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1.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070749

RESUMO

Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin-angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1-7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE-/- mice fed a high-fat diet (HFD). We have shown that DIZE stabilized atherosclerotic lesions and attenuated hepatic steatosis in apoE-/- mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in the atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated levels of HDL in the plasma, decreased levels of triglycerides, and increased biosynthesis and concentration of taurine in the liver of apoE-/- mice. However, exact molecular mechanisms of both anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Aterosclerose/tratamento farmacológico , Diminazena/análogos & derivados , Fígado Gorduroso/tratamento farmacológico , Placa Aterosclerótica/tratamento farmacológico , Taurina/biossíntese , Angiotensina I/genética , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Dieta Hiperlipídica , Diminazena/farmacologia , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Células THP-1 , Taurina/agonistas
2.
Nutrients ; 13(5)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064308

RESUMO

Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.


Assuntos
Glicemia/metabolismo , Metabolismo Energético/genética , Homeostase/genética , Obesidade/genética , Receptores para Leptina/deficiência , Animais , Modelos Animais de Doenças , Fígado Gorduroso/genética , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Teste de Tolerância a Glucose , Insulina/metabolismo , Obesidade/cirurgia , Período Pós-Operatório , Ratos , Ratos Wistar , Ratos Zucker , Perda de Peso/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-33941552

RESUMO

INTRODUCTION: Older age is associated with greater prevalence of hyperinsulinemia, type 2 diabetes, and fatty liver disease. These metabolic conditions and aging are bidirectionally linked to mitochondrial dysfunction and telomere attrition. Although effectively addressing these conditions is important for influencing the health and the lifespan, it is particularly challenging in older age. We reported that E4orf1, a protein derived from human adenovirus Ad36, reduces hyperinsulinemia, improves glucose clearance, and protects against hepatic steatosis in younger mice exposed to high fat diet (HFD). Here, we tested if E4orf1 will improve glycemic control, liver fat accumulation, mitochondrial integrity, and reduce telomere attrition in older mice. RESEARCH DESIGN AND METHODS: We used 9-month-old mice that inducibly expressed E4orf1 in adipose tissue and non-E4orf1 expressing control mice. Mice were maintained on a 60% (kcal) HFD for 20 weeks and glycemic control was determined by intraperitoneal glucose tolerance test at week 20. Following 20 weeks of HF-feeding, mice were sacrificed and liver tissues collected to determine the expression of aging genes using qRT-PCR based RT2 Profiler PCR array. RESULTS: Compared with the control mice, E4orf1 significantly improved glycemic control and reduced hepatic steatosis and fibrosis. Additionally, E4orf1 maintained markers of mitochondrial integrity and telomere attrition. CONCLUSION: E4orf1 has the potential to improve glycemic control in older mice, and the improvement persists even after longer term exposure. E4orf1 expression also maintains mitochondrial integrity and telomere attrition, thus delaying age-associated diseases. This provides strong evidence for therapeutic utility of E4orf1 in improving age-associated metabolic and cellular changes that occur with aging in humans.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Envelhecimento , Animais , Fígado Gorduroso/genética , Teste de Tolerância a Glucose , Hipoglicemiantes , Camundongos
4.
BMC Genomics ; 22(1): 328, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952209

RESUMO

BACKGROUND: Fatty liver has become a main problem that causes huge economic losses in many aquaculture modes. It is a common physiological or pathological phenomenon in aquaculture, but the causes and occurring mechanism are remaining enigmatic. METHODS: Each three liver samples from the control group of allogynogenetic gibel carp with normal liver and the overfeeding group with fatty liver were collected randomly for the detailed comparison of histological structure, lipid accumulation, transcriptomic profile, latent pathway identification analysis (LPIA), marker gene expression, and hepatocyte mitochondria analyses. RESULTS: Compared to normal liver, larger hepatocytes and more lipid accumulation were observed in fatty liver. Transcriptomic analysis between fatty liver and normal liver showed a totally different transcriptional trajectory. GO terms and KEGG pathways analyses revealed several enriched pathways in fatty liver, such as lipid biosynthesis, degradation accumulation, peroxidation, or metabolism and redox balance activities. LPIA identified an activated ferroptosis pathway in the fatty liver. qPCR analysis confirmed that gpx4, a negative regulator of ferroptosis, was significantly downregulated while the other three positively regulated marker genes, such as acsl4, tfr1 and gcl, were upregulated in fatty liver. Moreover, the hepatocytes of fatty liver had more condensed mitochondria and some of their outer membranes were almost ruptured. CONCLUSIONS: We reveal an association between ferroptosis and fish fatty liver for the first time, suggesting that ferroptosis might be activated in liver fatty. Therefore, the current study provides a clue for future studies on fish fatty liver problems.


