ; 32(4): 462-3, 2008 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-19026777

RESUMO

In this issue of Molecular Cell, Ditzel et al. (2008) show that DIAP1 polyubiquitinates DRONC, DCP-1, and drICE, leading to their nondegradative inactivation. Surprisingly, activation of DIAP1 requires caspase-mediated cleavage, revealing an elegant feedback mechanism by which caspases regulate their own fate.


Assuntos
Apoptose/fisiologia , Caspases/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Animais , Apoptose/genética , Caspases/genética , Sobrevivência Celular , Drosophila/citologia , Drosophila/genética , Drosophila/metabolismo , Retroalimentação Fisiológica , Proteínas Inibidoras de Apoptose/genética , Modelos Biológicos , Ubiquitinação
9.
Trends Biochem Sci ; 34(3): 104-7, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19168360

RESUMO

Apoptosis is a highly conserved form of cell death that is essential for controlling cell numbers throughout the lifetime of an organism. In Caenorhabditis elegans, the final step in the apoptotic cascade is activation of the death-inducing protease CED-3. Until now, no direct negative regulators of CED-3 had been identified, so the mechanism for maintaining a proper life-death balance was unclear. Now, a new study identifies CSP-3 as an important negative regulator of CED-3 during C. elegans development.


Assuntos
Apoptose/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Caspases/metabolismo , Animais , Apoptose/genética , Caenorhabditis elegans/citologia , Ativação Enzimática/fisiologia , Modelos Biológicos , Ligação Proteica
10.
medRxiv ; 2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-38196593

RESUMO

The R644C variant of lamin A is controversial, as it has been linked to multiple phenotypes in familial studies, but has also been identified in apparently healthy volunteers. Here we present data from a large midwestern US cohort showing that this variant associates genetically with hepatic steatosis, and with related traits in additional publicly available datasets, while in vitro testing demonstrated that this variant increased cellular lipid droplet accumulation. Taken together, these data support this LMNA variant's potential pathogenicity in lipodystrophy and metabolic liver disease.

11.
J Biol Chem ; 284(31): 20531-9, 2009 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-19506082

RESUMO

Inhibitor of apoptosis (IAP) proteins are key regulators of intracellular signaling that interact with tumor necrosis factor (TNF) receptor superfamily members as well as proapoptotic molecules such as Smac/DIABLO and caspases. Whereas the X-linked IAP is an established caspase inhibitor, the protective mechanisms utilized by the cellular IAP (c-IAP) proteins are less clear because c-IAPs bind to but do not inhibit the enzymatic activities of caspases. In this study, c-IAPs are shown to be highly unstable molecules that undergo autoubiquitination. The autoubiquitination of c-IAP1 is blocked upon coexpression with TNF receptor-associated factor (TRAF) 2, and this is achieved by inhibition of the E3 ubiquitin ligase activity intrinsic to the RING of c-IAP1. Consistent with these observations, loss of TRAF2 results in a decrease in c-IAP1 levels. Stabilized c-IAP1 was found to sequester and prevent Smac/DIABLO from antagonizing X-linked IAP and protect against cell death. Therefore, this study describes an intriguing cytoprotective mechanism utilized by c-IAP1 and provides critical insight into how IAP proteins function to alter the apoptotic threshold.


Assuntos
Citoproteção , Proteínas Inibidoras de Apoptose/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Animais , Apoptose , Proteínas Reguladoras de Apoptose , Linhagem Celular , Humanos , Proteínas Inibidoras de Apoptose/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Proteínas Mitocondriais/metabolismo , Proteínas Mutantes/metabolismo , Ligação Proteica , Biossíntese de Proteínas , Estabilidade Proteica , Estrutura Terciária de Proteína , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/deficiência , Ubiquitinação , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Proteína X Associada a bcl-2/metabolismo
12.
J Immunol ; 181(9): 6092-100, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18941198

