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1.
J Nat Prod ; 84(4): 1135-1148, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33788569

RESUMEN

The new polycyclic polyprenylated acylphloroglucinols, hyperforcinols A-J (1-10), were isolated from the fruits of Hypericum forrestii, together with 30 biogenetic congeners of known structures. The structures of hyperforcinols A-J were determined by HRESIMS and 1D/2D NMR spectroscopic analysis, and their absolute configurations were determined by a combination of the electronic circular dichroism (ECD) exciton chirality method, ECD calculations, and X-ray diffraction analysis. A selection of 25 isolates, possessing seven types of carbon skeletons, were assessed for their in vitro effects against nonalcoholic steatohepatitis (NASH) using a free fatty acid-induced L02 cell model. Compounds 20 and 40 significantly decreased intracellular lipid accumulation. QRT-PCR analyses revealed that compounds 20 and 40 regulate the expression of lipid metabolism-related genes, including CD36, FASN, PPARα, and ACOX1.


Asunto(s)
Hypericum/química , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Floroglucinol/farmacología , Línea Celular , China , Frutas/química , Humanos , Estructura Molecular , Floroglucinol/aislamiento & purificación , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Prenilación
2.
J Agric Food Chem ; 69(2): 646-654, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33426876

RESUMEN

In this work, 26 methylated acylphloroglucinol meroterpenoids with diverse skeletons, including 18 new ones (bellumones A-R, 1-18), were identified from the flowers of Hypericum bellum. Their structures including absolute configurations were elucidated by detailed spectroscopic data, calculated electronic circular dichroism (ECD), and X-ray diffraction (XRD). Through methylation at C-5, prenylation with different chain lengths of the acylphloroglucinol-derived core, along with different types of secondary cyclization, type A bicyclic polyprenylated acylphloroglucinols (BPAPs) (1-5 and 19-24) and dearomatized isoprenylated acylphloroglucinols (DIAPs) (6-18 and 25-26) were obtained. The significant results of anti-inflammatory, antioxidant, and anti-nonalcoholic steatohepatitis (anti-NASH) activities suggest its usefulness in daily health care.


Asunto(s)
Antiinflamatorios/química , Antioxidantes/química , Hypericum/química , Floroglucinol/química , Terpenos/farmacología , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Flores/química , Humanos , Estructura Molecular , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Terpenos/química , Terpenos/aislamiento & purificación
3.
J Pathol ; 253(1): 55-67, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32918742

RESUMEN

Nonalcoholic fatty liver disease is a chronic condition involving steatosis, steatohepatitis and fibrosis, and its progression remains unclear. Although the tetraspanin transmembrane 4 L six family member 5 (TM4SF5) is involved in hepatic fibrosis and cancer, its role in nonalcoholic steatohepatitis (NASH) progression is unknown. We investigated the contribution of TM4SF5 to liver pathology using transgenic and KO mice, diet- or drug-treated mice, in vitro primary cells, and in human tissue. TM4SF5-overexpressing mice exhibited nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and liver tissue exhibited lipid accumulation, decreased Sirtuin 1 (SIRT1), increased sterol regulatory-element binding proteins (SREBPs) and inactive STAT3 via suppressor of cytokine signaling (SOCS)1/3 upregulation. In older mice, TM4SF5 promoted inflammatory factor induction, SIRT1 expression and STAT3 activity, but did not change SOCS or SREBP levels, leading to active STAT3-mediated ECM production for NASH progression. A TM4SF5-associated increase in chemokines promoted SIRT1 expression and progression to NASH with fibrosis. Suppression of the chemokine CCL20 reduced immune cell infiltration and ECM production. Liver tissue from high-fat diet- or CCl4 -treated mice and human patients exhibited TM4SF5-dependent steatotic or steatohepatitic livers with links between TM4SF5-mediated SIRT1 modulation and SREBP or SOCS/STAT3 signaling axes. TM4SF5-mediated STAT3 activation in fibrotic NASH livers increased collagen I and laminin γ2. Both collagen I α1 and laminin γ2 suppression resulted in reduced SIRT1 and active STAT3, but no change in SREBP1 or SOCS, and abolished CCl4 -mediated mouse liver damage. TM4SF5-mediated signaling pathways that involve SIRT1, SREBPs and SOCS/STAT3 promoted progression to NASH. Therefore, TM4SF5 and its downstream effectors may be promising therapeutic targets to treat nonalcoholic fatty liver disease. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Matriz Extracelular/enzimología , Metabolismo de los Lípidos , Cirrosis Hepática Experimental/enzimología , Hígado/enzimología , Proteínas de la Membrana/metabolismo , Enfermedad del Hígado Graso no Alcohólico/enzimología , Sirtuina 1/metabolismo , Animales , Tetracloruro de Carbono , Línea Celular Tumoral , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Dieta Alta en Grasa , Progresión de la Enfermedad , Matriz Extracelular/patología , Humanos , Hígado/patología , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/patología , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal
4.
J Pathol ; 251(4): 429-439, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32472585