Assuntos
Carpas , Fígado Gorduroso , Ferroptose , Animais , Fígado Gorduroso/genética , Transcriptoma
5.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805516

RESUMO

Reactive oxygen species (ROS) metabolism is regulated by the oxygen-mediated enzyme reaction and antioxidant mechanism within cells under physiological conditions. Xanthine oxidoreductase (XOR) exhibits two inter-convertible forms (xanthine oxidase (XO) and xanthine dehydrogenase (XDH)), depending on the substrates. XO uses oxygen as a substrate and generates superoxide (O2•-) in the catalytic pathway of hypoxanthine. We previously showed that superoxide dismutase 1 (SOD1) loss induced various aging-like pathologies via oxidative damage due to the accumulation of O2•- in mice. However, the pathological contribution of XO-derived O2•- production to aging-like tissue damage induced by SOD1 loss remains unclear. To investigate the pathological significance of O2•- derived from XOR in Sod1-/- mice, we generated Sod1-null and XO-type- or XDH-type-knock-in (KI) double-mutant mice. Neither XO-type- nor XDH-type KI mutants altered aging-like phenotypes, such as anemia, fatty liver, muscle atrophy, and bone loss, in Sod1-/- mice. Furthermore, allopurinol, an XO inhibitor, or apocynin, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, failed to improve aging-like tissue degeneration and ROS accumulation in Sod1-/- mice. These results showed that XOR-mediated O2•- production is relatively uninvolved in the age-related pathologies in Sod1-/- mice.


Assuntos
Envelhecimento/fisiologia , Superóxido Dismutase-1/genética , Superóxidos/metabolismo , Xantina Desidrogenase/metabolismo , Acetofenonas/farmacologia , Envelhecimento/efeitos dos fármacos , Alopurinol/farmacologia , Anemia/genética , Animais , Fígado Gorduroso/genética , Camundongos Mutantes , Atrofia Muscular/genética , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Superóxido Dismutase-1/metabolismo , Xantina Desidrogenase/antagonistas & inibidores , Xantina Desidrogenase/genética
6.
Metabolism ; 119: 154776, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33862045

RESUMO

AIMS/HYPOTHESIS: Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome. METHODS: HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193 C-reactive protein, 53 lipodystrophy-like phenotypes). RESULTS: HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (Nliver fat = 1054, NHIC = 2254; Nalanineaminotranferase = 1985, NHIC = 2251). BMI-related SNPs were causally associated with HIC (NBMI = 2772, NHIC = 2259, p < 0.001) but not waist circumference-SNPs (NSNPs-waist circumference = 2751, NHIC = 2280). Genetically determined insulin sensitivity was not causally related to HIC (Ninsulin sensitivity = 2752, NHIC = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (NC-reactive protein = 2660, NHIC = 2240; NHDL = 2694, NHIC = 2275). CONCLUSIONS: This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction.


Assuntos
Insulina/metabolismo , Fígado/metabolismo , Análise da Randomização Mendeliana , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/epidemiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Estudos de Associação Genética/estatística & dados numéricos , Alemanha/epidemiologia , Intolerância à Glucose/complicações , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/epidemiologia , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Resistência à Insulina/genética , Secreção de Insulina/genética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos
7.
Nat Commun ; 12(1): 1822, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758172

RESUMO

Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Fígado Gorduroso/prevenção & controle , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Obesidade/metabolismo , Fosfoproteínas Fosfatases/deficiência , Adiponectina/metabolismo , Adiposidade/genética , Animais , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Regulação da Expressão Gênica/genética , Glucose/metabolismo , Homeostase , Humanos , Lipólise/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/genética , Obesidade/patologia , PPAR alfa/metabolismo , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Transdução de Sinais/genética , Esterol Esterase/metabolismo
8.
Toxicol Appl Pharmacol ; 418: 115494, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722668

