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1.
PLoS Genet ; 16(8): e1008941, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760060

RESUMO

Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology.


Assuntos
Proteínas de Transporte/genética , Lipídeos/genética , Lipoproteínas/genética , Triglicerídeos/genética , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Trato Gastrointestinal/metabolismo , Humanos , Imunoprecipitação , Gotículas Lipídicas/metabolismo , Lipoproteínas/metabolismo , Mutação de Sentido Incorreto/genética , Mutação Puntual/genética , Transporte Proteico/genética , Triglicerídeos/metabolismo , Peixe-Zebra/genética
2.
Nat Commun ; 11(1): 4150, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811819

RESUMO

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.


Assuntos
Adipócitos/metabolismo , Envelhecimento/fisiologia , Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Doenças Metabólicas/metabolismo , Adipócitos/patologia , Adipogenia/genética , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/fisiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Técnicas de Inativação de Genes , Glucose/genética , Glucose/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , PPAR gama/metabolismo
3.
Anat Sci Int ; 95(4): 489-497, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32361815

RESUMO

Steatohepatitis, fibrosis, and cirrhosis are common pathological features in the progression of hepatic steatosis. In the current work, we investigated the effect of germinated barely on the structure and function of the liver and its regulatory mechanism on SDC1 gene expression in a steatohepatitis rat model. Forty-eight adult male white Wistar rats were randomly divided into four groups: Group I, control; Group II, rats fed a germinated barley diet; Group III, rats fed a high-fat diet (HFD); and Group IV, rats fed both germinated barley (GB) and a high-fat diet for 14 weeks. Biochemical, histopathological, immunohistochemical, and morphometric studies, as well as qRT-PCR, were used to analyze the effect of germinated barley on steatohepatitis. The rats in Group IV had a lower liver index percentage and improved altered lipid profile and liver function tests compared to those in Group III. Supplementation of GB with a HFD ameliorated the histopathological features in the livers of rats fed a HFD, decreased the percentage of CD68-positive macrophages, and lowered the upregulated expression of SDC1. Supplementation of a HFD with GB prohibited the deterioration of liver function, lipid profile, and alteration of liver structure; it also decreased the associated hepatic inflammation and downregulated SDC1 in liver tissue.


Assuntos
Dieta , Regulação para Baixo/efeitos dos fármacos , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Expressão Gênica , Germinação , Hordeum , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Animais , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo dos Lipídeos , Fígado/metabolismo , Macrófagos , Masculino , Ratos Wistar , Sindecana-1
4.
PLoS One ; 15(5): e0232886, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396553

RESUMO

There is a significant organ shortage in the field of liver transplantation, partly due to a high discard rate of steatotic livers from donors. These organs are known to function poorly if transplanted but make up a significant portion of the available pool of donated livers. This study demonstrates the ability to improve the function of steatotic rat livers using a combination of ex situ machine perfusion and a "defatting" drug cocktail. After 6 hours of perfusion, defatted livers demonstrated lower perfusate lactate levels and improved bile quality as demonstrated by higher bile bicarbonate and lower bile lactate. Furthermore, defatting was associated with decreased gene expression of pro-inflammatory cytokines and increased expression of enzymes involved in mitochondrial fatty acid oxidation. Rehabilitation of marginal or discarded steatotic livers using machine perfusion and tailored drug therapy can significantly increase the supply of donor livers for transplantation.


Assuntos
Fígado Gorduroso/terapia , Fígado/fisiopatologia , Preservação de Órgãos/instrumentação , Animais , Bicarbonatos/análise , Citocinas/genética , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/fisiopatologia , Regulação da Expressão Gênica , Ácido Láctico/análise , Fígado/química , Transplante de Fígado , Masculino , Preservação de Órgãos/métodos , Perfusão , Ratos , Doadores de Tecidos
5.
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
6.
PLoS One ; 15(4): e0231650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315370

