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1.
PLoS One ; 15(8): e0238388, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866186

RESUMO

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) in the non-obese population has increased and NAFLD is not always recognized in individuals with metabolic syndrome (MS). The risk of cirrhosis is higher in patients having NAFLD with elevated alanine aminotransferase (ALT) levels than in those having NAFLD with normal ALT levels. OBJECTIVE: To measure the differences in clinical factors associated with NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and to measure differences in metabolites between MS subjects with and without NAFLD having elevation of ALT. METHODS: Among 7,054 persons undergoing health check-ups, we included 3,025 subjects who met the selection criteria. We measured differences in clinical factors for NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and compared metabolites between subjects with and without NAFLD having elevation of ALT in 32 subjects with MS. RESULTS: The prevalence of NAFLD and NAFLD having elevation of ALT was significantly progressively greater in subjects with Non-MS, Pre-MS, and MS (p <0.001, respectively). In the Non-MS group, there were significant differences between subjects with and without NAFLD having elevation of ALT with respect to body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, hemoglobin A1c, uric acid, aspartate aminotransferase (AST); In the Pre-MS group, there were significant differences in BMI, hypertension, AST, and gamma-glutamyl transpeptidase (GGT); In the MS group, there were significant differences in HDL-C, impaired glucose tolerance, AST, and GGT. There were significant differences in levels of metabolites of nicotinamide, inosine, and acetyl-L-carnitine between MS subjects with and without NAFLD having elevation of ALT (all p <0.05). CONCLUSIONS: Although NAFLD having elevation of ALT is important for development of NAFLD, differences in factors associated with NAFLD having elevation of ALT at various stages of MS should be considered. Additionally, several metabolites may play roles in the identification of risk for NAFLD in individuals with MS.


Assuntos
Alanina Transaminase/metabolismo , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Aspartato Aminotransferases/metabolismo , Índice de Massa Corporal , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Estudos Transversais , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Ácido Úrico/metabolismo , gama-Glutamiltransferase/metabolismo
2.
Medicine (Baltimore) ; 99(32): e21464, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769877

RESUMO

To investigate the effects of probiotics on liver function, glucose and lipids metabolism, and hepatic fatty deposition in patients with non-alcoholic fatty liver disease (NAFLD).Totally 140 NAFLD cases diagnosed in our hospital from March 2017 to March 2019 were randomly divided into the observation group and control group, 70 cases in each. The control group received the diet and exercise therapy, while the observation group received oral probiotics based on the control group, and the intervention in 2 groups lasted for 3 months. The indexes of liver function, glucose and lipids metabolism, NAFLD activity score (NAS), and conditions of fecal flora in 2 groups were compared before and after the treatment.Before the treatment, there were no significant differences on alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamine transferase (GGT), total bilirubin (TBIL), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), insulin resistance index (HOMA-IR), NAFLD activity score (NAS), and conditions of fecal flora in 2 groups (P > .05). After the treatment, ALT, AST, GGT, TC, TG, HOMA-IR, NAS, and conditions of fecal flora in the observation group were better than those in the control group, and the observation group was better after treatment than before. All these above differences were statistically significant (P < .05).Probiotics can improve some liver functions, glucose and lipids metabolism, hepatic fatty deposition in patients with NAFLD, which will enhance the therapeutic effects of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica/terapia , Probióticos/uso terapêutico , Adulto , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Resultado do Tratamento
3.
PLoS One ; 15(8): e0234750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785220

RESUMO

The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, including in Asian countries. We reported that the hepatic expression of bile salt export pump (BSEP) was downregulated in patients with NASH, suggesting that BSEP is involved in the pathogenesis of NASH. To identify the underlying mechanism, we analyzed Bsep heterozygous knock-out (Bsep+/- mice) and wild-type (WT) C57BL/6J mice fed a high-fat diet (HFD) (32.0% animal fat) or normal diet. We examined histological changes, levels of hepatic lipids and hepatic bile acids, and expression of genes related to bile acid and cholesterol metabolism. HFD-fed Bsep+/- mice exhibited milder hepatic steatosis and less weight gain, compared to HFD-fed WT mice. The concentrations of total bile acid, triglycerides, and cholesterols were reduced in the liver of HFD-fed Bsep+/- mice. Regarding hepatic bile acid metabolism, the expression levels of Farnesoid X receptor (Fxr) and Multidrug resistance-associated protein 2 were significantly upregulated in HFD-fed Bsep+/- mice, compared to HFD-fed WT mice. Furthermore, several alterations were observed in upstream cholesterol metabolism in the liver. The expression levels of bile acid metabolism-related genes were also altered in the intestine of HFD-fed Bsep+/- mice. In conclusion, HFD-fed Bsep+/- mice exhibited significant alterations of the expression levels of genes related to bile acid and lipid metabolism in both the liver and ileum, resulting in alleviated steatosis and less weight gain. These results suggest the importance of BSEP for maintenance of bile acid and cholesterol metabolism. Further investigations of the involvement of BSEP in the pathogenesis of NASH will provide greater insight and facilitate the development of novel therapeutic modalities.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/deficiência , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Modelos Animais de Doenças , Heterozigoto , Íleo/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/patologia
4.
PLoS Genet ; 16(8): e1008955, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776921