RESUMO

Patients and rodents with Goodpasture's syndrome (GPS) develop severe autoimmune crescentic glomerulonephritis, kidney failure, and lung hemorrhage due to binding of pathogenic autoantibodies to the NC1 domain of the alpha3 chain of type IV collagen. Target epitopes are cryptic, normally hidden from circulating Abs by protein-protein interactions and the highly tissue-restricted expression of the alpha3(IV) collagen chain. Based on this limited Ag exposure, it has been suggested that target epitopes are not available as B cell tolerogens. To determine how pathogenic anti-GPS autoantibody responses are regulated, we generated an Ig transgenic (Tg) mouse model that expresses an Ig that binds alpha3(IV)NC1 collagen epitopes recognized by serum IgG of patients with GPS. Phenotypic analysis reveals B cell depletion and L chain editing in Tg mice. To determine the default tolerance phenotype in the absence of receptor editing and endogenous lymphocyte populations, we crossed Tg mice two generations with mice deficient in Rag. Resulting Tg Rag-deficient mice have central B cell deletion. Thus, development of Tg anti-alpha3(IV)NC1 collagen B cells is halted in the bone marrow, at which point the cells are deleted unless rescued by a Rag enzyme-dependent process, such as editing. The central tolerance phenotype implies that tolerizing self-Ag is expressed in bone marrow.


Assuntos
Doença Antimembrana Basal Glomerular/imunologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Colágeno Tipo IV/imunologia , Colágeno Tipo IV/metabolismo , Tolerância Imunológica , Animais , Doença Antimembrana Basal Glomerular/genética , Anticorpos Monoclonais/metabolismo , Autoanticorpos/biossíntese , Autoanticorpos/fisiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteínas de Homeodomínio/genética , Humanos , Tolerância Imunológica/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
13.
Mol Immunol ; 44(6): 1274-85, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16890292

RESUMO

Defective anergy is a major cause of failed tolerance and is amenable to therapeutic manipulation. To better define the molecular basis of anergy in B cells tolerized by matrix self-antigen, we used complementary approaches of representational difference analysis (RDA) and microarray to identify genes differentially transcribed in anergic as compared to non-tolerant B cells isolated from a well-characterized murine autoantibody transgenic model. Forty RDA clones representing 16 genes were isolated from receptor-stimulated B cells and independently confirmed as differentially expressed in tolerant cells using custom microarray, dot blotting and/or quantitative PCR. Differential expression was conserved in tolerant cells from two different transgenic founder lineages and from two genetically disparate backgrounds. Prominent among recovered gene fragments were genes encoding multifunctional proteins not previously implicated in B cell biology, but with roles in biologic processes fundamental to the tolerance phenotype, including cell growth, proliferation and differentiation. RDA also identified a novel transcript not previously reported in nucleic acid databases. To further explore dependence on receptor stimulation and to identify additional genes, commercial oligonucleotide arrays were probed with labeled B cell transcripts and analyzed for genes differentially expressed in resting as well as stimulated cells and in both B6 and MRL mouse strains. Arrays identified differential expression of a subset of RDA genes as well as 46 additional genes, including subsets engaged in signal transduction, transcriptional regulation, cell growth and apoptosis. Immunoblotting confirmed differential protein expression for galectin-3 and galectin-1, two interactive members of the galectin family, suggesting a novel role for galectins as regulators of immune tolerance.


Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Anergia Clonal/imunologia , Substâncias de Crescimento/fisiologia , Animais , Células Cultivadas , Anergia Clonal/genética , Substâncias de Crescimento/biossíntese , Substâncias de Crescimento/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Transdução de Sinais/genética , Transdução de Sinais/imunologia
14.
Clin Imaging ; 50: 286-288, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29738996

RESUMO

Gastrointestinal anisakiasis is an uncommon zoonotic parasitic infection caused by consumption of raw or undercooked seafood infected with nematodes of genus Anisakis. Given the non-specific clinical presentation of acute abdomen, nausea, and vomiting these patients are often subject to radiologic imaging. We present ultrasound and computed tomography imaging features in a case of gastric anisakiasis demonstrating characteristic features of diffuse gastric submucosal edema, perigastric stranding and trace ascites that helped to further elaborate the clinical history of uncooked fish consumption prompting timely endoscopic diagnosis and management.