RESUMO

Exposure to ionizing radiation contributing to negative health outcomes is a widespread concern. However, the impact of low dose and sub-lethal dose radiation (SLDR) exposures remain contentious, particularly in pregnant women who represent a vulnerable group. The fetal programming hypothesis states that an adverse in utero environment or stress during development of an embryo or fetus can result in permanent physiologic changes often resulting in progressive metabolic dysfunction with age. To assess changes in gene expression profiles of glucose/insulin signaling and lipid metabolism caused by radiation exposure in utero, pregnant C57Bl/6J mice were irradiated using a dose response ranging from low dose to SLDR and compared to a Sham-irradiated group. mRNA expression analysis in 16 week old offspring (n = 84) revealed that genes involved in metabolic function including glucose metabolism, insulin signaling and lipid metabolism were unaffected by prenatal radiation exposures up to 300 mGy. However, female offspring of dams exposed to 1000 mGy had upregulated expression of genes contributing to insulin resistance and gluconeogenesis. In a second cohort of mice, the effects of SLDR on fetal programming of hepatic SOCS3 and PEPCK protein expression were assessed. 4 month old female offspring of dams irradiated at 1000 mGy had: 1) increased liver weights, 2) increased hepatic expression of proteins involved in glucose metabolism and 3) increased 18F-fluorodeoxyglucose (FDG) uptake in interscapular brown adipose tissue (IBAT) measured by positron emission tomography (PET) (n = 25). The results of this study indicate that prenatal radiation exposure does not affect metabolic function up to 300 mGy and 1000 mGy may be a threshold dose for sex-specific alterations in glucose uptake and hepatic gene and protein expression of SOCS3, PEPCK, PPARGC1A and PPARGC1B. These findings suggest that SLDR doses alter glucose uptake in IBAT and hepatic gene and protein expression of offspring and these changes may progress with age.


Assuntos
Tecido Adiposo Marrom/crescimento & desenvolvimento , Desenvolvimento Fetal/genética , Resistência à Insulina/genética , Fígado/metabolismo , Tecido Adiposo Marrom/efeitos da radiação , Animais , Glicemia/metabolismo , Metabolismo dos Carboidratos/genética , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Feminino , Desenvolvimento Fetal/efeitos da radiação , Feto , Glucose/metabolismo , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/efeitos da radiação , Fígado/patologia , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Radiação
7.
Metabolism ; 107: 154222, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32246987

RESUMO

Fructose over-consumption contributes to the development of liver steatosis in part by stimulating ChREBPα-driven de novo lipogenesis. However, the mechanisms by which fructose activates ChREBP pathway remain largely undefined. Here we performed affinity purification of ChREBPα followed by mass spectrometry and identified DDB1 as a novel interaction protein of ChREBPα in the presence of fructose. Depletion and overexpression of Ddb1 showed opposite effects on the ChREBPα stability in hepatocytes. We next tested the impact of hepatic Ddb1 deficiency on the fructose-induced ChREBP pathway. After 3-week high-fructose diet feeding, both Ddb1 liver-specific knockout and AAV-TBG-Cre-injected Ddb1flox/flox mice showed significantly reduced ChREBPα, lipogenic enzymes, as well as triglycerides in the liver. Mechanistically, DDB1 stabilizes ChREBPα through CRY1, a known ubiquitination target of DDB1 E3 ligase. Finally, overexpression of a degradation-resistant CRY1 mutant (CRY1-585KA) reduces ChREBPα and its target genes in the mouse liver following high-fructose diet feeding. Our data revealed DDB1 as an intracellular sensor of fructose intake to promote hepatic de novo lipogenesis and liver steatosis by stabilizing ChREBPα in a CRY1-dependent manner.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Criptocromos/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Carboidratos da Dieta/farmacologia , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Frutose/farmacologia , Proteínas Imediatamente Precoces/metabolismo , Proteínas de Membrana/metabolismo , Animais , Hepatócitos/metabolismo , Proteínas Imediatamente Precoces/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Cultura Primária de Células , Ubiquitinação
8.
J Pediatr ; 220: 146-153.e2, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32143931