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excess lipid accumulation in the liver without significant consumption of alcohol. The transmembrane 6 superfamily member 2 (TM6SF2) E167K missense variant strongly associates with NAFLD in humans. The E167K mutation destabilizes TM6SF2, resulting in hepatic lipid accumulation and low serum lipid levels. However, the molecular mechanism by which TM6SF2 regulates lipid metabolism remains unclear. By using tandem affinity purification in combination with mass spectrometry, we found that apolipoprotein B (APOB), ER lipid raft protein (ERLIN) 1 and 2 were TM6SF2-interacting proteins. ERLINs and TM6SF2 mutually bound and stabilized each other. TM6SF2 bound and stabilized APOB via two luminal loops. ERLINs did not interact with APOB directly but still increased APOB stability through stabilizing TM6SF2. This APOB stabilization was hampered by the E167K mutation that reduced the protein expression of TM6SF2. In mice, knockout of Tm6sf2 and knockdown of Tm6sf2 or Erlins decreased hepatic APOB protein level, causing lipid accumulation in the liver and lowering lipid levels in the serum. We conclude that defective APOB stabilization, as a result of ERLINs or TM6SF2 deficiency or E167K mutation, is a key factor contributing to NAFLD.


Assuntos
Apolipoproteína B-100/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Hepatopatia Gordurosa não Alcoólica/genética , Animais , Colesterol/genética , Colesterol/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Imunoprecipitação , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Lipídeos/genética , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica/genética , Transfecção
5.
PLoS One ; 15(8): e0237360, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845887

RESUMO

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has been associated with small bowel bacterial overgrowth (SIBO) and cardiometabolic dysfunction. This cross-sectional study aimed to evaluate the cardio-metabolic parameters and SIBO in patients with different degrees of hepatic fibrosis estimated by NAFLD fibrosis score (NFS). METHODS: Subjects (n = 78) were allocated to three groups: Healthy control (n = 30), NAFLD with low risk of advanced fibrosis (NAFLD-LRAF, n = 17) and NAFLD with a high risk of advanced fibrosis (NAFLD-HRAF, n = 31). Anthropometrics, blood pressure, electrocardiogram and heart rate variability (HRV) were evaluated. Only the NAFLD-LRAF and NAFLD-HRAF groups were submitted to blood biochemical analysis and glucose hydrogen breath tests. RESULTS: The NAFLD-HRAF group had higher age and body mass index when compared to the control and NAFLD-LRAF groups. The prevalence of SIBO in the NAFLD group was 8.33%. The low frequency/high-frequency ratio (LF/HF ratio) was augmented in NAFLD-LRAF (p < 0.05) when compared with control group. NAFLD-HRAF group had a wide QRS complex (p < 0.05) and reduced LF/HF ratio (p < 0.05) compared to the control and NAFLD-LRAF groups. Serum levels of albumin and platelets were more reduced in the NAFLD-HRAF subjects (p < 0.05) than in the NAFLD-LRAF. CONCLUSIONS: NAFLD impairs cardiac autonomic function. Greater impairment was found in subjects with a worse degree of hepatic fibrosis estimated by NFS. Hypoalbuminemia and thrombocytopenia were higher in subjects with a worse degree of hepatic fibrosis, whereas prevalence of SIBO positive was similar between the groups.