Assuntos
Anisaquíase/diagnóstico por imagem , Estômago/diagnóstico por imagem , Adulto , Feminino , Humanos , Alimentos Marinhos , Tomografia Computadorizada por Raios X , Ultrassonografia
15.
Artigo em Inglês | MEDLINE | ID: mdl-29610677

RESUMO

BACKGROUND: Juvenile dermatomyositis (JDM) is an auto-immune muscle disease which presents with skin manifestations and muscle weakness. At least 10% of the patients with JDM present with acquired lipodystrophy. Laminopathies are caused by mutations in the lamin genes and cover a wide spectrum of diseases including muscular dystrophies and lipodystrophy. The p.T10I LMNA variant is associated with a phenotype of generalized lipodystrophy that has also been called atypical progeroid syndrome. CASE PRESENTATION: A previously healthy female presented with bilateral proximal lower extremity muscle weakness at age 4. She was diagnosed with JDM based on her clinical presentation, laboratory tests and magnetic resonance imaging (MRI). She had subcutaneous fat loss which started in her extremities and progressed to her whole body. At age 7, she had diabetes, hypertriglyceridemia, low leptin levels and low body fat on dual energy X-ray absorptiometry (DEXA) scan, and was diagnosed with acquired generalized lipodystrophy (AGL). Whole exome sequencing (WES) revealed a heterozygous c.29C > T; p.T10I missense pathogenic variant in LMNA, which encodes lamins A and C. Muscle biopsy confirmed JDM rather than muscular dystrophy, showing perifascicular atrophy and perivascular mononuclear cell infiltration. Immunofluroscence of skin fibroblasts confirmed nuclear atypia and fragmentation. CONCLUSIONS: This is a unique case with p.T10I LMNA variant displaying concurrent JDM and AGL. This co-occurrence raises the intriguing possibility that LMNA, and possibly p.T10I, may have a pathogenic role in not only the occurrence of generalized lipodystrophy, but also juvenile dermatomyositis. Careful phenotypic characterization of additional patients with laminopathies as well as individuals with JDM is warranted.

16.
J Clin Invest ; 127(7): 2855-2867, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28628040

RESUMO

Epidemiologic and animal studies implicate overconsumption of fructose in the development of nonalcoholic fatty liver disease, but the molecular mechanisms underlying fructose-induced chronic liver diseases remain largely unknown. Here, we have presented evidence supporting the essential function of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP) in mediating adaptive responses to fructose and protecting against fructose-induced hepatotoxicity. In WT mice, a high-fructose diet (HFrD) activated hepatic lipogenesis in a ChREBP-dependent manner; however, in Chrebp-KO mice, a HFrD induced steatohepatitis. In Chrebp-KO mouse livers, a HFrD reduced levels of molecular chaperones and activated the C/EBP homologous protein-dependent (CHOP-dependent) unfolded protein response, whereas administration of a chemical chaperone or Chop shRNA rescued liver injury. Elevated expression levels of cholesterol biosynthesis genes in HFrD-fed Chrebp-KO livers were paralleled by an increased nuclear abundance of sterol regulatory element-binding protein 2 (SREBP2). Atorvastatin-mediated inhibition of hepatic cholesterol biosynthesis or depletion of hepatic Srebp2 reversed fructose-induced liver injury in Chrebp-KO mice. Mechanistically, we determined that ChREBP binds to nuclear SREBP2 to promote its ubiquitination and destabilization in cultured cells. Therefore, our findings demonstrate that ChREBP provides hepatoprotection against a HFrD by preventing overactivation of cholesterol biosynthesis and the subsequent CHOP-mediated, proapoptotic unfolded protein response. Our findings also identified a role for ChREBP in regulating SREBP2-dependent cholesterol metabolism.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Carboidratos da Dieta/efeitos adversos , Frutose/efeitos adversos , Fígado/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colesterol/genética , Colesterol/metabolismo , Carboidratos da Dieta/farmacologia , Frutose/farmacologia , Fígado/lesões , Fígado/patologia , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas/genética
17.
Cell Mol Gastroenterol Hepatol ; 4(3): 365-383, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28913408