RESUMO

Tumor progression locus 2 (Tpl2, gene name MAP3K8), a mitogen-activated protein kinase, is widely expressed in immune and non-immune cells to integrate tumor necrosis factor (TNF), toll-like receptors (TLRs), and interleukin-1 (IL1) receptor signaling to regulate inflammatory response. Given its central role in inflammatory response, Tpl2 is an attractive small molecule drug target. However, the role of Tpl2 as an oncogene or tumor suppressor gene remains controversial, and its function outside immune cells is not understood. We therefore utilized a Tpl2 kinase dead (Tpl2-KD) mouse model in an 18-month aging study to further elucidate Tpl2 effects on lifespan and chronic disease. Histopathological studies revealed the incidence and severity of spontaneous tumors and non-neoplastic lesions were comparable between wild type and Tpl2-KD mice. The only finding was that male Tpl2-KD mice had higher bodyweight and an increased incidence of liver steatosis, suggesting a sex-specific role for Tpl2 in hepatic lipid metabolism. In conclusion, loss of Tpl2 kinase activity did not lead to increased tumorigenesis over aging in mice but affected likely alterations in lipid metabolism in male animals.


Assuntos
Fígado Gorduroso/enzimologia , Inflamação/enzimologia , Fígado/enzimologia , MAP Quinase Quinase Quinases/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fatores Etários , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Genótipo , Inflamação/genética , Metabolismo dos Lipídeos , Fígado/patologia , MAP Quinase Quinase Quinases/deficiência , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/genética , Neoplasias/patologia , Fenótipo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Fatores Sexuais
9.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33604686

RESUMO

Hepatic steatosis, an indicator of atherosclerosis (AS), is always accompanied by inflammatory responses and disturbances in lipid metabolism. The present study investigated the protective effect of urantide, a urotensin II (UII) receptor antagonist, on the liver of rats with AS with hepatic steatosis by regulating the MAPK pathway. AS was induced in rats via an intraperitoneal injection of vitamin D3 and the administration of a high­fat diet. Urantide treatment was then administered to the rats. Pathology, liver index, lipid levels and liver function were measured to determine liver injury. The expression levels of UII and G protein­coupled receptor 14 (GPR14) were determined using immunohistochemistry, reverse transcription­quantitative PCR and western blotting. The expression levels of MAPK­related proteins in hepatocytes from each group were quantified using western blotting and immunofluorescence staining. Rats with AS had typical pathological changes associated with AS and hepatic steatosis, which were significantly improved by urantide treatment. Blood lipid levels, body weight, liver index and liver function were recovered in rats with AS after urantide treatment. Urantide downregulated the expression levels of UII and GPR14 in the livers of rats with AS; concurrently, the phosphorylation of Erk1/2 and JNK was significantly decreased. Moreover, no significant changes were observed in the phosphorylation of p38 MAPK in AS rat livers. In conclusion, urantide inhibits the activation of Erk1/2 and JNK by blocking the binding of UII and GPR14, thereby alleviating hepatic steatosis in rats with AS, ultimately restoring lipid metabolism in the liver and alleviating AS lesions.


Assuntos
Aterosclerose/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Fígado/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Urotensinas/farmacologia , Animais , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Humanos , Fígado/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Fosforilação/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
10.
Theranostics ; 11(7): 3489-3501, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33537099

RESUMO

The rapid development and remarkable success of checkpoint inhibitors have provided significant breakthroughs in cancer treatment, including hepatocellular carcinoma (HCC). However, only 15-20% of HCC patients can benefit from checkpoint inhibitors. Cancer stem cells (CSCs) are responsible for recurrence, metastasis, and local and systemic therapy resistance in HCC. Accumulating evidence has suggested that HCC CSCs can create an immunosuppressive microenvironment through certain intrinsic and extrinsic mechanisms, resulting in immune evasion. Intrinsic evasion mechanisms mainly include activation of immune-related CSC signaling pathways, low-level expression of antigen presenting molecules, and high-level expression of immunosuppressive molecules. External evasion mechanisms are mainly related to HBV/HCV infection, alcoholic/nonalcoholic steatohepatitis, hypoxia stimulation, abnormal angiogenesis, and crosstalk between CSCs and immune cells. A better understanding of the complex mechanisms of CSCs involved in immune evasion will contribute to therapies for HCC. Here we will outline the detailed mechanisms of immune evasion for CSCs, and provide an overview of the current immunotherapies targeting CSCs in HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/terapia , Células-Tronco Neoplásicas/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Apresentação do Antígeno/efeitos dos fármacos , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Fígado Gorduroso/genética , Fígado Gorduroso/imunologia , Fígado Gorduroso/patologia , Fígado Gorduroso/terapia , Regulação Neoplásica da Expressão Gênica , Hepatite B/genética , Hepatite B/imunologia , Hepatite B/patologia , Hepatite B/terapia , Hepatite C/genética , Hepatite C/imunologia , Hepatite C/patologia , Hepatite C/terapia , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Transdução de Sinais , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
11.
Nat Commun ; 12(1): 213, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431899

RESUMO

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.


Assuntos
Dieta Hiperlipídica , Exossomos/metabolismo , Resistência à Insulina/genética , Fosfatidilcolinas/metabolismo , Regulação para Cima/genética , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/complicações , Dislipidemias/genética , Dislipidemias/patologia , Células Epiteliais/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Fezes , Regulação da Expressão Gênica , Intolerância à Glucose , Proteínas de Fluorescência Verde/metabolismo , Humanos , Insulina/metabolismo , Interleucina-6/sangue , Intestinos/citologia , Lipídeos/química , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Tetraspanina 30/metabolismo , Fator de Necrose Tumoral alfa/sangue
12.
Nat Commun ; 12(1): 102, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397994

RESUMO

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.


Assuntos
Tecido Adiposo/metabolismo , Sistemas de Liberação de Medicamentos , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Inflamação/genética , Inflamação/patologia , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Obesidade/genética , Obesidade/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Perda de Peso/efeitos dos fármacos
13.
BMC Genomics ; 22(1): 8, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407101

RESUMO

BACKGROUND: DNA methylation, a biochemical modification of cytosine, has an important role in lipid metabolism. Fatty liver hemorrhagic syndrome (FLHS) is a serious disease and is tightly linked to lipid homeostasis. Herein, we compared the methylome and transcriptome of chickens with and without FLHS. RESULTS: We found genome-wide dysregulated DNA methylation pattern in which regions up- and down-stream of gene body were hypo-methylated in chickens with FLHS. A total of 4155 differentially methylated genes and 1389 differentially expressed genes were identified. Genes were focused when a negative relationship between mRNA expression and DNA methylation in promoter and gene body were detected. Based on pathway enrichment analysis, we found expression of genes related to lipogenesis and oxygenolysis (e.g., PPAR signaling pathway, fatty acid biosynthesis, and fatty acid elongation) to be up-regulated with associated down-regulated DNA methylation. In contrast, genes related to cellular junction and communication pathways (e.g., vascular smooth muscle contraction, phosphatidylinositol signaling system, and gap junction) were inhibited and with associated up-regulation of DNA methylation. CONCLUSIONS: In the current study, we provide a genome-wide scale landscape of DNA methylation and gene expression. The hepatic hypo-methylation feature has been identified with FLHS chickens. By integrated analysis, the results strongly suggest that increased lipid accumulation and hepatocyte rupture are central pathways that are regulated by DNA methylation in chickens with FLHS.


Assuntos
Galinhas , Fígado Gorduroso , Animais , Galinhas/genética , Metilação de DNA , Epigenoma , Fígado Gorduroso/genética , Transcriptoma
15.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33443222

RESUMO

Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatly warranted. Toll-like receptor 7 (TLR7) is a pattern recognition receptor for single-stranded RNA, and its activation prevents liver fibrosis. We examined liver and intestinal damage in Tlr7 -/- mice to determine the role of TLR7 in ALD pathogenesis. In an alcoholic hepatitis (AH) mouse model, hepatic steatosis, injury, and inflammation were induced by chronic binge ethanol feeding in mice, and Tlr7 deficiency exacerbated these effects. Because these results demonstrated that endogenous TLR7 signaling activation is protective in the AH mouse model, we hypothesized that TLR7 activation may be an effective therapeutic strategy for ALD. Therefore, we investigated the therapeutic effect of TLR7 agonistic agent, 1Z1, in the AH mouse model. Oral administration of 1Z1 was well tolerated and prevented intestinal barrier disruption and bacterial translocation, which thus suppressed ethanol-induced hepatic injury, steatosis, and inflammation. Furthermore, 1Z1 treatment up-regulated the expression of antimicrobial peptides, Reg3b and Reg3g, in the intestinal epithelium, which modulated the microbiome by decreasing and increasing the amount of Bacteroides and Lactobacillus, respectively. Additionally, 1Z1 up-regulated intestinal interleukin (IL)-22 expression. IL-22 deficiency abolished the protective effects of 1Z1 in ethanol-induced liver and intestinal damage, suggesting intestinal IL-22 as a crucial mediator for 1Z1-mediated protection in the AH mouse model. Collectively, our results indicate that TLR7 signaling exerts protective effects in the AH mouse model and that a TLR7 ligand, 1Z1, holds therapeutic potential for the treatment of AH.


Assuntos
Etanol/toxicidade , Interleucinas/metabolismo , Mucosa Intestinal/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Glicoproteínas de Membrana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/metabolismo , Administração Oral , Animais , Bacteroides/efeitos dos fármacos , Modelos Animais de Doenças , Fígado Gorduroso/complicações , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/complicações , Inflamação/genética , Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Lactobacillus/efeitos dos fármacos , Ligantes , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/fisiopatologia , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs , Proteínas Associadas a Pancreatite/genética , Proteínas Associadas a Pancreatite/metabolismo , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Transdução de Sinais/genética , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/patologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/genética
16.
Am J Physiol Endocrinol Metab ; 320(3): E609-E618, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33459178

RESUMO

Obesity is associated with alterations in hepatic lipid metabolism. We previously identified the prorenin receptor (PRR) as a potential contributor to liver steatosis. Therefore, we aimed to determine the relative contribution of PRR and its soluble form, sPRR, to lipid homeostasis. PRR-floxed male mice were treated with an adeno-associated virus with thyroxine-binding globulin promoter-driven Cre to delete PRR in the liver [liver PRR knockout (KO) mice]. Hepatic PRR deletion did not change the body weight but increased liver weights. The deletion of PRR in the liver decreased peroxisome proliferator-activated receptor gamma (PPARγ) and triglyceride levels, but liver PRR KO mice exhibited higher plasma cholesterol levels and lower hepatic low-density lipoprotein receptor (LDLR) and Sortilin 1 (SORT1) proteins than control (CTL) mice. Surprisingly, hepatic PRR deletion elevated hepatic cholesterol, and up-regulated hepatic sterol regulatory element-binding protein 2 (SREBP2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-R) genes. In addition, the plasma levels of sPRR were significantly higher in liver PRR KO mice than in controls. In vitro studies in HepG2 cells demonstrated that sPRR treatment upregulated SREBP2, suggesting that sPRR could contribute to hepatic cholesterol biosynthesis. Interestingly, PRR, total cleaved and noncleaved sPRR contents, furin, and Site-1 protease (S1P) were elevated in the adipose tissue of liver PRR KO mice, suggesting that adipose tissue could contribute to the circulating pool of sPRR. Overall, this work supports previous works and opens a new area of investigation concerning the function of sPRR in lipid metabolism and adipose tissue-liver cross talk.NEW & NOTEWORTHY Hepatic PRR and its soluble form, sPRR, contribute to triglyceride and cholesterol homeostasis and hepatic inflammation. Deletion of hepatic PRR decreased triglyceride levels through a PRR-PPARγ-dependent mechanism but increased hepatic cholesterol synthesis through sPRR-medicated upregulation of SREBP-2. Our study highlighted a new paradigm of cross talk between the liver and the adipose tissue involving cholesterol and sPRR.


Assuntos
Homeostase/genética , Metabolismo dos Lipídeos/genética , Receptores de Superfície Celular/fisiologia , Tecido Adiposo/metabolismo , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Células Hep G2 , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Receptores de Superfície Celular/química , Receptores de Superfície Celular/genética , Solubilidade , Triglicerídeos/metabolismo
17.
Diabetes ; 70(1): 182-195, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33046512

RESUMO

Becn1/Beclin-1 is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although Becn1 has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of Becn1 in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific Becn1 knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Ablation of Becn1 in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated endoplasmic reticulum (ER) stress gene expression. Furthermore, we observed that Becn1 depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte Becn1 would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Proteína Beclina-1/metabolismo , Resistência à Insulina/genética , Lipodistrofia/metabolismo , Doenças Metabólicas/metabolismo , Animais , Proteína Beclina-1/genética , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Homeostase/genética , Inflamação/genética , Inflamação/metabolismo , Lipodistrofia/genética , Doenças Metabólicas/genética , Camundongos , Camundongos Knockout
18.
Am J Clin Pathol ; 155(1): 87-96, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-32885245