RESUMO

OBJECTIVE: To assess the importance of genetic and nongenetic risk factors contributing to hepatic fat accumulation in a multiethnic population of youth. STUDY DESIGN: We investigated the relationship between genetic factors and hepatic fat fraction (HFF) in 347 children aged 12.5-19.5 years. We examined 5 single nucleotide polymorphisms previously associated with HFF and a weighted genetic risk score (GRS) and examined how these associations varied with ethnicity (Hispanic vs non-Hispanic white) and body mass index (BMI) category. We also compared how much variation in HFF was explained by genetic factors vs cardiometabolic factors (BMI z-score and the Homeostasis Model of Insulin Resistance) or diet. RESULTS: PNPLA3 rs738409 and the GRS were each associated with HFF among Hispanic (ß = 0.39; 95% CI, 0.16-0.62; P = .001; and ß = 0.20; 95% CI, 0.05-0.34; P = .007, respectively) but not non-Hispanic white (ß = 0.04; 95% CI, -0.18 to 0.26; P = .696; and ß = 0.03; 95% CI, -0.09 to 0.14; P = .651, respectively) youth. Cardiometabolic risk factors explained more of the variation in HFF than genetic risk factors among non-lean Hispanic individuals (27.2% for cardiometabolic markers vs 6.4% for rs738409 and 4.3% for the GRS), and genetic risk factors were more important among lean individuals (2.7% for cardiometabolic markers vs 12.6% for rs738409 and 4.4% for the GRS). CONCLUSIONS: Poor cardiometabolic health may be more important than genetic factors when predicting HFF in overweight and obese young populations. Genetic risk is an important contributor to pediatric HFF among lean Hispanics, but further studies are necessary to elucidate the strength of the association between genetic risk and HFF in non-Hispanic white youth.


Assuntos
Fígado Gorduroso/epidemiologia , Fígado Gorduroso/genética , Tecido Adiposo/anatomia & histologia , Adolescente , Índice de Massa Corporal , Criança , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Hispano-Americanos , Humanos , Fígado/anatomia & histologia , Masculino , Polimorfismo de Nucleotídeo Único , Medição de Risco , Adulto Jovem
9.
Am J Physiol Gastrointest Liver Physiol ; 318(5): G955-G965, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200644

RESUMO

Functional fermentable fibers are considered essential for a healthy diet. Recently, we demonstrated that gut microbiota dysbiotic mice fed an inulin-containing diet (ICD) developed hepatocellular carcinoma (HCC) within 6 mo. In particular, a subset of Toll-like receptor 5-deficient (T5KO) mice prone to HCC exhibited rapid onset of hyperbilirubinemia (HB) and cholemia; these symptoms provide rationale that ICD induces cholestasis. Our objective in the present study was to determine whether inulin-fed T5KO-HB mice exhibit other known consequences of cholestasis, including essential fatty acid and fat-soluble vitamin deficiencies. Here, we measured hepatic fatty acids and serum vitamin A and D levels from wild-type (WT), T5KO low bilirubin (LB) and T5KO-HB mice fed ICD for 4 wk. Additionally, hepatic RNAseq and proteomics were performed to ascertain other metabolic alterations. Compared with WT and T5KO-LB, T5KO-HB mice exhibited steatorrhea, i.e., ~50% increase in fecal lipids. This could contribute to the significant reduction of linoleate in hepatic neutral lipids in T5KO-HB mice. Additionally, serum vitamins A and D were ~50% reduced in T5KO-HB mice, which was associated with metabolic compromises. Overall, our study highlights that fermentable fiber-induced cholestasis is further characterized by depletion of macro-and micronutrients.NEW & NOTEWORTHY Feeding a dietary, fermentable fiber diet to a subset of Toll-like receptor 5 deficient (T5KO) mice induces early onset hyperbilirubinemia and cholemia that later manifests to hepatocellular carcinoma (HCC). Our study highlights that fermentable fiber-induced cholestasis is characterized with modest macro- and micronutrient deficiencies that may further contribute to hepatic biliary disease. Compared with chemical induction, immunization, surgery, or genetic manipulation, these findings provide a novel approach to study the cholestatic subtype of HCC.