Assuntos
Bactérias/crescimento & desenvolvimento , Progressão da Doença , Intestinos/microbiologia , Miocárdio/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Adulto , Estudos de Casos e Controles , Estudos Transversais , Eletrocardiografia , Feminino , Fibrose , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Risco
6.
Chem Biol Interact ; 330: 109199, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32805210

RESUMO

Obesity is characterized by the deposition of excessive body fat, and is caused by energy imbalance, especially when consuming fat-rich diets. High fat diet (HFD)-associated obesity is greatly common in patients with non-alcoholic fatty liver disease (NAFLD) that is emerging as one of the most universal causes of liver disease worldwide, especially in Western countries. In spite of its high prevalence, only a small proportion of affected individuals will become inflamed, followed by fibrosis and chronic liver diseases, and most patients only show simple steatosis. In this case, the full comprehension of the mechanisms underlying the progression of NAFLD is of extreme significance; in spite of progress in this field, awareness on the development of NAFLD is still incomplete. Traditionally, liver steatosis is commonly connected with HFD, obesity, and insulin resistance (IR). Recently, various possible mechanisms have been put forward for liver damage, including endoplasmic reticulum stress, perturbation of autophagy, mitochondrial dysfunction, hepatocellular apoptosis, gut microbiota imbalance, dysregulation of microRNAs, and genetic/epigenetic risk factors, as well as an increase in inflammatory responses, among many others. Collectively, these proposed mechanisms allow for a variety of hits acting together on subjects to mediated NAFLD and will offer a more accurate explanation for progression of NAFLD. Therefore, this review summarizes the present information concerning NAFLD after HFD exposure, as well as discusses possible mechanisms through which it may arise.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações
7.
Life Sci ; 257: 118125, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32702444

RESUMO

AIM: Nonalcoholic fatty liver disease (NAFLD) is a growing health problem worldwide. Impaired autophagy has been linked to NAFLD pathogenesis. Whether transfer RNA (tRNA)-derived fragments (tRFs) regulate the progression of NAFLD via autophagy is not clear. Here, we aimed to identify autophagy- or adipogenesis-related tRFs and investigate their roles in NAFLD. METHODS: Small RNA sequencing was performed on NAFLD and control mice, and candidate tRFs were validated using quantitative reverse transcription PCR (qRT-PCR). The role of a key tRF was investigated using Oil red O staining, western blotting, qRT-PCR and a luciferase reporter assay. KEY FINDINGS: In NAFLD mice, the expression of p62 was increased and the ratio of LC3B-II/LC3-I was decreased compared to control mice. We identified nine differentially expressed tRFs, among which tRF-3001b was found to be significantly upregulated in NAFLD mice compared to the control liver tissues. Autophagy was decreased in FA (fatty acids)-induced LO2 cells, while silencing of tRF-3001b significantly abrogated the decrease in autophagy and increase in lipid formation. Moreover, chloroquine (CQ) dramatically abrogated the effect of tRF-3001b inhibition on lipid formation. Mechanistically, tRF-3001b targeted and inhibited the expression of the autophagy-related gene Prkaa1. In vivo, tRF-3001b silencing significantly improved pathology and decreased the levels of triglycerides and cholesterol in NAFLD mice, while CQ dramatically abrogated the effect of tRF-3001b deficiency. SIGNIFICANCE: tRF-3001b may aggravate the development of NAFLD by inhibiting autophagy via targeting Prkaa1.


Assuntos
Autofagia , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA de Transferência/metabolismo , Animais , Western Blotting , Linhagem Celular , Colesterol/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , RNA de Transferência/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA , Triglicerídeos/sangue
8.
J Cancer Res Clin Oncol ; 146(10): 2461-2477, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32685988

RESUMO

PURPOSE: The aim of this study was to investigate DNA methylation alterations in non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinomas (HCCs). METHODS: Genome-wide DNA methylation analysis was performed using the Infinium Human Methylation 450 K BeadChip, and levels of mRNA expression were analyzed by quantitative reverse transcription-PCR. RESULTS: Compared to 36 samples of normal control liver tissue (C), DNA methylation alterations were observed on 19,281 probes in 22 samples of cancerous tissue (T) obtained from patients showing histological features compatible with NASH in their non-cancerous liver tissue (N). Among those probes, 1396 were located within CpG islands or their shores and shelves, designed around the transcription start sites of 726 genes. In representative genes, such as DCAF4L2, CKLF, TRIM4, PRC1, UBE2C and TUBA1B, both DNA hypomethylation and mRNA overexpression were observed in T samples relative to C samples, and the levels of DNA methylation and mRNA expression were inversely correlated with each other. DNA hypomethylation occurred even in N samples at the precancerous NASH stage, and this was inherited by or further strengthened in T samples. DNA hypomethylation of DCAF4L2, CKLF and UBE2C was observed in both NASH-related and viral hepatitis-related HCCs, whereas that of TRIM4, PRC1 and TUBA1B occurred in a NASH-related HCC-specific manner. DNA hypomethylation and/or mRNA overexpression of these genes was frequently associated with the necroinflammatory grade of NASH and was correlated with poorer tumor differentiation. CONCLUSION: DNA methylation alterations may occur under the necroinflammatory conditions characteristic of NASH and participate in NASH-related hepatocarcinogenesis through aberrant expression of tumor-related genes.