RESUMEN

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1nih ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17ß-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Asunto(s)
Aterosclerosis/patología , Estrógenos/metabolismo , Hidroxicolesteroles/farmacología , Inflamación/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal/efectos de los fármacos , Animales , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Hígado/metabolismo , Hígado/patología , Macrófagos/patología , Masculino , Ratones , Factores Sexuales
5.
Postgrad Med ; 132(7): 590-594, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32442058

RESUMEN

OBJECTIVES: Psychotic disorders can exact a toll on both patients and caregivers. Whilst the desired teaching goals include gaining an understanding of the manifestations, neurobiology and treatment of these conditions, such concepts may appear abstract to medical undergraduates new to psychiatry before their clinical rotation. This study aimed to examine the use of patient narratives in teaching. Based on self-determination and Kolb's learning theories, it was hypothesized that intermediate processes (such as engagement, motivation, reflection) mediate narratives' effectiveness as a pedagogical tool. METHODS: Narratives in the form of stories of prominent individuals with psychotic disorders (such as John Nash) were incorporated in undergraduate teaching. Overall, 1014 out of 1500 (67.6%) medical undergraduates provided feedback over 2014-2018 through an anonymized questionnaire after the teaching session. Relationships between the use of narratives, intermediate processes, and overall effectiveness of session were assessed using correlation, regression, and structural equation modeling analyses. RESULTS: Most learners (97.2%) found that use of narratives helped them better appreciate the topic. Use of narratives correlated with better engagement, motivation, feeling equipped, reflection about the topic, and effectiveness as a pedagogical medium. The use of narratives was significantly predictive of ratings on these intermediate processes (all p < 0.001), which in turn mediated the relationship between narratives and overall session ratings. CONCLUSION: Consistent with adult learning theories, the use of narratives can improve appreciation of psychotic spectrum disorders via better engagement, motivation, and reflection within learners. Appropriate narratives can be incorporated into other topics to enhance undergraduate psychiatry education.


Asunto(s)
Anécdotas como Asunto , Educación de Pregrado en Medicina/métodos , Psiquiatría/educación , Autoeficacia , Estudiantes del Área de la Salud/psicología , Adulto , Curriculum , Femenino , Humanos , Masculino
6.
J Pathol ; 248(4): 488-500, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30945293

RESUMEN

The role of macrophages in fibrosing steatohepatitis is largely unclear. We characterized the origin and molecular mechanisms of macrophages and its targeted therapy of fibrosing steatohepatitis. Fibrosing steatohepatitis was established in Alms1 mutant (foz/foz) and C57BL/6J wildtype mice fed high-fat/high-cholesterol or methionine- and choline-deficient diet. Bone marrow transplantation was performed to track the macrophage origin in fibrosing steatohepatitis. Macrophages were depleted using liposomal clodronate. Primary macrophages were isolated from bone marrow for adoptive transfer into mice. We found that macrophage infiltration is induced in two mouse models of fibrosing steatohepatitis and human nonalcoholic steatohepatitis-fibrosis patients. Bone marrow-derived macrophages (BMMs) contribute to the hepatic macrophage accumulation in experimental fibrosing steatohepatitis. Depletion of hepatic BMMs by liposomal clodronate during liver injury attenuated fibrosing steatohepatitis, whilst BMMs depletion after liver injury delayed the regression of fibrosing steatohepatitis. The pro-fibrotic effect of macrophages was associated with reduced activation of hepatic stellate cells (HSCs), collagen deposition and hepatic expression of key pro-fibrotic factors (TIMP1, TIMP2, and TGFß1) and endoplasmic reticulum stress markers (GRP78, IRE1α, and PDI). Conversely, adoptive transfer of BMMs significantly aggravated fibrosing steatohepatitis. Moreover, macrophage-conditioned medium directly promoted the phenotypic transition of primary quiescent HSCs to activated HSCs; it enhanced activation and proliferation but decreased apoptosis of HSC cell lines (LX-2 and HSC-T6). The effect of BMMs in promoting fibrosing steatohepatitis was mediated by inducing key pro-fibrosis factors and signaling pathways including cytokine/chemokine, TGFß and complement cascade as assessed by cDNA expression array. Complement 3a receptor (C3ar1) was a predominant effector of macrophage mediated fibrosing steatohepatitis. Knockout of C3ar1 in mice blunted development of fibrosing steatohepatitis. In conclusion, BMMs promoted the progression of fibrosing steatohepatitis during injury, whereas macrophages reduced fibrosing steatohepatitis in the recovery phase of liver injury. Increasing anti-fibrotic macrophages and decreasing pro-fibrotic macrophages are promising approaches for fibrosing steatohepatitis. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Asunto(s)
Células Estrelladas Hepáticas/metabolismo , Macrófagos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , Animales , Biomarcadores/metabolismo , Estudios de Casos y Controles , Proliferación Celular , Células Estrelladas Hepáticas/patología , Humanos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología
7.
J Pathol ; 247(3): 283-286, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30374976

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) often develops in concert with related metabolic diseases, such as obesity, dyslipidemia and insulin resistance. Prolonged lipid accumulation and inflammation can progress to non-alcoholic steatohepatitis (NASH). Although factors associated with the development of NAFLD are known, triggers for the progression of NAFLD to NASH are poorly understood. Recent findings published in The Journal of Pathology reveal the possible regulation of NASH progression by metabolites of the mevalonate pathway. Mevalonate can be converted into the isoprenoids farnesyldiphosphate (FPP) and geranylgeranyl diphosphate (GGPP). GGPP synthase (GGPPS), the enzyme that converts FPP to GGPP, is dysregulated in humans and mice during NASH. Both FPP and GGPP can be conjugated to proteins through prenylation, modifying protein function and localization. Deletion or knockdown of GGPPS favors FPP prenylation (farnesylation) and augments the function of liver kinase B1, an upstream kinase of AMP-activated protein kinase (AMPK). Despite increased AMPK activation, livers in Ggpps-deficient mice on a high-fat diet poorly oxidize lipids due to mitochondrial dysfunction. Although work from Liu et al provides evidence as to the potential importance of the prenylation portion of the mevalonate pathway during NAFLD, future studies are necessary to fully grasp any therapeutic or diagnostic potential. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa , Farnesiltransferasa , Fibrosis , Glucosa , Humanos , Hígado , Ratones , Prenilación , Reino Unido
8.
J Pathol ; 246(3): 277-288, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29971772

RESUMEN

Patients with obesity have a high prevalence of non-alcoholic fatty liver disease (NAFLD) and, in parallel, increased susceptibility to fibrosis/cirrhosis/hepatocellular carcinoma (HCC). Herein, we report that a high-fat diet (HFD) can augment glycolysis and then accelerate NAFLD-fibrosis progression by downregulating the expression of geranylgeranyl diphosphate synthase (GGPPS), which is a critical enzyme in the mevalonate pathway. Long-term HFD overloading decreases GGPPS expression in mice, which shifts the fuel preference from fatty acids towards glucose. Liver-specific Ggpps deficiency drives the Warburg effect by impairing mitochondrial function, and then induces hepatic inflammation, thus exacerbating fibrosis. Ggpps deficiency also enhances the hyperfarnesylation of liver kinase B1, and promotes metabolic reprogramming by regulating 5'-AMP-activated protein kinase activity. Clinical data further imply that GGPPS expression can predict the stage of NAFLD and recurrence of NAFLD-associated HCC. We conclude that the level of GGPPS is a susceptibility factor for NAFLD-fibrosis progression, and requires more stringent surveillance to ensure early prediction and precision of treatment of NAFLD-related HCC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Metabolismo Energético , Farnesiltransferasa/metabolismo , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Hepatocitos/enzimología , Cirrosis Hepática/enzimología , Hígado/enzimología , Enfermedad del Hígado Graso no Alcohólico/enzimología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Células Cultivadas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Farnesiltransferasa/deficiencia , Farnesiltransferasa/genética , Glucólisis , Hepatocitos/patología , Humanos , Hígado/patología , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias Hepáticas/enzimología , Mitocondrias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Oxidación-Reducción , Prenilación de Proteína , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal
9.
AJNR Am J Neuroradiol ; 39(2): 217-218, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29191869

RESUMEN

The concept of Nash equilibrium, developed by John Forbes Nash Jr, states that an equilibrium in noncooperative games is reached when each player takes the best action for himself or herself, taking into account the actions of the other players. We apply this concept to the provision of endovascular thrombectomy in the treatment of acute ischemic stroke and suggest that collaboration among hospitals in a health care jurisdiction could result in practices such as shared call pools for neurointervention teams, leading to better patient care through streamlined systems.


Asunto(s)
Teoría del Juego , Administración Hospitalaria , Colaboración Intersectorial , Neurología/organización & administración , Accidente Cerebrovascular/cirugía , Procedimientos Endovasculares , Humanos , Trombectomía
10.
Phytother Res ; 31(1): 132-139, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27762456

RESUMEN

Hovenia dulcis Thunb. (HDT) was known to have anti-fatigue, anti-diabetes, neuroprotective, and hepatoprotective effects. In the present study, the anti-fatty liver mechanism of HDT was elucidated in oleic acid (OA)-treated Hep G2 cells and acute hyperlipidemia mouse model using Triton WR-1339. Here, HDT activated p-AMP-activated protein kinase (p-AMPK), proliferator activated receptor-α, carnitine palmitoyltransferase and also inhibited the expression of lipogenesis and cholesterol synthesis proteins, such as 3-hydroxy-3-methylglutaryl-CoA reductase, sterol regulatory element binding protein-1c, SREBP-2, and fatty acid synthase in OA-treated Hep G2 cells. Conversely, AMPK inhibitor compound C blocked the anti-fatty liver effect of HDT to induce AMPK phosphorylation and decrease 3-hydroxy-3-methylglutaryl-CoA reductase and lipid accumulation by oil red O staining in OA-treated Hep G2 cells. Additionally, HDT pretreatment protected against the increase of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol and phospholipid in an acute hyperlipidemia mouse model with enhancement of glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase activities. Taken together, HDT inhibits OA-induced hepatic lipid accumulation via activation of AMPK and proliferator activated receptor-α/carnitine palmitoyltransferase signaling and enhancement of antioxidant activity as a potent candidate for nonalcoholic fatty liver disease and hyperlipidemia. Copyright © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Hiperlipidemias/genética , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/patología , Ácido Oléico/química , PPAR alfa/metabolismo , Rhamnaceae/química , Semillas/química , Animales , Carnitina O-Palmitoiltransferasa/metabolismo , Modelos Animales de Enfermedad , Humanos , Hiperlipidemias/metabolismo , Lipoproteínas LDL/metabolismo , Ratones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo
11.
J Pathol ; 241(1): 36-44, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27757953

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a continuous spectrum of diseases characterized by excessive lipid accumulation in hepatocytes. NAFLD progresses from simple liver steatosis to non-alcoholic steatohepatitis and, in more severe cases, to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Because of its growing worldwide prevalence, various animal models that mirror both the histopathology and the pathophysiology of each stage of human NAFLD have been developed. The selection of appropriate animal models continues to be one of the key questions faced in this field. This review presents a critical analysis of the histopathology and pathogenesis of NAFLD, the most frequently used and recently developed animal models for each stage of NAFLD and NAFLD-induced HCC, the main mechanisms involved in the experimental pathogenesis of NAFLD in different animal models, and a brief summary of recent therapeutic targets found by the use of animal models. Integrating the data from human disease with those from animal studies indicates that, although current animal models provide critical guidance in understanding specific stages of NAFLD pathogenesis and progression, further research is necessary to develop more accurate models that better mimic the disease spectrum, in order to provide both increased mechanistic understanding and identification/testing of novel therapeutic approaches. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico/patología , Animales , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/genética , Citocinas/fisiología , Dieta/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Estrés Oxidativo/fisiología
12.
J Pathol ; 240(4): 437-449, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27577682

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein-level impact of the observed mutations. To determine whether the observed changes are tissue-specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase-γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28-fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4-fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (∼98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the 'missing heritability' of NAFLD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Genoma Mitocondrial , Enfermedad del Hígado Graso no Alcohólico/genética , Adulto , Estudios de Casos y Controles , ADN Mitocondrial/genética , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Haplotipos , Humanos , Cirrosis Hepática/genética , Masculino , Persona de Mediana Edad , Mitocondrias Hepáticas/genética , Mutación , Mutación Missense/genética , Fosforilación Oxidativa , Polimorfismo Genético , Índice de Severidad de la Enfermedad
13.
Curr Protoc Mouse Biol ; 6(2): 185-200, 2016 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-27248434

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It is associated with obesity and type 2 diabetes and represents a spectrum of histological abnormalities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which can further progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver failure. To gain insight into the pathogenesis and evaluate treatment options, mouse models of NAFLD/NASH are of utmost importance. There is a high phenotypical variety in the available mouse models, however, models that truly display the full spectrum of histopathological and metabolic features associated with human NASH are rare. In this review, we summarize the most important NAFLD/NASH mouse models that have been developed over the years and briefly highlight the pros and cons. Also, we illustrate the preclinical research in which these models have been used. © 2016 by John Wiley & Sons, Inc.


Asunto(s)
Modelos Animales de Enfermedad , Ratones , Enfermedad del Hígado Graso no Alcohólico/etiología , Animales , Humanos
14.
Curr Protoc Mouse Biol ; 6(2): 201-210, 2016 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-27248435

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the Western world. It represents a disease spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH). In particular, NASH can evolve to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The development of novel treatment strategies is hampered by the lack of representative NASH mouse models. Here, we describe a NASH mouse model, which is based on feeding non-genetically manipulated C57BL6/J mice a 'Western style' high-fat/high-sucrose diet (HF-HSD). HF-HSD leads to early obesity, insulin resistance, and hypercholesterolemia. After 12 weeks of HF-HSD, all mice exhibit the complete spectrum of features of NASH, including steatosis, hepatocyte ballooning, and lobular inflammation, together with fibrosis in the majority of mice. Hence, this model closely mimics the human disease. Implementation of this mouse model will lead to a standardized setup for the evaluation of (i) underlying mechanisms that contribute to the progression of NAFLD to NASH, and (ii) therapeutic interventions for NASH. © 2016 by John Wiley & Sons, Inc.


Asunto(s)
Modelos Animales de Enfermedad , Ratones , Enfermedad del Hígado Graso no Alcohólico/etiología , Animales , Dieta de Carga de Carbohidratos , Dieta Alta en Grasa , Humanos , Ratones Endogámicos C57BL
15.
Phytother Res ; 30(10): 1559-1571, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27307131

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) has been known as the hepatic feature of metabolic syndrome. Extra fat depots, especially in visceral areas, develop insulin resistance as a result of mild oxidation and inflammation. Insulin resistance induces lipolysis and releases free fatty acids into the circulation, where they are transported to the liver. In the liver, free fatty acids are converted to triglycerides and accumulate, causing simple steatosis that, if left untreated, can lead to steatohepatitis, and subsequently liver necrosis and cirrhosis.Flavonoids, a group of plant compounds with incredible biological characteristics, have shown advantages in pathological conditions. Beneficial effects of flavonoids against NAFLD and its related disorders have been observed in both animal and human studies. Various mechanisms have been found for their protection. Flavonoids prevent hepatosteatosis by increasing fatty acid oxidation in the liver. They can also reduce caloric intake and decrease body weight and fat deposition in visceral tissues. Flavonoids are unique antioxidants that exert their beneficial effects through inhibition of nuclear factor κB, thereby attenuating release of inflammatory cytokines, which are triggers of insulin resistance. Finally, flavonoids have shown to increase adiponectin, improve insulin sensitivity and glucose tolerance, correct dyslipidemia, and reduce blood pressure in patients with NAFLD. Copyright © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Flavonoides/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Flavonoides/farmacología , Humanos
16.
Phytother Res ; 30(9): 1540-8, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27270872

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a global health problem. Although many aspects of NAFLD pathogenesis have been understood, there is a paucity of effective treatments to be used as the second line when lifestyle modification is insufficient. Curcumin, a natural polyphenol from turmeric, has been shown to be effective against development of hepatic steatosis and its progression to steatohepatitis, yet these beneficial effects have not been explored in clinical practice. The aim of this study is to investigate the effects of curcumin on hepatic fat content as well as biochemical and anthropometric features of patients with NAFLD. In this randomized double-blind placebo-controlled trial, patients with ultrasonographic evidence of NAFLD were randomly assigned to receive an amorphous dispersion curcumin formulation (500 mg/day equivalent to 70-mg curcumin) or matched placebo for a period of 8 weeks. Liver fat content (assessed through ultrasonography), glycemic and lipid profile, transaminase levels, and anthropometric indices were evaluated at baseline and at the end of follow-up period. The clinical trial protocol was registered under the Iranian Registry of Clinical Trials ID: IRCT2014110511763N18. Compared with placebo, curcumin was associated with a significant reduction in liver fat content (78.9% improvement in the curcumin vs 27.5% improvement in the placebo group). There were also significant reductions in body mass index and serum levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, glucose, and glycated hemoglobin compared with the placebo group. Curcumin was safe and well tolerated during the course of trial. Findings of the present proof-of-concept trial suggested improvement of different features of NAFLD after a short-term supplementation with curcumin. Copyright © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Curcumina/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
17.
Diabetologia ; 59(6): 1104-11, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27091184

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) increases risk of mortality from liver and cardiovascular disease (CVD) and is the major cause of hepatocellular carcinoma (HCC), which may develop without cirrhosis. NAFLD predicts type 2 diabetes, even independently of obesity. Globally, the prevalence of NAFLD averages 25% and is as common as the metabolic syndrome. The majority of patients with type 2 diabetes have NAFLD. The challenge for the diabetologist is to identify patients at risk of advanced liver disease and HCC. At a minimum, liver function tests (LFTs), despite being neither specific nor sensitive, should be performed in all patients with the metabolic syndrome or type 2 diabetes. Increases in LFTs, for which the updated reference values are lower (serum ALT ≈30 U/l in men and ≈20 U/l in women) than those hitherto used in many laboratories, should prompt assessment of fibrosis biomarkers and referral of individuals at risk to a NAFLD/hepatology clinic. Preferably, evaluation of NAFLD should be based on measurement of steatosis biomarkers or ultrasound if easily available. A large number of individuals carry the patatin-like phospholipase domain containing 3 (PNPLA3) I148M variant (30-50%) or the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant (11-15%). These variants increase the risk of advanced liver disease and HCC but not of diabetes or CVD. Genotyping of selected patients for these variants is recommended. Many patients have 'double trouble', i.e. carry both a genetic risk factor and have the metabolic syndrome. Excess use of alcohol could be a cause of 'triple trouble', but such patients would be classified as having alcoholic fatty liver disease. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1 , and by John Jones, DOI: 10.1007/s00125-016-3940-5 ) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x ).


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico/metabolismo , Alanina Transaminasa/metabolismo , Genotipo , Humanos , Lipasa/genética , Lipasa/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Triglicéridos/metabolismo
18.
Diabetologia ; 59(6): 1112-20, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27101131

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions in patients with type 2 diabetes. Patients with NAFLD are at increased risk of more aggressive liver disease (non-alcoholic steatohepatitis [NASH]) and at a higher risk of death from cirrhosis, hepatocellular carcinoma and cardiovascular disease. Dysfunctional adipose tissue and insulin resistance play an important role in the pathogenesis of NASH, creating the conditions for hepatocyte lipotoxicity. Mitochondrial defects are at the core of the paradigm linking chronic excess substrate supply, insulin resistance and NASH. Recent work indicates that patients with NASH have more severe insulin resistance and lipotoxicity compared with matched obese controls with only isolated steatosis. This review focuses on available agents and future drugs under development for the treatment of NAFLD/NASH in type 2 diabetes. Reversal of lipotoxicity with pioglitazone is associated with significant histological improvement, which occurs within 6 months and persists with continued treatment (or for at least 3 years) in patients with prediabetes or type 2 diabetes, holding potential to modify the natural history of the disease. These results also suggest that pioglitazone may become the standard of care for this population. Benefit has also been reported in non-diabetic patients. Recent promising results with glucagon-like peptide 1 receptor agonists have opened another new treatment avenue for NASH. Many agents in Phase 2-3 of development are being tested, aiming to restore glucose/lipid metabolism, ameliorate adipose tissue and liver inflammation, or to inhibit liver fibrosis. By targeting a diversity of relevant pathways, combination therapy in NASH will likely provide greater success in the future. In summary, increased clinical awareness and improved screening strategies (as currently done for diabetic retinopathy and nephropathy) are needed, to translate recent treatment progress into early treatment and improved quality of life for patients with type 2 diabetes and NASH. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by John Jones, DOI: 10.1007/s00125-016-3940-5 , and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1 ) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x ).


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Receptor del Péptido 1 Similar al Glucagón/genética , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Pioglitazona , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/metabolismo , Tiazolidinedionas/uso terapéutico
19.
Diabetes Metab Res Rev ; 32(2): 200-16, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26381272

RESUMEN

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has a high prevalence in patients with type 2 diabetes mellitus (T2DM). In this study, we sought to provide a comprehensive assessment regarding the effects of anti-diabetic agents on NAFLD in patients with T2DM. METHODS: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) with different anti-diabetic agents in T2DM. Observational trials were also recruited to expand our population. Hepatic fat content and liver histology were evaluated as primary outcomes. Pooled estimates were calculated using a fixed effect model. RESULTS: One thousand one hundred ninety-six participants in 19 RCTs and 14 non-randomized studies were included. Evidence from RCTs and observational studies suggested that greater hepatic fat content reduction and improved liver histology were seen in thiazolidinediones for 12-72 weeks; glucagon-like peptide-1 receptor agonists had beneficial effects on hepatic fat content after 26-50 weeks intervention, and insulin/metformin combination with 3-7 months improved hepatic fat content. Initiating metformin or dapagliflozin showed no benefit on hepatic fat content or liver histology in 16-48 weeks. Besides, nateglinide for 18 months was reported in a small sample-size RCT to improve hepatic fat content and liver histology. Sitagliptin therapy of 1 year also provided benefit on nonalcoholic steatohepatitis score in an observational study. CONCLUSIONS: For T2DM with NAFLD, administrating thiazolidinediones and glucagon-like peptide-1 receptor agonists seems to provide more identified advances in attenuating hepatic fat content. Further RCTs are warranted to assess the efficacy of various hypoglycemic agents on clinical outcomes associated with NAFLD in T2DM. Copyright © 2015 John Wiley & Sons, Ltd.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Ensayos Clínicos como Asunto , Humanos , Pronóstico
20.
J Pathol ; 238(4): 531-42, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26415102

RESUMEN

Obese animals and non-alcoholic fatty liver disease (NAFLD) patients exhibit elevated blood alcohol, suggesting potential contributions of alcohol metabolism to the development of NAFLD. Liver gene expression in patients with biopsy-proven mild (N = 40) and severe (N = 32) NAFLD were compared to that in healthy liver donors (N = 7) and alcoholic hepatitis (AH; N = 15) using microarrays. Principal components analyses (PCA) revealed similar gene expression patterns between mild and severe NAFLD which clustered with those of AH but were distinct from those of healthy livers. Differential gene expression between NAFLD and healthy livers was consistent with established NAFLD-associated genes and NAFLD pathophysiology. Alcohol-metabolizing enzymes including ADH, ALDH, CYP2E1, and CAT were up-regulated in NAFLD livers. The expression level of alcohol-metabolizing genes in severe NAFLD was similar to that in AH. The NAFLD gene expression profiles provide new directions for future investigations to identify disease markers and targets for prevention and treatment, as well as to foster our understanding of NAFLD pathogenesis and pathophysiology. Particularly, increased expression of alcohol-metabolizing genes in NAFLD livers supports a role for endogenous alcohol metabolism in NAFLD pathology and provides further support for gut microbiome therapy in NAFLD management. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley © Sons, Ltd.


Asunto(s)
Alcoholes/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Adulto , Biopsia , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Obesidad/genética , Obesidad/metabolismo , Transcriptoma
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