Assuntos
Fibras na Dieta , Fígado Gorduroso/metabolismo , Absorção Intestinal , Inulina , Metabolismo dos Lipídeos , Fígado/metabolismo , Síndromes de Malabsorção/metabolismo , Receptor 5 Toll-Like/deficiência , Deficiência de Vitamina A/metabolismo , Deficiência de Vitamina D/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Colestase/genética , Colestase/metabolismo , Colestase/patologia , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Fermentação , Fígado/patologia , Síndromes de Malabsorção/genética , Síndromes de Malabsorção/patologia , Masculino , Camundongos Knockout , Receptor 5 Toll-Like/genética , Deficiência de Vitamina A/genética , Deficiência de Vitamina D/genética
10.
Am J Pathol ; 190(6): 1271-1283, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32188584

RESUMO

Snail is a transcription factor that regulates many cellular events involved in development, homeostasis, and disease. In hepatocellular carcinoma (HCC), Snail induces epithelial-to-mesenchymal transition that confers invasive properties on tumor cells during HCC progression and malignancy. Snail activation observed in HCC mouse models suggests its involvement not only in progression, but also onset of HCC. However, it remains unclear whether Snail directly contributes to HCC initiation or whether it supports HCC initiation promoted by other oncogenes. In this study, we generated mouse models for liver-specific and hepatocyte-specific overexpression of Snail to show the independent roles of Snail in liver homeostasis and disease. Enforced Snail expression resulted in liver and hepatocyte enlargement, inflammatory cell infiltration in the liver, lipid accumulation in hepatocytes, substantial increases in serum alanine aminotransferase and bile acids, yellow discoloration of tissues caused by bilirubin accumulation, and liver tumorigenesis. Snail overexpression suppressed mRNA expression of the tight junction components claudins and occludin and that of proteins associated with bile acid metabolism, leading to disruption of the biliary canaliculus formed among hepatocytes and excretion of abnormal amounts of unusual bile acids from hepatocytes. In conclusion, enforced Snail expression in hepatocytes is sufficient for induction of steatohepatitis and liver tumorigenesis through disruption of the biliary canaliculus and bile acid homeostasis in the liver.


Assuntos
Carcinogênese/metabolismo , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/fisiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Regulação Neoplásica da Expressão Gênica , Hepatócitos/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Transgênicos , Fatores de Transcrição da Família Snail/genética
11.
J Toxicol Sci ; 45(2): 87-94, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32062620

RESUMO

Mice lacking the farnesoid X receptor (FXR) are used as a genetic model for nonalcoholic fatty liver disease because their livers exhibit hepatic steatosis and inflammation. The influence of taurine drinking on disrupted hepatic function was investigated using female Fxr-null mice. Significant decreases in the levels of hepatic damage-associated diagnostic markers, hepatic triglycerides, non-esterified fatty acids, and total bile acids were found in Fxr-null mice that had drunk water containing 0.5% taurine for four weeks. Hepatic but not serum taurine concentrations were significantly increased in these mice. The expression levels of oxidative stress-related genes (Hmox1 and Gsta1) and fatty acid synthetic genes (Acc1 and Scd1) were significantly decreased in these mice. These results suggest that drinking taurine improves hepatic steatosis and dysfunction caused by a lack of FXR.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Taurina/uso terapêutico , Acetil-CoA Carboxilase , Animais , Modelos Animais de Doenças , Feminino , Glutationa Transferase , Heme Oxigenase-1 , Isoenzimas , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/genética , Receptores Citoplasmáticos e Nucleares , Estearoil-CoA Dessaturase
12.
Artigo em Inglês | MEDLINE | ID: mdl-31913683

RESUMO

Induced by overfeeding, hepatic steatosis is a process exploited for the "foie gras" production in mule ducks. To better understand the mechanisms underlying its development, the physiological responses of mule ducks overfed with corn for a duration of 11 days were analyzed. A kinetic analysis of glucose and lipid metabolism and cell protection mechanisms was performed on 96 male mule ducks during overfeeding with three sampling times (after the 4th, the 12th, and the 22nd meal). Gene expression and protein analysis realized on the liver, muscle, and abdominal fat showed an activation of a cholesterol biosynthetic pathway during the complete overfeeding period mainly in livers with significant correlations between its weight and its cholesterolemia (r = 0.88; P < 0.0001) and between the liver weight and the hmgcr and soat1 expression (r = 0.4, P < 0.0001 and r = 0.67; P < 0.0001, respectively). Results also revealed an activation of insulin and amino acid cells signaling a pathway suggesting that ducks boost insulin sensitivity to raise glucose uptake and use via glycolysis and lipogenesis. Cellular stress analysis revealed an upregulation of key autophagy-related gene expression atg8 and sqstm1(P < 0.0001) during the complete overfeeding period, mainly in the liver, in contrast to an induction of cyp2e1(P < 0.0001), suggesting that autophagy could be suppressed during steatosis development. This study has highlighted different mechanisms enabling mule ducks to efficiently handle the starch overload by keeping its liver in a nonpathological state. Moreover, it has revealed potential biomarker candidates of hepatic steatosis as plasma cholesterol for the liver weight.