Assuntos
Carcinoma Hepatocelular/genética , Metilação de DNA , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Metabolism ; 110: 154307, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32622843

RESUMO

BACKGROUND: Aberrant concentration, structure and functionality of High Density Lipoprotein (HDL) are associated with many prevalent diseases, including cardiovascular disease and non-alcoholic fatty liver disease (NAFLD). Mice with liver-specific ablation of Hnf4α (H4LivKO) present steatosis and dyslipidemia by mechanisms that are not completely understood. The aim of this study was to explore the role of liver HNF4A in HDL metabolism and the development of steatosis. METHODS AND RESULTS: Serum and tissue samples were obtained from 6-weeks old H4LivKO mice and their littermate controls. Liver and serum lipids were measured and HDL structure and functionality were assessed. Global gene expression changes in the liver were analyzed by expression arrays, validations were performed by RT-qPCR and DNA-protein interactions were studied by chromatin immunoprecipitation (ChIP). H4LivKO mice presented liver steatosis, increased liver triglyceride content and decreased concentration of serum total cholesterol, HDL cholesterol, triglycerides, phospholipids and cholesteryl esters. Most classes of phospholipids showed significant changes in species ratio and sphingosine-1-phosphate (S1P) levels were reduced. H4LivKO serum was enriched in the smaller, denser HDL particles, devoid of APOA2 and APOM apolipoproteins, exhibiting decreased activity of paraoxonase-1 but retaining macrophage cholesterol efflux capacity and phospho-AKT activation in endothelial cells. Global gene expression analysis revealed the association of liver HNF4A with known and novel regulators of HDL metabolism as well as NAFLD-susceptibility genes. CONCLUSIONS: HNF4A ablation in mouse liver causes hepatic steatosis, perturbations in HDL structure and function and significant global changes in gene expression. This study reveals new targets of HNF4A involved in HDL metabolism and the development of steatosis and enriches our knowledge on HDL functionality in NAFLD.


Assuntos
Fator 4 Nuclear de Hepatócito/fisiologia , Lipoproteínas HDL/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Transportador 1 de Cassete de Ligação de ATP/fisiologia , Animais , Arildialquilfosfatase/metabolismo , Perfilação da Expressão Gênica , Metabolismo dos Lipídeos , Lipoproteínas HDL/química , Lisofosfolipídeos/sangue , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Esfingosina/análogos & derivados , Esfingosina/sangue
10.
PLoS One ; 15(6): e0232972, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32512581

RESUMO

Various dietary fibers are considered to prevent obesity by modulating the gut microbiota. Cordyceps sinensis polysaccharide (CSP) is a soluble dietary fiber known to have protective effects against obesity and related diseases, but whether these effects induce any side effects remains unknown. The function and safety of CSP were tested in high-fat diet (HFD)-feding C57BL/6J mice. The results revealed that even though CSP supplementation could prevent an increase in body weight, it aggravated liver fibrosis and steatosis as evidenced by increased inflammation, lipid metabolism markers, insulin resistance (IR) and alanine aminotransferase (ALT) in HFD-induced obesity. 16S rDNA gene sequencing was used to analyze the gut microbiota composition, and the relative abundance of the Actinobacteria phylum, including the Olsenella genus, was significantly higher in CSP-treated mice than in HFD-fed mice. CSP supplementation may increase the proportion of Actinobacteria, which can degrade CSP. The high level of Actinobacteria aggravated the disorder of the intestinal flora and contributed to the progression from obesity to nonalcoholic steatohepatitis (NASH) and related diseases.


Assuntos
Cordyceps , Dieta Hiperlipídica/efeitos adversos , Fibras na Dieta/administração & dosagem , Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polissacarídeos/administração & dosagem , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Peso Corporal , Cordyceps/metabolismo , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/metabolismo , Resistência à Insulina , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Polissacarídeos/isolamento & purificação
11.
Nat Commun ; 11(1): 3067, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546794