RESUMO

BACKGROUND & AIMS: Lamins are nuclear intermediate filament proteins that comprise the major components of the nuclear lamina. Mutations in LMNA, which encodes lamins A/C, cause laminopathies, including lipodystrophy, cardiomyopathy, and premature aging syndromes. However, the role of lamins in the liver is unknown, and it is unclear whether laminopathy-associated liver disease is caused by primary hepatocyte defects or systemic alterations. METHODS: To address these questions, we generated mice carrying a hepatocyte-specific deletion of Lmna (knockout [KO] mice) and characterized the KO liver and primary hepatocyte phenotypes by immunoblotting, immunohistochemistry, microarray analysis, quantitative real-time polymerase chain reaction, and Oil Red O and Picrosirius red staining. RESULTS: KO hepatocytes manifested abnormal nuclear morphology, and KO mice showed reduced body mass. KO mice developed spontaneous male-selective hepatosteatosis with increased susceptibility to high-fat diet-induced steatohepatitis and fibrosis. The hepatosteatosis was associated with up-regulated transcription of genes encoding lipid transporters, lipid biosynthetic enzymes, lipid droplet-associated proteins, and interferon-regulated genes. Hepatic Lmna deficiency led to enhanced signal transducer and activator of transcription 1 (Stat1) expression and blocked growth hormone-mediated Janus kinase 2 (Jak2), signal transducer and activator of transcription 5 (Stat5), and extracellular signal-regulated kinase (Erk) signaling. CONCLUSIONS: Lamin A/C acts cell-autonomously to maintain hepatocyte homeostasis and nuclear shape and buffers against male-selective steatohepatitis by positively regulating growth hormone signaling and negatively regulating Stat1 expression. Lamins are potential genetic modifiers for predisposition to steatohepatitis and liver fibrosis. The microarray data can be found in the Gene Expression Omnibus repository (accession number: GSE93643).

18.
Autoimmunity ; 46(3): 188-204, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23157336

RESUMO

Autoantibodies to diverse antigens escape regulation in systemic lupus erythematosus under the influence of a multitude of predisposing genes. To gain insight into the differential impact of diverse genetic backgrounds on tolerance mechanisms controlling autoantibody production in lupus, we established a single lupus-derived nephritis associated anti-basement membrane Ig transgene on each of four inbred murine lupus strains, including BXSB, (NZBxNZW)F1, NZB, and MRL/lpr, as approved by the Duke University and the Durham Veterans Affairs Medical Centers' Animal Care and Use Committees. In nonautoimmune C57BL/6 mice, B cells bearing this anti-laminin Ig transgene are stringently regulated by central deletion, editing, and anergy. Here, we show that tolerance is generally intact in unmanipulated Ig transgenic BXSB, (NZBxNZW)F1, and NZB mice, based on absence of serum transgenic anti-laminin autoantibodies and failure to recover spontaneous anti-laminin monoclonal antibodies. Four- to six-fold depletion of splenic B cells in transgenic mice of these strains, as well as in MRL/lpr transgenic mice, and reduced frequency of IgM+ bone marrow B cells suggest that central deletion is grossly intact. Nonetheless the 4 strains demonstrate distinct transgenic B cell phenotypes, including endotoxin-stimulated production of anti-laminin antibodies by B cells from transgenic NZB mice, and in vitro hyperproliferation of both endotoxin- and BCR-stimulated B cells from transgenic BXSB mice, which are shown to have an enrichment of CD21-high marginal zone cells. Rare anti-laminin transgenic B cells spontaneously escape tolerance in MRL/lpr mice. Further study of the mechanisms underlying these strain-specific B cell fates will provide insight into genetic modification of humoral autoimmunity in lupus.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Tolerância Imunológica/imunologia , Laminina/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Apoptose , Autoimunidade/imunologia , Sequência de Bases , Células da Medula Óssea/imunologia , Relação CD4-CD8 , Feminino , Cadeias Pesadas de Imunoglobulinas/imunologia , Imunoglobulina M/imunologia , Nefrite Lúpica/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Camundongos Transgênicos , Alinhamento de Sequência , Análise de Sequência de DNA
19.
Mol Cell Biol ; 30(8): 1923-36, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20154138