Assuntos
Glicemia/metabolismo , Patos/metabolismo , Ingestão de Energia , Metabolismo Energético , Fígado Gorduroso/metabolismo , Lipogênese , Fígado/metabolismo , Estresse Fisiológico , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Animais , Glicemia/genética , Metabolismo Energético/genética , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Regulação Enzimológica da Expressão Gênica , Cinética , Lipogênese/genética , Fígado/patologia , Masculino , Estado Nutricional , Tamanho do Órgão
13.
Int J Med Sci ; 16(12): 1593-1603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839747

RESUMO

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its pathogenesis and mechanism are intricate. In the present study, we aimed to evaluate the role of PPAR δ in LPS associated NAFLD and to investigate the signal transduction pathways underlying PPAR δ treatment in vitro. Material and Methods: L02 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of PPAR δ inhibition and/or activation. Results: LPS treatment markedly increased lipid deposition, FFA contents, IL-6 and TNF-α levels, and cell apoptosis in PA treatment (NAFLD model). PPAR δ inhibition protects L02 cells against LPS-induced lipidosis and injury. Conversely, the result of PPAR δ activation showed the reverse trend. LPS+PA treatment group significantly decreases the relative expression level of IRS-1, PI3K, AKT, phosphorylation of AKT, TLR-4, MyD88, phosphorylation of IKKα, NF-κB, Bcl-2 and increases the relative expression level of Bax, cleaved caspase 3 and cleaved caspase 8, compared with the cells treated with NAFLD model. PPAR δ inhibition upregulated the related proteins' expression level in insulin resistance and inflammation pathway and downregulated apoptotic relevant proteins. Instead, PPAR δ agonist showed the reverse trend. Conclusion: Our data show that PPAR δ inhibition reduces steatosis, inflammation and apoptosis in LPS-related NAFLD damage, in vitro. PPAR δ may be a potential therapeutic implication for NAFLD.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Lipidoses/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR delta/genética , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hepatócitos/efeitos dos fármacos , Humanos , Lipidoses/genética , Lipidoses/metabolismo , Lipidoses/patologia , Lipídeos/genética , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR delta/agonistas , PPAR delta/antagonistas & inibidores , Ácido Palmítico/toxicidade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia
14.
Lipids Health Dis ; 18(1): 234, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883528

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, although its pathogenesis remains to be elucidated. A recent study revealed that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver expressed on the bile canalicular membrane, is an exacerbation factor of NAFLD. Indeed, transgenic mice with hepatic expression of human NPC1L1 under a liver-specific promoter (L1-Tg mice) developed steatosis with a high-fat diet (HFD) containing cholesterol within a few weeks. However, the mechanism underlying diet-induced hepatic NPC1L1-mediated lipid accumulation is poorly defined. METHODS: To achieve a deeper understanding of steatosis development in L1-Tg mice, the biochemical features of hepatic NPC1L1-mediated steatosis were investigated. Hemizygous L1-Tg mice and wild-type littermate controls fed a HFD or control-fat diet were used. At the indicated time points, the livers were evaluated for cholesterol and triglyceride (TG) contents as well as mRNA levels of hepatic genes involved in the maintenance of lipid homeostasis. The hepatic ability to secrete very low-density lipoprotein (VLDL)-TG was also investigated. RESULTS: Unlike the livers of wild-type mice that have little expression of hepatic Npc1l1, the livers of L1-Tg mice displayed time-dependent changes that indicated steatosis formation. In steatosis, there were three different stages of development: mild accumulation of hepatic cholesterol and TG (early stage), acceleration of hepatic TG accumulation (middle stage), and further accumulation of hepatic cholesterol (late stage). In the early stage, between WT and L1-Tg mice fed a HFD for 2 weeks, there were no significant differences in the hepatic expression of Pparα, Acox1, Fat/Cd36, Srebf1, and Srebf2; however, the hepatic ability to secrete VLDL-TG decreased in L1-Tg mice (P < 0.05). Furthermore, this decrease was completely prevented by administration of ezetimibe, an NPC1L1-selective inhibitor. CONCLUSION: Hepatic NPC1L1 exacerbates diet-induced steatosis, which was accompanied by decreased hepatic ability of VLDL-TG secretion. The obtained results provide a deeper understanding of L1-Tg mice as a promising NAFLD animal model that is able to re-absorb biliary-secreted cholesterol similar to humans. Furthermore, this work supports further studies of the pathophysiological impact of re-absorbed biliary cholesterol on the regulation of hepatic lipid homeostasis.