RESUMO

OBJECTIVES: Steatohepatitic hepatocellular carcinoma is a distinct variant of hepatocellular carcinoma strongly associated with underlying nonalcoholic steatohepatitis. The molecular biology of steatohepatitic hepatocellular carcinoma is not fully elucidated, and thus we aimed to investigate the molecular underpinnings of this entity. METHODS: Transcriptomic analysis using RNAseq was performed on eight tumor-nonneoplastic pairs of steatohepatitic hepatocellular carcinoma with comparison to conventional hepatocellular carcinoma transcriptomes curated in The Cancer Genome Atlas. Immunohistochemistry was used to validate key RNA-level findings. RESULTS: Steatohepatitic hepatocellular carcinoma demonstrated a distinctive differential gene expression profile compared with The Cancer Genome Atlas curated conventional hepatocellular carcinomas (n = 360 cases), indicating the distinctive steatohepatitic hepatocellular carcinoma morphology is associated with a unique gene expression profile. Pathway analysis comparing tumor-nonneoplastic pairs revealed significant upregulation of the hedgehog pathway based on GLI1 overexpression and significant downregulation of carnitine palmitoyltransferase 2 transcript. Glutamine synthetase transcript was significantly upregulated, and fatty acid binding protein 1 transcript was significantly downregulated and immunohistochemically confirmed, indicating steatohepatitic hepatocellular carcinoma tumor cells display a zone 3 phenotype. CONCLUSIONS: Steatohepatitic hepatocellular carcinoma demonstrates a distinctive morphology and gene expression profile, phenotype of zone 3 hepatocytes, and activation of the hedgehog pathway and repression of carnitine palmitoyltransferase 2, which may be important in tumorigenesis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Fígado Gorduroso/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Proteoma , Transcriptoma , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteômica
19.
Diabetes ; 70(1): 119-131, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33087457

RESUMO

Sirtuin 3 (SIRT3) is a protein deacetylase regulating ß-cell function through inhibiting oxidative stress in obese and diabetic mice, but the detailed mechanism and potential effect of ß-cell-specific SIRT3 on metabolic homeostasis, and its potential effect on other metabolic organs, are unknown. We found that glucose tolerance and glucose-stimulated insulin secretion were impaired in high-fat diet (HFD)-fed ß-cell-selective Sirt3 knockout (Sirt3 f/f;Cre/+) mice. In addition, Sirt3 f/f;Cre/+ mice had more severe hepatic steatosis than Sirt3 f/f mice upon HFD feeding. RNA sequencing of islets suggested that Sirt3 deficiency overactivated 5-hydroxytryptamine (5-HT) synthesis as evidenced by upregulation of tryptophan hydroxylase 1 (TPH1). 5-HT concentration was increased in both islets and serum of Sirt3 f/f;Cre/+ mice. 5-HT also facilitated the effect of palmitate to increase lipid deposition. Treatment with TPH1 inhibitor ameliorated hepatic steatosis and reduced weight gain in HFD-fed Sirt3 f/f;Cre/+ mice. These data suggested that under HFD feeding, SIRT3 deficiency in ß-cells not only regulates insulin secretion but also modulates hepatic lipid metabolism via the release of 5-HT.


Assuntos
Fígado Gorduroso/metabolismo , Obesidade/metabolismo , Pâncreas/metabolismo , Serotonina/metabolismo , Sirtuína 3/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/genética , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Knockout , Obesidade/etiologia , Sirtuína 3/genética
20.
Eur J Med Genet ; 64(1): 104034, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32781271

RESUMO

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare disorder of hepatic long-chain fatty acid oxidation. Most patients with CPT1A deficiency present with hypoketotic hypoglycemia and hepatic encephalopathy. We describe an atypical case of an 8-year-old male with CPT1A deficiency presenting with chronic liver steatosis and cirrhosis. He also had a history of developmental delay, autism spectrum disorder, and mild dysmorphic features of unknown cause. His newborn screening test suggested CPT1A deficiency, but confirmatory biochemical testing was not conclusive. The patient never experienced a metabolic crisis. At age six, hepatomegaly was detected. Further investigations showed transaminitis, hepatosteatosis and cirrhosis. Repeat acylcarnitine profile and total/free carnitine were consistent with CPT1A deficiency. The CPTI enzyme activity was 18% of normal on fibroblast enzyme assay. A novel homozygous variant in the CPT1A gene, c.1394G > A (p.Gly465Glu) was identified from whole-exome sequencing. To our knowledge, the patient is the first reported individual with CPT1A deficiency and chronic liver steatosis and fibrosis. Developmental delay and autistic spectrum disorder are not typical features of CPT1A deficiency, given that the patient never experienced any metabolic decompensation.


Assuntos
Transtorno do Espectro Autista/genética , Carnitina O-Palmitoiltransferase/genética , Deficiências do Desenvolvimento/genética , Fígado Gorduroso/genética , Transtorno do Espectro Autista/patologia , Criança , Deficiências do Desenvolvimento/patologia , Fígado Gorduroso/patologia , Homozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Fenótipo
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