RESUMO

Lipid transport and ATP synthesis are critical for the progression of non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) forms complexes with NAFLD-relevant transcripts. It associates with intron 24 of Apob pre-mRNA, with the 3'UTR of Uqcrb, and with the 5'UTR of Ndufb6 mRNA, thereby regulating the splicing of Apob mRNA and the translation of UQCRB and NDUFB6. Hepatocyte-specific HuR knockout reduces the expression of APOB, UQCRB, and NDUFB6 in mice, reducing liver lipid transport and ATP synthesis, and aggravating high-fat diet (HFD)-induced NAFLD. Adenovirus-mediated re-expression of HuR in hepatocytes rescues the effect of HuR knockout in HFD-induced NAFLD. Our findings highlight a critical role of HuR in regulating lipid transport and ATP synthesis.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Proteína Semelhante a ELAV 1/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Trifosfato de Adenosina/biossíntese , Animais , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Proteína Semelhante a ELAV 1/genética , Homeostase , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Precursores de RNA
12.
PLoS One ; 15(6): e0234096, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484830

RESUMO

OBJECTIVES: To investigate changes of fat in bone marrow (BM) and paraspinal muscle (PSM) associated with the degree of fatty liver in pediatric patients with non-alcoholic fatty liver disease (NAFLD) in consideration of age and body mass index (BMI). METHODS: Hepatic fat, BM fat, and PSM fat from proton density fat fraction of liver MRI between June 2015 and April 2019 were quantitatively evaluated on axial images of the fat map at the mid-level of T11-L2 vertebral bodies for BM fat and at the mid-level of L2 for PSM fat. Age, height, and weight at the time of MRI were recorded and BMI was calculated. Correlation analysis was performed. RESULTS: A total of 147 patients (114 male) were included with a mean age of 13.3 ± 2.9 years (range 7-18 years). The mean fat fractions were 24.3 ± 13.0% (2-53%) in liver, 37.4 ± 8.6% (17.3-56%) in vertebral BM, and 2.7 ± 1.1% (1.0-6.9%) in PSM. Age, height, weight, and BMI were not correlated with liver fat or BM fat. However, weight (ρ = 0.174, p = 0.035) and BMI (ρ = 0.247, p = 0.003) were positively correlated with PSM fat. Liver fat showed positive correlation with BM fat when adjusting age and BMI (ρ = 0.309, p<0.001), but not with PSM fat. CONCLUSIONS: BM fat positively correlates with liver fat, but not with age or BMI in pediatric NAFLD patients.


Assuntos
Hepatopatia Gordurosa não Alcoólica/patologia , Adolescente , Índice de Massa Corporal , Medula Óssea/diagnóstico por imagem , Criança , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lipídeos/análise , Fígado/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Músculos Paraespinais/diagnóstico por imagem , Estudos Retrospectivos
13.
Medicine (Baltimore) ; 99(22): e20399, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481431

RESUMO

Cytokeratin 18 (CK18) and fibroblast growth factor 21 (FGF21) are elevated in patients with nonalcoholic fatty liver disease (NAFLD) and are useful markers for identifying or monitoring outcomes. Exercise therapy is one of the established treatments for NAFLD; however, few studies have investigated the effectiveness of exercise therapy on CK18 and FGF21 levels. Therefore, the aim of the present study was to assess the effects of 12 weeks of simple resistance exercise on CK18 and FGF21 levels in patients with NAFLD.Fifty patients with NAFLD were assigned to a resistance exercise group (n = 23) or a control group (n = 27) for a trial period of 12 weeks. During the study, the resistance exercise group performed two exercises (push-ups and squats) three times a week on nonconsecutive days, whereas the control group proceeded with regular physical activities under a restricted diet. We then compared serum levels of CK18 fragments (M65) and FGF21 between groups just before and after the 12-week period.Serum M65 levels (880.0 ±â€Š503.6 vs 648.9 ±â€Š450.2 U/L; P < .01) were significantly decreased in the exercise group. However, no significant differences were observed in body mass index or skeletal muscle. The decreases in serum M65 (-231.1 ±â€Š354.7 vs 56.2 ±â€Š375.0 U/L; P = .02), and FGF21 levels (-41.7 ±â€Š98.2 vs. 33.2 ±â€Š127.6 pg/mL; P = .03) were significantly greater in the exercise than in the control group. Changes in M65 levels in the exercise group were significantly correlated with changes in alanine aminotransferase levels (r = 0.618, P < .01).Simple resistance exercise reduced CK18 and FGF21 levels in patients with NAFLD. These findings suggest that resistance exercise consisting of push-ups and squats helps prevent the progression of NAFLD.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Queratina-18/sangue , Hepatopatia Gordurosa não Alcoólica/terapia , Treinamento de Resistência/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estudos Retrospectivos
14.
PLoS One ; 15(6): e0234985, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569304