Assuntos
VLDL-Colesterol/genética , Fígado Gorduroso/genética , Reabsorção Intestinal/genética , Proteínas de Membrana Transportadoras/genética , Animais , Azetidinas/farmacologia , Bile/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ezetimiba/farmacologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Hipercolesterolemia/fisiopatologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Transgênicos , Triglicerídeos/genética
15.
Food Funct ; 10(12): 8218-8229, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31701992

RESUMO

Previously, we reported that feeding soy protein isolate (SPI) reduced liver steatosis in obese rats compared to those fed a casein (CAS)-based diet; however, the mechanism for this protection is unknown. To gain insight into the ability of SPI to ameliorate liver steatosis, we conducted transcriptomic (RNAseq) analysis on liver samples from obese rats fed either the SPI- or CAS-based diets (n = 8 per group) for 8 weeks using an Ilumina HiSeq with 100 base paired end reads for sequencing. Data were analyzed by Ingenuity Pathway Analysis (IPA) software using a P < 0.05 and 1.3-fold differential expression cutoff values between the SPI- and CAS-based groups. To independently validate the RNAseq data, we conducted targeted mRNA expression analysis using quantitative PCR (qPCR) on a subset of differently expressed genes. The results indicate that mRNA expression by qPCR concurred with RNAseq for NPTX2, GPT, INMT, and HAL that were up-regulated in SPI-fed rats (P < 0.05) and PRSS8, AJUBA, CSF2RB, and Cyp2c12 that were down-regulated (P < 0.05) in SPI-fed rats compared to CAS-fed rats. Our findings may shed light on understanding mechanisms enabling SPI diet to reduce liver steatosis in this obese Zucker rat model.


Assuntos
Caseínas/metabolismo , Fígado Gorduroso/dietoterapia , Fígado Gorduroso/genética , Fígado/metabolismo , Obesidade/dietoterapia , Obesidade/genética , Proteínas de Soja/metabolismo , Animais , Subunidade beta Comum dos Receptores de Citocinas/genética , Subunidade beta Comum dos Receptores de Citocinas/metabolismo , Fígado Gorduroso/metabolismo , Expressão Gênica , Humanos , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Obesidade/metabolismo , Reação em Cadeia da Polimerase , Ratos , Ratos Zucker
16.
J Physiol Pharmacol ; 70(4)2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31642820

RESUMO

There is an established correlation between the PNPLA3 rs738409 C > G single nucleotide polymorphism (SNP) and hepatic steatosis and fibrosis in hepatitis C virus (HCV) infected patients. However not all data is convergent regarding the exact impact of this SNP on the pattern of disease progression in different clinical settings. In this study, we aimed to further bridge the knowledge gap on this topic by investigating the role of the G allele in promoting steatosis, fibrosis and disease progression in relation to other metabolic and anthropometric host factors. Two hundred and fifty consecutive patients, previously diagnosed with chronic hepatitis C (CHC) underwent liver biopsy. Histology was assessed using the Metavir scoring system. Transient elastography was used for follow-up. Ninety-eight patients were genotyped for PNPLA3 rs738409 and followed up for fibrosis progression. PNPLA3 rs738409[G] allele was significantly correlated with severe steatosis (P = 0.04), severe fibrosis at the time of enrollment (P = 0.0005) and fibrosis progression with an OR of 10.31 (95% CI 1.06 - 99.59, P = 0.04), after a mean follow-up time of 62.85 (95%CI: 52.21 - 76.15) months. Severe steatosis at the time of enrollment had an OR of 11.02 (95% CI 1.48 - 82.09, P = 0.01) for the association with fibrosis progression. The HOMA-IR index was also positively correlated with severe fibrosis (P = 0.03) and fibrosis progression on univariate analysis (P = 0.02). PNPLA3 rs738409[G] allele is a reliable predictor for steatosis and fibrosis in CHC. The presence of G allele, along with severe steatosis and insulin resistance are significant predictors for fibrosis progression.