RESUMO

In order to balance the cellular requirements for copper with its toxic properties, an elegant set of mechanisms has evolved to regulate and buffer intracellular copper. The X-linked inhibitor of apoptosis (XIAP) protein was recently identified as a copper-binding protein and regulator of copper homeostasis, although the mechanism by which XIAP binds copper in the cytosol is unclear. Here we describe the identification of the copper chaperone for superoxide dismutase (CCS) as a mediator of copper delivery to XIAP in cells. We also find that CCS is a target of the E3 ubiquitin ligase activity of XIAP, although interestingly, ubiquitination of CCS by XIAP was found to lead to enhancement of its chaperone activity toward its physiologic target, superoxide dismutase 1, rather than proteasomal degradation. Collectively, our results reveal novel links among apoptosis, copper metabolism, and redox regulation through the XIAP-CCS complex.


Assuntos
Cobre/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Linhagem Celular , Ativação Enzimática , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Proteínas de Saccharomyces cerevisiae/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Distribuição Tecidual , Ubiquitinação , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
20.
J Immunol ; 172(9): 5313-21, 2004 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15100270

RESUMO

We explored mechanisms involved in B cell self-tolerance in a double- and triple-transgenic mouse model bearing the LamH-C mu Ig H chain conventional transgene and a gene-targeted replacement for a functional V kappa 8J kappa 5 L chain gene. Whereas the H chain is known to generate anti-laminin Ig in combination with multiple L chains, the H + L Ig binds ssDNA in addition to laminin. Immune phenotyping indicates that H + L transgenic B cells are regulated by clonal deletion, receptor editing via secondary rearrangements at the nontargeted kappa allele, and anergy. Collectively, the data suggest that multiple receptor-tolerogen interactions regulate autoreactive cells in the H + L double-transgenic mice. Generation of H + LL triple-transgenic mice homozygous for the targeted L chain to exclude secondary kappa rearrangements resulted in profound B cell depletion with absence of mature B cells in the bone marrow. We propose that the primary tolerogen of dual reactive B cells in this model is not ssDNA, but a strongly cross-linking tolerogen, presumably basement membrane laminin, that triggers recombination-activating gene activity, L chain editing, and deletion.


Assuntos
Especificidade de Anticorpos/genética , Autoanticorpos/genética , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Deleção Clonal/genética , Cadeias kappa de Imunoglobulina/genética , Laminina/imunologia , Tolerância a Antígenos Próprios/genética , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/genética , Autoanticorpos/biossíntese , Autoanticorpos/metabolismo , Subpopulações de Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Divisão Celular/genética , Divisão Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Rearranjo Gênico de Cadeia Leve de Linfócito B , Regiões Constantes de Imunoglobulina/genética , Cadeias Pesadas de Imunoglobulinas/biossíntese , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/biossíntese , Cadeias kappa de Imunoglobulina/metabolismo , Cadeias mu de Imunoglobulina/biossíntese , Laminina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Edição de RNA/imunologia , Baço/imunologia , Baço/metabolismo , Baço/patologia , Transfecção
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA