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1.
PLoS One ; 15(12): e0244013, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33320899

RESUMO

The generation of large metabolomic data sets has created a high demand for software that can fit statistical models to one-metabolite-at-a-time on hundreds of metabolites. We provide the %polynova_2way macro in SAS to identify metabolites differentially expressed in study designs with a two-way factorial treatment and hierarchical design structure. For each metabolite, the macro calculates the least squares means using a linear mixed model with fixed and random effects, runs a 2-way ANOVA, corrects the P-values for the number of metabolites using the false discovery rate or Bonferroni procedure, and calculate the P-value for the least squares mean differences for each metabolite. Finally, the %polynova_2way macro outputs a table in excel format that combines all the results to facilitate the identification of significant metabolites for each factor. The macro code is freely available in the Supporting Information.


Assuntos
Fígado/metabolismo , Metaboloma , Metabolômica/métodos , Software , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Fígado/microbiologia , Espectrometria de Massas/métodos , Probióticos/uso terapêutico , Suínos
2.
PLoS One ; 15(7): e0236741, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730300

RESUMO

Aryl hydrocarbon receptor (AHR) agonists such as dioxin have been associated with obesity and the development of diabetes. Whole-body Ahr knockout mice on high-fat diet (HFD) have been shown to resist obesity and hepatic steatosis. Tissue-specific knockout of Ahr in mature adipocytes via adiponectin-Cre exacerbates obesity while knockout in liver increases steatosis without having significant effects on obesity. Our previous studies demonstrated that treatment of subcutaneous preadipocytes with exogenous or endogenous AHR agonists disrupts maturation into functional adipocytes in vitro. Here, we used platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice, a Cre model previously established to knock out genes in preadipocyte lineages and other cell types, but not liver cells, to further define AHR's role in obesity. We demonstrate that Pdgfrα-Cre Ahr-floxed (Ahrfl/fl) knockout mice are protected from HFD-induced obesity compared to non-knockout Ahrfl/fl mice (control mice). The Pdgfrα-Cre Ahrfl/fl knockout mice were also protected from increased adiposity, enlargement of adipocyte size, and liver steatosis while on the HFD compared to control mice. On a regular control diet, knockout and non-knockout mice showed no differences in weight gain, indicating the protective phenotype arises only when animals are challenged by a HFD. At the cellular level, cultured cells from brown adipose tissue (BAT) of Pdgfrα-Cre Ahrfl/fl mice were more responsive than cells from controls to transcriptional activation of the thermogenic uncoupling protein 1 (Ucp1) gene by norepinephrine, suggesting an ability to burn more energy under certain conditions. Collectively, our results show that knockout of Ahr mediated by Pdgfrα-Cre is protective against diet-induced obesity and suggest a mechanism by which enhanced UCP1 activity within BAT might confer these effects.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Integrases/metabolismo , Obesidade/prevenção & controle , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/fisiologia , Receptores de Hidrocarboneto Arílico/fisiologia , Adiposidade , Animais , Metabolismo Energético , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/patologia , Termogênese
3.
Nutr Metab Cardiovasc Dis ; 30(10): 1653-1661, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32631703

RESUMO

BACKGROUND AND AIMS: Coffee is known to have a beneficial effect on various liver diseases. The aim of this retrospective longitudinal study was to investigate an association between the amount of coffee consumption and the incidence of fatty liver disease in Korean adults. METHODS AND RESULTS: Data from a total of 91,436 male and female subjects with the mean follow-up period of 2.8 years were analyzed. The incidence of fatty liver was not associated with the amount of coffee consumption at baseline, but it was associated with the change in the amount of coffee consumption at the follow-up period. Multiple linear regression analyses showed that hazard ratios for incidence of fatty liver disease were significantly low in "increase" group comparing with "no change" group in fully adjusted model. When a subgroup analysis by gender was conducted, similar significant results were observed in male subjects, but not in females. CONCLUSIONS: The increment in the amount of coffee consumption is associated with the lower incidence of fatty liver in Korean men and suggests that increasing the coffee consumption may have a protective effect on fatty liver.


Assuntos
Café , Fígado Gorduroso/prevenção & controle , Adulto , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/epidemiologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Estudos Retrospectivos , Fatores de Risco , Seul/epidemiologia , Fatores Sexuais
4.
Am J Physiol Endocrinol Metab ; 319(2): E354-E362, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603260

RESUMO

Browning of white adipose tissue (WAT) has been shown to reduce obesity and obesity-related complications, suggesting that factors that promote WAT browning may have applications in the development of therapeutic strategies for treating obesity. Here, we show that ablation of spinophilin (SPL), a ubiquitously expressed, multidomain scaffolding protein, increases metabolism and improves energy balance. Male and female SPL knockout (KO) and wild-type (WT) littermate controls were fed a chow diet or a high-fat diet (HFD). Body weight, hepatic steatosis, glucose and insulin tolerance, physical activity, and expression of browning genes in adipose tissues were measured and compared. Male SPL knockout (KO) mice fed a chow diet were significantly leaner, had lower body weights, and exhibited better glucose tolerance and insulin sensitivity than wild-type (WT) littermate controls. When fed an HFD, SPL KO mice were protected from increased body fat, weight gain, hepatic steatosis, hyperinsulinemia, and insulin resistance. Physical activity of SPL KO mice was markedly increased compared with WT controls. Furthermore, expression of the brown adipocyte marker, uncoupling protein-1 (UCP-1), and the mitochondrial activity markers, cd137 and c-idea, were significantly increased in visceral WAT (vWAT) of SPL KO mice, suggesting that SPL knockout protected the mice from HFD-induced obesity and its metabolic complications, at least in part, by promoting the browning of white adipocytes in vWAT. Our data identify a critical role of SPL in regulating glucose homeostasis, obesity, and adipocyte browning. These results suggest SPL may serve as a drug target for obesity and diabetes.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/fisiologia , Proteínas dos Microfilamentos/deficiência , Proteínas do Tecido Nervoso/deficiência , Obesidade/prevenção & controle , Adiponectina/sangue , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/fisiopatologia , Animais , Metabolismo Energético , Fígado Gorduroso/fisiopatologia , Fígado Gorduroso/prevenção & controle , Feminino , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Obesidade/etiologia , Obesidade/fisiopatologia , Esforço Físico/fisiologia
5.
Am J Physiol Gastrointest Liver Physiol ; 319(2): G212-G226, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32597709

RESUMO

Short bowel syndrome (SBS) is associated with changes in the intestinal microbiome and marked local and systemic inflammation. There is also a late complication of SBS, intestinal failure associated liver disease (IFALD) in which hepatic steatosis progresses to cirrhosis. Most patients with SBS arrive at massive intestinal resection after a contaminating intraabdominal catastrophe and have a history of exposure to broad-spectrum antibiotics. We therefore investigated whether the administration of broad-spectrum antibiotics in conjunction with SBS in zebrafish (ZF) would replicate these systemic effects observed in humans to identify potentially druggable targets to aid in the management of SBS and resulting IFALD. In zebrafish with SBS, broad-spectrum antibiotics altered the microbiome, decreased inflammation, and reduced the development of hepatic steatosis. After two weeks of broad-spectrum antibiotics, these fish exhibited decreased alpha diversity, with less variation in microbial community composition between SBS and sham fish. Additionally, administration of broad-spectrum antibiotics was associated with decreased expression of intestinal toll-like receptor 4 (tlr4), increased expression of the intestinal gene encoding the Farnesoid X receptor (fxr), decreased expression of downstream hepatic cyp7a1, and decreased development of hepatic steatosis. SBS in zebrafish reproducibly results in increased epithelial surface area as occurs in human patients who demonstrate intestinal adaptation, but antibiotic administration in zebrafish with SBS reduced these gains with increased cell death in the intervillus pocket that contains stem/progenitor cells. These alternate states in SBS zebrafish might direct the development of future human therapies.NEW & NOTEWORTHY In a zebrafish model that replicates a common clinical scenario, systemic effects of the administration of broad-spectrum antibiotics in a zebrafish model of SBS identified two alternate states that led to the establishment of fat accumulation in the liver or its absence. Broad-spectrum antibiotics given to zebrafish with SBS over 2 wk altered the intestinal microbiome, decreased intestinal and hepatic inflammation, and decreased hepatic steatosis.


Assuntos
Antibacterianos/farmacologia , Fígado Gorduroso/prevenção & controle , Receptores Citoplasmáticos e Nucleares/metabolismo , Síndrome do Intestino Curto/microbiologia , Animais , Peixe-Zebra
6.
Life Sci ; 254: 117776, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437790

RESUMO

AIMS: Rg1 is the most active component of traditional Chinese medicine ginseng, having anti-aging and anti-oxidative stress features in multiple organs. Cellular senescence of hepatocytes is involved in the progression of a wide spectrum of chronic liver diseases. In this study, we investigated the potential benefits and mechanism of action of Rg1 on aging-driven chronic liver diseases. MATERIALS AND METHODS: A total of 40 male C57BL/6 mice were randomly divided into four groups: control group; Rg1 group; Rg1+d-gal group; and d-gal group. Blood and liver tissue samples were collected for determination of liver function, biochemical and molecular markers, as well as histopathological investigation. KEY FINDINGS: Rg1 played an anti-aging role in reversing d-galactose induced increase in senescence-associated SA-ß-gal staining and p53, p21 protein in hepatocytes of mice and sustained mitochondria homeostasis. Meanwhile, Rg1 protected livers from d-galactose caused abnormal elevation of ALT and AST in serum, hepatic steatosis, reduction in hepatic glucose production, hydrogenic degeneration, inflammatory phenomena including senescence-associated secretory phenotype (SASP) IL-1ß, IL-6, MCP-1 elevation and lymphocyte infiltration. Furthermore, Rg1 suppressed drastic elevation in FOXO1 phosphorylation resulting in maintaining FOXO1 protein level in the liver after d-galactose treatment, followed by FOXO1 targeted antioxidase SOD and CAT significant up-regulation concurrent with marked decrease in lipid peroxidation marker MDA. SIGNIFICANCE: Rg1 exerts pharmaceutic effects of maintaining FOXO1 activity in liver, which enhances anti-oxidation potential of Rg1 to ameliorate SASP and to inhibit inflammation, also promotes metabolic homeostasis, and thus protects livers from senescence induced fatty liver disease. The study provides a potential therapeutic strategy for alleviating chronic liver pathology.


Assuntos
Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Proteína Forkhead Box O1/metabolismo , Ginsenosídeos/farmacologia , Animais , Antioxidantes/farmacologia , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Galactose/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Fatores de Transcrição/metabolismo
7.
Nat Commun ; 11(1): 2080, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350271

RESUMO

Excessive insulin signaling through the insulin receptor (IR) may play a role in the pathogenesis of diet-induced metabolic disease, including obesity and type 2 diabetes. Here we investigate whether heterozygous impairment of insulin receptor (IR) expression limited to peripheral, i.e. non-CNS, tissues of adult mice impacts the development of high-fat diet-induced metabolic deterioration. While exhibiting some features of insulin resistance, PerIRKO+/- mice display a hepatic energy deficit accompanied by induction of energy-sensing AMPK, mitochondrial biogenesis, PPARα, unexpectedly leading to protection from, and reversal of hepatic lipid accumulation (steatosis hepatis, NAFLD). Consistently, and unlike in control mice, the PPARα activator fenofibrate fails to further affect hepatic lipid accumulation in PerIRKO+/- mice. Taken together, and opposing previously established diabetogenic features of insulin resistance, incomplete impairment of insulin signaling may mimic central aspects of calorie restriction to limit hepatic lipid accumulation during conditions of metabolic stress.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Jejum/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Receptor de Insulina/metabolismo , Animais , Composição Corporal , Metabolismo Energético , Comportamento Alimentar , Glucose/metabolismo , Homeostase , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
8.
Balkan Med J ; 37(4): 196-202, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32270948

RESUMO

Background: Donor organs for liver transplantation may often have fatty liver disease, which confers a higher sensitivity to ischemia/reperfusion injury. At present, there is no effective treatment for the condition. Evidence has suggested that metformin, the first-line medication for diabetes, has protective effects against many disorders. However, the potential role of metformin in ischemia/reperfusion injury in fatty liver disease remains unclear. Aims: To examine the effect of metformin treatment during ischemia/reperfusion injury in fatty liver and determine the possible mechanisms. Study Design: Animal experimentation. Methods: Sprague-Dawley male rats were fed a high-fat diet (520 kcal/100 g) for 14 weeks and then were subjected to the orthotopic autologous liver transplantation model. Sections of liver tissue were stained with hematoxylin and eosin to visualize the damage. Blood and liver samples were used to analyze the related proteins and components involved in the inflammatory signaling pathway. Results: We found that metformin significantly ameliorated the ischemia/reperfusion injury of the fatty liver through a reduction in alanine aminotransferase/aspartate aminotransferase concentrations in the serum and a decrease in dead cells, as shown by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay (p<0.05). In addition, metformin significantly attenuated interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α production and increased the expression of active caspase-3 and Bax in the liver (p<0.05). Mechanistically, metformin suppressed the activation of toll-like receptor 4 (TLR4)/NF-κB signaling (p<0.05), resulting in a decreased inflammatory response and apoptosis. Conclusion: Our findings demonstrated that metformin attenuated ischemia/reperfusion injury in fatty liver disease via the TLR4/NF-κB axis, suggesting that metformin could have potential therapeutic applications in ischemia/reperfusion injury associated with liver transplantation.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Metformina/uso terapêutico , Fatores de Proteção , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Fígado Gorduroso/prevenção & controle , Hipoglicemiantes/uso terapêutico , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/prevenção & controle , Receptor 4 Toll-Like/efeitos dos fármacos
9.
Life Sci ; 253: 117677, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32305525

RESUMO

Impaired vascularization of adipose tissue leads to local hypoxia and results in chronic inflammation and obesity-related metabolic disorders. We have recently constructed an engineered protein named tPep-VEGF-B by bridging vascular endothelial growth factor (VEGF-B) with an adipose-targeted peptide. Here, we reported tPep-VEGF-B diminishes obesity and alleviates metabolic syndrome. High fat diet (HFD) treated mice had reduced adipose vascular density and showed adipose hypoxia and metabolic complications. In contrast, the treatment of tPep-VEGF-B repressed HFD-induced body weight gain, which led to increased adipose vasculature and reduced hypoxia. This treatment also alleviated obesity associated hyperlipidemia and fatty liver disease. This study provided a leading molecule for the treatment of type 2 diabetes and other metabolic diseases. It also provided experimental support for the theory that modulation of angiogenesis plays a key role in the treatment of metabolic diseases.


Assuntos
Tecido Adiposo/irrigação sanguínea , Sistemas de Liberação de Medicamentos , Fígado Gorduroso/prevenção & controle , Obesidade/prevenção & controle , Fator B de Crescimento do Endotélio Vascular/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Hiperlipidemias/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/química , Fator B de Crescimento do Endotélio Vascular/farmacologia
10.
J Dairy Sci ; 103(7): 6557-6568, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32331890

RESUMO

Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is a key regulator of energy metabolism in the liver. In nonruminants, the hepatic abundance of SIRT3 is decreased in individuals with nonalcoholic fatty liver diseases, and recovery of SIRT3 alleviates hepatic triacylglycerol (TG) deposition. However, the level of SIRT3 expression and its effects on lipid metabolism in dairy cows have not been characterized. Here we studied the hepatic expression of SIRT3 in cows with fatty liver and the role of SIRT3 in fatty acid metabolism in bovine hepatocytes. This in vivo study involved 10 healthy cows and 10 cows with fatty liver, from which we collected samples of liver tissue and blood. Primary hepatocytes were isolated from Holstein calves and treated with 0, 0.5, or 1.0 mM nonesterified fatty acids (NEFA) for 24 h or transinfected with SIRT3 overexpression adenovirus (Ad-SIRT3)/SIRT3-short interfering (si)RNA for 48 h. Cows with fatty liver displayed lower serum glucose concentrations but higher serum NEFA and ß-hydroxybutyrate concentrations relative to healthy cows. Cows with fatty liver also had significant lower mRNA and protein abundance of hepatic SIRT3. Incubation of primary hepatocytes with NEFA reduced SIRT3 abundance in primary hepatocytes in a dose-dependent manner. Fatty acid (1 mM) treatment also markedly increased the abundance of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) but significantly decreased the abundance of carnitine palmitoyltransferase I (CPT1A), carnitine palmitoyltransferase II (CPT2), and acyl-CoA oxidase (ACO). Knockdown of SIRT3 by SIRT3-siRNA downregulated the mRNA abundance of CPT1A, CPT2, and ACO. In contrast, overexpression of SIRT3 by Ad-SIRT3 upregulated the mRNA abundance of CPT1A, CPT2, and ACO; downregulated the mRNA abundance of ACC1 and FAS; and consequently, decreased intracellular TG concentrations. Overexpression of SIRT3 ameliorated exogenous NEFA-induced TG accumulation by downregulating the abundance of ACC1 and FAS and upregulating the abundance of CPT1A, CPT2, and ACO in calf hepatocytes. Our data demonstrated that cows with fatty liver had lower hepatic SIRT3 contents, and an increase in SIRT3 abundance by overexpression mitigated TG deposition by modulating the expression of lipid metabolism genes in bovine hepatocytes. These data suggest a possible role of SIRT3 as a therapeutic target for fatty liver disease prevention in periparturient dairy cattle.


Assuntos
Doenças dos Bovinos/metabolismo , Ácidos Graxos não Esterificados/administração & dosagem , Fígado Gorduroso/veterinária , Metabolismo dos Lipídeos/efeitos dos fármacos , Sirtuína 3/metabolismo , Ácido 3-Hidroxibutírico/sangue , Acetil-CoA Carboxilase/efeitos dos fármacos , Acil-CoA Oxidase/efeitos dos fármacos , Animais , Carnitina O-Palmitoiltransferase/efeitos dos fármacos , Bovinos , Doenças dos Bovinos/prevenção & controle , Ácidos Graxos/metabolismo , Ácidos Graxos não Esterificados/sangue , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mitocôndrias/enzimologia , Sirtuína 3/genética , Triglicerídeos/metabolismo
11.
J Dairy Sci ; 103(6): 5561-5574, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278565

RESUMO

Inflammation is critical in the progression from benign hepatic lipidosis to pathological hepatic steatosis. The objective of this study was to examine the potential role of the outer mitochondrial membrane protein mitofusin 2 (MFN2) in the etiology of hepatic steatosis in dairy cows during early lactation. Using a nested case-control design, we compared blood and liver samples from 10 healthy cows and 10 age-matched cows with moderate fatty liver. Cows with moderate fatty liver had high liver triacylglycerols, elevated plasma concentrations of free fatty acids (FFA) and ß-hydroxybutyrate, and low concentrations of glucose. Cows with moderate fatty liver had overactivated inflammatory pathways in the liver, as indicated by increased abundance of phosphorylated nuclear factor κB (NF-κB) p65, NLR family pyrin domain containing 3 (NLRP3) and caspase-1 inflammasome protein, and elevated plasma concentrations and hepatic mRNA abundance of their molecular targets IL-1ß, IL-6, and tumor necrosis factor α (TNF-α). In the cell culture model, we were able to replicate our findings in cows with moderate fatty liver: 1.2 mM exogenous FFA decreased the abundance of MFN2 and upregulated phosphorylation levels of the inhibitor of NF-κB (IκB) α and NF-κB p65, the IκB kinase ß activity, and the abundance of NLRP3, caspase-1, IL-1ß, IL-6, and TNF-α. Whereas MFN2 knockdown potentiated the FFA-induced activation of these inflammatory pathways, overexpression of MFN2 attenuated the detrimental effect of excess exogenous FFA by improving mitochondrial function and decreasing the release of reactive oxygen species, suggesting that MFN2 may be a potential therapeutic target for FFA-induced hepatic inflammation in dairy cows during early lactation.


Assuntos
Doenças dos Bovinos/prevenção & controle , Ácidos Graxos não Esterificados/efeitos adversos , Fígado Gorduroso/veterinária , GTP Fosfo-Hidrolases/antagonistas & inibidores , Inflamação/veterinária , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/antagonistas & inibidores , Animais , Estudos de Casos e Controles , Bovinos , Ácidos Graxos não Esterificados/sangue , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/prevenção & controle , Feminino , GTP Fosfo-Hidrolases/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lactação/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
PLoS Genet ; 16(4): e1008629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32282858

RESUMO

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.


Assuntos
Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Predisposição Genética para Doença , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto/genética , Oxirredutases/genética , Alelos , LDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Conjuntos de Dados como Assunto , Fígado Gorduroso/sangue , Fígado Gorduroso/enzimologia , Feminino , Homozigoto , Humanos , Fígado/enzimologia , Cirrose Hepática/sangue , Cirrose Hepática/enzimologia , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/enzimologia , Cirrose Hepática Alcoólica/genética , Cirrose Hepática Alcoólica/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade
13.
Br J Nutr ; 124(3): 286-295, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32234086

RESUMO

Maternal nutritional programming by a high-fat (HF) diet is related to hepatic lipid accumulation and steatosis in offspring. Conjugated linoleic acid (CLA) might ameliorate impaired hepatic lipid homoeostasis; therefore, the aim was to investigate the potential preventive effect of maternal CLA consumption on TAG metabolism alterations induced by HF diets in adult male rat offspring receiving or not receiving CLA. Female Wistar rats were fed a control (C) diet, HF diet or HF diet supplemented with CLA (HF+CLA) for 4 weeks before mating and throughout pregnancy and lactation. After weaning, for 9 weeks, male offspring of C or HF rats continued with the same diets as their mothers (C/C or HF/HF groups, respectively) and male offspring of HF+CLA rats were fed HF or HF+CLA diets (HF+CLA/HF or HF+CLA/HF+CLA groups, respectively). Nutritional parameters, serum and liver TAG levels, the TAG secretion rate (TAG-SR) and the activities as well as gene expression of key hepatic enzymes involved in TAG regulation were assessed. The most interesting results were that maternal CLA decreased epididymal white adipose tissue weight and prevented serum and liver TAG accumulation induced by a HF diet in adult male offspring receiving or not receiving CLA. The prevention of liver steatosis in HF+CLA/HF+CLA and HF+CLA/HF offspring was associated with an increased hepatic TAG-SR. Overall, this study provides evidence that maternal CLA consumption programmes TAG regulation and in this way contributes to lowering lipid levels in tissues and preventing liver steatosis in particular.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Fígado Gorduroso/prevenção & controle , Ácidos Linoleicos Conjugados/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Tecido Adiposo Branco/metabolismo , Animais , Fígado Gorduroso/etiologia , Feminino , Fígado/metabolismo , Masculino , Exposição Materna/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Wistar
14.
PLoS Biol ; 18(3): e3000688, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32218572

RESUMO

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.


Assuntos
Tecido Adiposo Marrom/metabolismo , Fármacos Antiobesidade/uso terapêutico , Cumarínicos/uso terapêutico , Obesidade/prevenção & controle , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/prevenção & controle , Intolerância à Glucose/prevenção & controle , Resistência à Insulina , Reação de Maillard , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Propiltiouracila/toxicidade , Termogênese , Tri-Iodotironina/antagonistas & inibidores , Tri-Iodotironina/metabolismo , Ganho de Peso/efeitos dos fármacos
15.
Poult Sci ; 99(2): 1019-1027, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32036959

RESUMO

To investigate the etiopathogenesis of fatty liver hemorrhagic syndrome (FLHS) and the protective effects of resveratrol (RSV) against FLHS in laying hens, 144 healthy 90-day-old laying hens were randomly divided into 4 groups including control (Con) group, high-energy low-protein (HELP) group, RSV group, and HELP + RSV group, each of which contained 36 hens with 3 replicates. Birds in the 4 groups were fed a basal diet, HELP diet, basal diet supplemented with 400 mg/kg RSV, and HELP diet supplemented with 400 mg/kg RSV. The histopathology of the ovary lesions on day 120, egg production, antioxidative function, and mRNA expression levels of inflammatory cytokines on days 40, 80, and 120 were determined. The lipid accumulation and hemorrhaging were more severe in the HELP group than those in the HELP + RSV group. The laying rate was markedly decreased in the HELP group compared with that in the Con and HELP + RSV groups. Furthermore, the malondialdehyde concentration was significantly increased (P < 0.05), while the levels of superoxide dismutase (SOD), catalase, and glutathione were significantly decreased (P < 0.05) in the HELP group compared with those in the Con and HELP + RSV groups. The mRNA levels of antioxidant genes (Nrf2, SOD-1, and HO-1) were markedly increased (P < 0.05) in the HELP + RSV group compared with those in the HELP group. In addition, the mRNA levels of inflammation-related genes (nuclear factor kappa B, tumor necrosis factor-α, IL-1ß, and IL-6) were significantly increased (P < 0.05) in the HELP group compared with those in the Con and HELP + RSV groups. Collectively, these results indicate that oxidative stress and inflammation are involved in the occurrence and development of FLHS in the ovaries of laying hens, but RSV effectively attenuates oxidative stress and inflammation in hens with FLHS. Hence, RSV can be used as an effective feed additive to protect against FLHS.


Assuntos
Antioxidantes/metabolismo , Galinhas , Fígado Gorduroso/veterinária , Expressão Gênica , Hemorragia/veterinária , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Animais , Proteínas Aviárias , Citocinas/genética , Citocinas/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Feminino , Hemorragia/etiologia , Hemorragia/prevenção & controle , Ovário/metabolismo , Ovário/fisiopatologia , Oxirredução , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodução/efeitos dos fármacos
16.
Nat Commun ; 11(1): 807, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042044

RESUMO

Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPARα to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.


Assuntos
Autofagia/genética , Jejum/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fígado/metabolismo , Animais , Autofagia/efeitos dos fármacos , Epigênese Genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/deficiência , Hepatócitos/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Lipólise , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Obesos , PPAR alfa/metabolismo , Fosforilação , Ligação Proteica , Transdução de Sinais , Regulação para Cima
17.
Artigo em Inglês | MEDLINE | ID: mdl-32007744

RESUMO

The administration of iron induces liver oxidative stress and depletion of long-chain polyunsaturated fatty acids (LCPUFAs), n-6/n-3 LCPUFA ratio enhancement and fat accumulation, which may be prevented by antioxidant-rich extra virgin olive oil (AR-EVOO) supplementation. Male Wistar rats were subjected to a control diet (50 mg iron/kg diet) or iron-rich diet (IRD; 200 mg/kg diet) with alternate AR-EVOO for 21 days. Liver fatty acid (FA) analysis was performed by gas-liquid chromatography (GLC) after lipid extraction and fractionation, besides Δ-5 desaturase (Δ-5 D) and Δ6-D mRNA expression (qPCR) and activity (GLC) measurements. The IRD significantly (p < 0.05) increased hepatic total fat, triacylglycerols, free FA contents and serum transaminases levels, with diminution in those of n-6 and n-3 LCPUFAs, higher n-6/n-3 ratios, lower unsaturation index and Δ5-D and Δ6-D activities, whereas the mRNA expression of both desaturases was enhanced over control values, changes that were prevented by concomitant AR-EVOO supplementation. N-6 and n-3 LCPUFAs were also decreased by IRD in extrahepatic tissues and normalized by AR-EVOO. In conclusion, AR-EVOO supplementation prevents IRD-induced changes in parameters related to liver FA metabolism and steatosis, an effect that may have a significant impact in the treatment of iron-related pathologies or metabolic disorders such as non-alcoholic fatty liver disease.


Assuntos
Antioxidantes/administração & dosagem , Ácidos Graxos Dessaturases/genética , Fígado Gorduroso/prevenção & controle , Ferro/efeitos adversos , Linoleoil-CoA Desaturase/genética , Azeite de Oliva/administração & dosagem , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Cromatografia Gasosa , Modelos Animais de Doenças , Ácidos Graxos/análise , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/epidemiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Azeite de Oliva/química , Azeite de Oliva/farmacologia , Ratos , Ratos Wistar
18.
Nutrients ; 12(2)2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991934

RESUMO

This study aimed to investigate the effect of sesamol (SEM) on the protein kinase A (PKA) pathway in obesity-related hepatic steatosis treatment by using high-fat diet (HFD)-induced obese mice and a palmitic acid (PA)-treated HepG2 cell line. SEM reduced the body weight gain of obese mice and alleviated related metabolic disorders such as insulin resistance, hyperlipidemia, and systemic inflammation. Furthermore, lipid accumulation in the liver and HepG2 cells was reduced by SEM. SEM downregulated the gene and protein levels of lipogenic regulator factors, and upregulated the gene and protein levels of the regulator factors responsible for lipolysis and fatty acid ß-oxidation. Meanwhile, SEM activated AMP-activated protein kinase (AMPK), which might explain the regulatory effect of SEM on fatty acid ß-oxidation and lipogenesis. Additionally, the PKA-C and phospho-PKA substrate levels were higher after SEM treatment. Further research found that after pretreatment with the PKA inhibitor, H89, lipid accumulation was increased even with SEM administration in HepG2 cells, and the effect of SEM on lipid metabolism-related regulator factors was abolished by H89. In conclusion, SEM has a positive therapeutic effect on obesity and obesity-related hepatic steatosis by regulating the hepatic lipid metabolism mediated by the PKA pathway.


Assuntos
Benzodioxóis/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fígado Gorduroso/prevenção & controle , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Fenóis/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Ativação Enzimática , Fígado Gorduroso/enzimologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Células Hep G2 , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/enzimologia , Fosforilação , Transdução de Sinais , Ganho de Peso/efeitos dos fármacos
19.
J Nutr ; 150(4): 775-783, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851339

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death in the world. Choline deficiency has been well studied in the context of liver disease; however, less is known about the effects of choline supplementation in HCC. OBJECTIVE: The objective of this study was to test whether choline supplementation could influence the progression of HCC in a high-fat-diet (HFD)-driven mouse model. METHODS: Four-day-old male C57BL/6J mice were treated with the chemical carcinogen, 7,12-dimethylbenz[a]anthracene, and were randomly assigned at weaning to a cohort fed an HFD (60% kcal fat) or an HFD with supplemental choline (60% kcal fat, 1.2% choline; HFD+C) for 30 wk. Blood was isolated at 15 and 30 wk to measure immune cells by flow cytometry, and glucose-tolerance tests were performed 2 wk prior to killing. Overall tumor burden was quantified, hepatic lipids were measured enzymatically, and phosphatidylcholine species were measured by targeted MS methods. Gene expression and mitochondrial DNA were quantified by quantitative PCR. RESULTS: HFD+C mice exhibited a 50-90% increase in both circulating choline and betaine concentrations in the fed state (P ≤ 0.05). Choline supplementation resulted in a 55% decrease in total tumor numbers, a 67% decrease in tumor surface area, and a 50% decrease in hepatic steatosis after 30 wk of diet (P ≤ 0.05). Choline supplementation increased the abundance of mitochondria and the relative expression of ß-oxidation genes by 21% and ∼75-100%, respectively, in the liver. HFD+C attenuated circulating myeloid-derived suppressor cells at 15 wk of feeding (P ≤ 0.05). CONCLUSIONS: Choline supplementation attenuated HFD-induced HCC and hepatic steatosis in male C57BL/6J mice. These results suggest a therapeutic benefit of choline supplementation in blunting HCC progression.


Assuntos
Colina/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Animais , Betaína/sangue , Colina/sangue , DNA Mitocondrial/análise , Suplementos Nutricionais , Fígado Gorduroso/prevenção & controle , Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/química , Fígado/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/patologia , Tamanho do Órgão/efeitos dos fármacos
20.
Biochem Pharmacol ; 171: 113693, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706843

RESUMO

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ. Administration of Δ9-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.


Assuntos
Adiposidade/efeitos dos fármacos , Dronabinol/análogos & derivados , Doenças Metabólicas/prevenção & controle , Obesidade/prevenção & controle , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Dronabinol/metabolismo , Dronabinol/farmacologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Células HEK293 , Humanos , Masculino , Doenças Metabólicas/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , PPAR gama/agonistas , PPAR gama/metabolismo , Rosiglitazona/metabolismo , Rosiglitazona/farmacologia
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