Assuntos
Fígado Gorduroso/genética , Hepatite C Crônica/genética , Lipase/genética , Cirrose Hepática/genética , Proteínas de Membrana/genética , Antivirais/uso terapêutico , Progressão da Doença , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico
17.
Am J Physiol Endocrinol Metab ; 317(6): E1094-E1107, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31638854

RESUMO

Clinical and animal studies have reported an association between low birth weight and the development of nonalcoholic fatty liver disease (NAFLD) in offspring. Using a model of prenatal maternal 70% food restriction diet (FR30) in the rat, we previously showed that maternal undernutrition predisposes offspring to altered lipid metabolism in adipose tissue, especially on a high-fat (HF) diet. Here, using microarray-based expression profiling combined with metabolic, endocrine, biochemical, histological, and lipidomic approaches, we assessed whether FR30 procedure sensitizes adult male offspring to impaired lipid metabolism in the liver. No obvious differences were noted in the concentrations of triglycerides, cholesterol, and bile acids in the liver of 4-mo-old FR30 rats whichever postweaning diet was used. However, several clues suggest that offspring's lipid metabolism and steatosis are modified by maternal undernutrition. First, lipid composition was changed (i.e., higher total saturated fatty acids and lower elaidic acid) in the liver, whereas larger triglyceride droplets were observed in hepatocytes of undernourished rats. Second, FR30 offspring exhibited long-term impact on hepatic gene expression and lipid metabolism pathways on a chow diet. Although the transcriptome profile was globally modified by maternal undernutrition, cholesterol and bile acid biosynthesis pathways appear to be key targets, indicating that FR30 animals were predisposed to impaired hepatic cholesterol metabolism. Third, the FR30 protocol markedly modifies hepatic gene transcription profiles in undernourished offspring in response to postweaning HF. Overall, FR30 offspring may exhibit impaired metabolic flexibility, which does not enable them to properly cope with postweaning nutritional challenges influencing the development of nonalcoholic fatty liver.


Assuntos
Fígado Gorduroso/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Desnutrição , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Perfilação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Gotículas Lipídicas/patologia , Fígado/patologia , Masculino , Ácidos Oleicos/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética , Ratos , Triglicerídeos/metabolismo
18.
J Agric Food Chem ; 67(44): 12208-12218, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31608624

RESUMO

To explore the role of apple polyphenol extract (APE) in ameliorating hepatic steatosis and the potential mechanisms involved, we conducted this study. Thirty-three male C57BL/6 mice were randomly divided into three groups: high-fat diet (HFD) with aseptic water ig. (CON), HFD with 125 or 500 mg/(kg·bw·day) APE ig., namely 100 or 400 mg/(kg·bw·day) apple polyphenols (LAP or HAP) for 12 weeks. Compared with the CON group, the APE treatment significantly decreased the body weight gain and increased the ratio of serum albumin/globulin. High dose of APE treatment significantly decreased the liver weight, reduced the hepatic contents of triglyceride and cholesterol, and improved the histopathological features of hepatic steatosis, accompanied by significantly upregulated protein expressions of LKB1, phosphorylated-AMPK, phosphorylated-ACC, and SIRT1, downregulated mTOR, p70 s6k, and HMGCR in the liver, increased mRNA expressions of Ampk and Cyp27a1, and reduced expressions of Srebp-1c, Fas, and Hmgcr. Our data provided new evidence supporting the preventive role of 500 mg/(kg·bw·day) APE treatment in the HFD-induced hepatic steatosis in C57BL/6 mice via the LKB1/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Clorogênico/administração & dosagem , Fígado Gorduroso/tratamento farmacológico , Flavonoides/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Taninos/administração & dosagem , Proteínas Quinases Ativadas por AMP/genética , Animais , Colesterol , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/genética , Triglicerídeos/metabolismo
19.
J Diabetes Res ; 2019: 6320839, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612150