RESUMO

BACKGROUND: Nonalcoholic Fatty Liver Disease (NAFLD) is a common co-morbidity of obesity. Elevated TSH levels (eTSH), also associated with obesity, may contribute to the dysmetabolic state that predisposes to NAFLD. OBJECTIVE: To assess the relationship between TSH levels and NAFLD in children with biopsy-proven NAFLD compared to controls. DESIGN AND METHODS: In this retrospective study of children with biopsy-proven NAFLD and age-matched controls, the association of eTSH with NAFLD was investigated and the role of TSH as a mediator between obesity and NAFLD was assessed. RESULTS: Sixty-six cases and 4067 controls (69.7 vs 59% Hispanic/Latino ancestry, p = 0.1) of the same age range seen in the same time duration at an urban Children's Hospital were studied. Children with NAFLD were more likely to be male (74.6 vs 39.4%, p < 0.001), have higher modified BMI-z scores (median 2.4 (IQR 1.7) vs 1.9 (IQR 1.7), p < 0.001), and abnormal metabolic parameters (TSH, ALT, HDL-C, non-HDL-C, and TG). Multivariate analyses controlling for age, sex and severity of obesity showed significant association between the 4th quartile of TSH and NAFLD. Causal mediation analysis demonstrates that TSH mediates 33.8% of the effect of modified BMI-z score on NAFLD. This comprises of 16.0% (OR = 1.1, p = 0.002) caused by the indirect effect of TSH and its interaction with modified BMI-z, and 17.7% (OR = 1.1, p = 0.05) as an autonomous effect of TSH on NAFLD. Overall, 33.8% of the effect can be eliminated by removing the mediator, TSH (p = 0.001). CONCLUSIONS: The association of eTSH and biopsy-proven NAFLD is demonstrated in children of Hispanic/Latino ancestry. Further, a causal mediation analysis implicates an effect of TSH on NAFLD, independent of obesity.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Obesidade Pediátrica , Tireotropina/sangue , Adolescente , Biomarcadores/sangue , Criança , Estudos de Coortes , Feminino , Hispano-Americanos , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/metabolismo , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia
15.
Eur J Clin Invest ; 50(10): e13338, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32589264

RESUMO

BACKGROUND: Initial evidence from China suggests that most vulnerable subjects to COVID-19 infection suffer from pre-existing illness, including metabolic abnormalities. The pandemic characteristics and high-lethality rate of COVID-19 infection have raised concerns about interactions between virus pathobiology and components of the metabolic syndrome. METHODS: We harmonized the information from the recent existing literature on COVID-19 acute pandemic and mechanisms of damage in non-alcoholic fatty liver disease (NAFLD), as an example of chronic (non-communicable) metabolic pandemic. RESULTS: COVID-19-infected patients are more fragile with underlying metabolic illness, including hypertension, cardiovascular disease, type 2 diabetes, chronic lung diseases (e.g. asthma, chronic obstructive pulmonary disease and emphysema) and metabolic syndrome. During metabolic abnormalities, expansion of metabolically active fat ('overfat condition') parallels chronic inflammatory changes, development of insulin resistance and accumulation of fat in configuring NAFLD. The deleterious interplay of inflammatory pathways chronically active in NAFLD and acutely in COVID-19-infected patients, can explain liver damage in a subgroup of patients and might condition a worse outcome in metabolically compromised NAFLD patients. In a subgroup of patients with NAFLD, the underlying liver fibrosis might represent an additional and independent risk factor for severe COVID-19 illness, irrespective of metabolic comorbidities. CONCLUSIONS: NAFLD can play a role in the outcome of COVID-19 illness due to frequent association with comorbidities. Initial evidences suggest that increased liver fibrosis in NAFLD might affect COVID-19 outcome. In addition, long-term monitoring of post-COVID-19 NAFLD patients is advisable, to document further deterioration of liver damage. Further studies are required in this field.


Assuntos
Infecções por Coronavirus/epidemiologia , Síndrome Metabólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Pneumonia Viral/epidemiologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Síndrome da Liberação de Citocina/imunologia , Humanos , Inflamação/imunologia , Resistência à Insulina , Fígado/imunologia , Fígado/metabolismo , Síndrome Metabólica/imunologia , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo
16.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G87-G96, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475129

RESUMO

Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) plays a critical role in hepatic energy homeostasis. Liver X receptors (LXRs) are implicated in multiple physiological functions, including the inhibition of hepatocyte proliferation and regulation of fatty acid and cholesterol metabolism. We have previously reported that SULT2B1b promotes hepatocyte proliferation by inactivating LXR signaling in vivo and in vitro, leading to our hypothesis that SULT2B1b promotes fatty liver regeneration. In the present study, female C57BL/6 and S129 mice were fed a high-fat diet for 8 wk to establish a nonalcoholic fatty liver disease (NAFLD) mouse model. 70% partial hepatectomy (PH) was performed to induce liver regeneration. Our experiments revealed that the SULT2B1b overexpression significantly promotes the regeneration of hepatocytes in NAFLD C57BL/6 mice after PH, increasing liver regrowth by 11% within 1 day, and then by 21%, 33%, and 24% by 2, 3, and 5 days post-PH, respectively. Compared with the wild-type NAFLD S129 mice, SULT2B1 deletion NAFLD S129 mice presented reduced hepatocyte regeneration at postoperative day 2, as verified by decreased liver regrowth (37.4% vs. 46.1%, P < 0.05) and the results of immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot analysis. Moreover, LXRα signaling and SULT2B1b expression are highly correlated in the regeneration of NAFLD mouse liver; SULT2B1b overexpression suppresses LXRα signaling, while the LXRα-signaling agonist T0901317 blocks SULT2B1b-induced hepatocyte regeneration in NAFLD mouse liver. Thus, the upregulation of SULT2B1b may promote hepatocyte regeneration via the suppression of LXRα activation in NAFLD mice, providing a potential strategy for improving hepatic-steatosis-related liver regeneration disorders.NEW & NOTEWORTHY This study demonstrates for the first time that hydroxysteroid sulfotransferase 2B1b (SULT2B1b) overexpression promotes the regeneration of fatty liver after partial hepatectomy in mice with nonalcoholic fatty liver disease, while reducing triglyceride accumulation in the regenerative fatty liver. Liver X receptor signaling may be crucial in the SULT2B1b-mediated regeneration of fatty liver. Thus, SULT2B1b may be a potential target for treating hepatic steatosis-related liver regeneration disorders.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Hepatectomia/métodos , Hidrocarbonetos Fluorados/farmacologia , Metabolismo dos Lipídeos/fisiologia , Receptores X do Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sulfonamidas/farmacologia
17.
Expert Opin Pharmacother ; 21(13): 1637-1650, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32543284

RESUMO

INTRODUCTION: Chronic liver disease is due to various causes of persistent liver damage and will eventually lead to the development of liver fibrosis. If no treatment is initiated, this condition may progress to cirrhosis and hepatocellular carcinoma. Current treatments comprise the elimination of the cause of injury, such as by lifestyle changes, alcohol abstinence, and antiviral agents. However, such etiology-driven therapy is often insufficient in patients with late-stage fibrosis/cirrhosis, therefore maintaining the need for efficient antifibrotic pharmacotherapeutic interventions. AREAS COVERED: The authors discuss the recent advances in the development of antifibrotic drugs, which target various pathways of the fibrogenesis process, including cell death, inflammation, gut-liver axis, and myofibroblast activation. Due to the significant burden of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), various agents which specifically target metabolic pathways and their related receptors/ligands have been developed. For some of them, e.g., obeticholic acid, advanced stage clinical trials indicate antifibrotic efficacy in NAFLD and NASH. EXPERT OPINION: Significant advances have been made in the development of novel antifibrotic pharmacotherapeutics. The authors expect that the development of combinatorial therapies, which combine compounds that target various pathways of fibrosis progression, will have a major impact as future etiology-independent therapies.


Assuntos
Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ensaios Clínicos como Assunto , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
18.
Toxicol Appl Pharmacol ; 401: 115101, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512072

RESUMO

Non-alcoholic steatohepatitis (NASH) is becoming of increasing significance due to its growing global prevalence and risk of progression to end-stage liver disease. This study was carried out to investigate the potential anti-inflammatory, insulin sensitizing, and antifibrotic effects of diosmin in an experimental model of NASH induced in rats using high-fat diet (HFD) and 30 mg/kg streptozotocin (STZ). Diosmin was administered orally at dose of 100 mg/kg for 8 weeks. Stained tissue sections were examined for histopathological signs of NASH, collagen deposition, and alpha smooth muscle actin (α-SMA) expression. In addition, insulin resistance, dyslipidemia, inflammation, and fibrosis markers were assessed. HFD/STZ successfully induced different NASH features such as insulin resistance seen by elevated fasting blood glucose levels and homeostasis model assessment for insulin resistance. Moreover, induced rats demonstrated dyslipidemia, a significant elevation in tumor necrosis factor alpha (TNF-α) and interleukin-6 levels, and an imbalance in the oxidative status of the liver. Those events altogether precipitated initiation of liver fibrosis as confirmed by elevated transforming growth factor beta (TGF-ß) levels. Treatment with diosmin demonstrated multiple beneficial effects as it significantly ameliorated histopathological NASH findings, lowered TNF-α, interleukin-6, and malondialdehyde levels, improved lipid and glucose metabolism, and lowered hepatic TGF-ß, α-SMA, and collagen content compared to untreated rats. The present study represents a drug repositioning scenario as diosmin is widely used for management of blood vessel disorders and is known to be well tolerated. This encourages the extension of our study to the clinical setting to explore diosmin effects in NASH patients.


Assuntos
Diosmina/uso terapêutico , Resistência à Insulina/fisiologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Diosmina/farmacologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Cirrose Hepática/etiologia , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
19.
Life Sci ; 256: 117978, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553927

RESUMO

AIMS: The mechanism of physical activity and calorie restriction remedying non-alcoholic fatty liver disease (NAFLD) remains elusive. The purpose of this study is to explore the effects of eccentric exercise and dietary regulation allied or alone on high-fat diet (HFD) induced NAFLD and its potential mechanism. MATERIALS AND METHODS: Mice were fed with HFD for 12 weeks and subsequently treated with chronic downhill running and caloric restriction for 8 weeks. Related biochemical index were examined both before and during intervention to evaluate the liver injury and dyslipidemia. Levels of MCP1, TNFα, IL-1ß, IL-6 and IL-10 were detected by ELISA. Liver morphology was observed by H&E and oil red O staining. Protein contents of iNOS, Arg-1, IL-1ß and IL-10 were determined by Western blot. CD86 and CD206 fluorescence were determined by Immunofluorescence. KEY FINDING: (1) 12 weeks' HFD induced hyperlipemia and hepatic steatosis by activating M1 macrophages phenotype and inhibiting M2 macrophages. (2) Chronic downhill running and caloric restriction promoted liver M2 macrophages phenotype, and inhibited M1 macrophages, to attenuate chronic inflammation and ameliorate hepatic steatosis. (3) The effects of downhill running and dietary regulation allied were more effective on improving NAFLD compared with downhill running or caloric restriction alone. SIGNIFICANCE: Eccentric exercise accompanied by caloric restriction attenuates HFD-related NAFLD by promoting M2 macrophages phenotype and inhibiting M1 macrophages in liver. These findings may be help to designing better non-pharmacological intervention programs for NAFLD patients.


Assuntos
Restrição Calórica/métodos , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Macrófagos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Fígado/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/terapia , Condicionamento Físico Animal/métodos
20.
Life Sci ; 256: 117990, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32574665

RESUMO

AIM: Luteolin and lycopene are common natural products, widely existing in nature, and both of which were reported to have various biological functions including anti-inflammatory, anti-obesity and anti-NAFLD. In the present study, we aimed to evaluate the therapeutic efficacy of luteolin and lycopene in combination and its latent molecular mechanisms in vitro and in vivo models of NAFLD. MAIN METHODS: Sodium palmitate (PA)-induced steatotic HepG2 cells and primary hepatocytes, and high-fat diet-induced C57BL/6J obese mice were treated with luteolin, lycopene and their combination. Metabolic parameters were measured. KEY FINDINGS: We found that luteolin (20 µM) + lycopene (10 µM) was the best therapeutic combination in PA-induced HepG2 cells, and significantly improve cell viability and lipid accumulation in PA-induced HepG2 cells and primary hepatocytes. In addition, luteolin (20 mg/kg) + lycopene (20 mg/kg) could ameliorate increased body weight and hepatocyte steatosis; regulate serum triglycerides, serum total cholesterol, hepatic triglycerides and hepatic total cholesterol; decrease serum alanine transaminase and aspartate transaminase. Furthermore, in vivo and in vitro, luteolin, lycopene and their combination had no effect on Sirt1 expression, but all of them could upregulate the expression of NAMPT, which could increase the level of NAD+, the co-substrate of Sirt1, indirectly activating Sirt1/AMPK pathway, and then inhibited lipogenesis and increased ß-oxidation, defensing the "first hit"; they also inactivated nuclear factor-κB (NF-κB) and decreased the levels of IL-6, IL-1ß and TNF-α, defensing the "second hit". SIGNIFICANCE: Thus, luteolin and lycopene in combination can effectively ameliorate "two-hit" in NAFLD through activation of the Sirt1/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Luteolina/administração & dosagem , Licopeno/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Sirtuína 1/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Substâncias Protetoras/administração & dosagem , Distribuição Aleatória
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