RESUMO

It is understood that intrauterine hyperglycemia increases the risk of obesity and diabetes in offspring of consecutive generations but its mechanisms remain obscure. This study is aimed at establishing an intrauterine hyperglycemia rat model to investigate the growth and glycolipid metabolic characteristics in transgenerational offspring and discuss the effects of Rho guanine nucleotide exchange factor 11 (ARHGEF11) and the PI3K/AKT signaling pathway in offspring development. The severe intrauterine hyperglycemia rat model was caused by STZ injection before mating, while offspring development and glycolipid metabolism were observed for the following two generations. The expression of ARHGEF11, ROCK1, PI3K, and AKT was tested in the liver and muscle tissue of F2 offspring. The results showed severe growth restriction in F1 offspring and obesity, fatty liver, and insulin resistance in female F2 offspring, especially the offspring of female intrauterine hyperglycemia-exposed parents (F2G♀C♂) and both (F2G♀G♂). The expression of ARHGEF11 and ROCK1 was significantly elevated; PI3K and phosphorylation of AKT were significantly decreased in liver tissues of F2G♀C♂ and F2G♀G♂. Our study revealed that intrauterine hyperglycemia could cause obesity and abnormal glycolipid metabolism in female transgenerational offspring; the programming effect of the intrauterine environment could cause a more obvious phenotype in the maternal line. Further exploration suggested that increased expression of ARHGEF11 and ROCK1 and the decreased expression of PI3K and phosphorylation of AKT in the liver could be responsible for the abnormal development in F2 offspring.


Assuntos
Glicemia/metabolismo , Diabetes Gestacional/metabolismo , Metabolismo Energético , Glicolipídeos/sangue , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Animais , Diabetes Gestacional/sangue , Diabetes Gestacional/genética , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Resistência à Insulina , Fígado/patologia , Masculino , Músculo Esquelético/metabolismo , Obesidade/sangue , Obesidade/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Índice de Gravidade de Doença , Transdução de Sinais , Quinases Associadas a rho/metabolismo
20.
Am J Physiol Regul Integr Comp Physiol ; 317(5): R733-R745, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31483154

RESUMO

Agonists for PPARα are used clinically to reduce triglycerides and improve high-density lipoprotein (HDL) cholesterol levels in patients with hyperlipidemia. Whether the mechanism of PPARα activation to lower serum lipids occurs in the liver or other tissues is unknown. To determine the function of hepatic PPARα on lipid profiles in diet-induced obese mice, we placed hepatocyte-specific peroxisome proliferator-activated receptor-α (PPARα) knockout (PparaHepKO) and wild-type (Pparafl/fl) mice on high-fat diet (HFD) or normal fat diet (NFD) for 12 wk. There was no significant difference in weight gain, percent body fat mass, or percent body lean mass between the groups of mice in response to HFD or NFD. Interestingly, the PparaHepKO mice on HFD had worsened hepatic inflammation and a significant shift in the proinflammatory M1 macrophage population. These changes were associated with higher hepatic fat mass and decreased hepatic lean mass in the PparαHepKO on HFD but not in NFD as measured by Oil Red O and noninvasive EchoMRI analysis (31.1 ± 2.8 vs. 20.2 ± 1.5, 66.6 ± 2.5 vs. 76.4 ± 1.5%, P < 0.05). We did find that this was related to significantly reduced peroxisomal gene function and lower plasma ß-hydroxybutyrate in the PparaHepKO on HFD, indicative of reduced metabolism of fats in the liver. Together, these provoked higher plasma triglyceride and apolipoprotein B100 levels in the PparaHepKO mice compared with Pparafl/fl on HFD. These data indicate that hepatic PPARα functions to control inflammation and liver triglyceride accumulation that prevent hyperlipidemia.


Assuntos
Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Hiperlipidemias/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Obesidade/metabolismo , PPAR alfa/deficiência , Adiposidade , Animais , Apolipoproteína B-100/sangue , Citocinas/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Hepatócitos/patologia , Hiperlipidemias/sangue , Hiperlipidemias/genética , Hiperlipidemias/patologia , Inflamação/sangue , Inflamação/genética , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Fígado/patologia , Camundongos Knockout , Obesidade/sangue , Obesidade/genética , Obesidade/patologia , PPAR alfa/genética , Triglicerídeos/sangue
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