RESUMO
In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the pathophysiology of ALD remains unclear. Our prior data indicate that a RARß agonist limits the pathology of alcohol-related liver disease. Thus, we generated liver-specific AlbCre-RARß knockout (BKO) mice and compared them to wild type (WT) mice in an early ALD model. Both strains showed similar blood ethanol concentrations and ETOH-metabolizing enzymes. However, the livers of pair-fed-BKO and ETOH-BKO mice developed higher levels of steatosis and triglycerides than pair-fed-WT and ETOH-WT mice. The increased hepatic steatosis observed in the pair-fed-BKO and ETOH-BKO mice was associated with higher lipid synthesis/trafficking transcripts and lower beta-oxidation transcripts. ETOH-BKO mice also exhibited a higher integrated stress response (ISR) signature, including higher transcript and protein levels of ATF4 and its target, 4-EBP1. In human hepatocytes (HepG2) that lack RARß (RARß-KO), ETOH treatments resulted in greater reactive oxygen species compared to their parental cells. Notably, even without ETOH, ATF4 and 4-EBP1 protein levels were higher in the RARß-KO cells than in their parental cells. These 4-EBP1 increases were greatly attenuated in cultured ATF4-deficient and RARß/ATF4-deficient HepG2, suggesting that RARß is a crucial negative regulator of 4-EBP1 through ATF4 in cultured hepatocytes. Here, we identify RARß as a negative regulator of lipid metabolism and cellular stress in ALD.
Assuntos
Fígado Gorduroso , Hepatopatias Alcoólicas , Camundongos , Humanos , Animais , Etanol/toxicidade , Etanol/metabolismo , Vitamina A/metabolismo , Camundongos Knockout , Hepatopatias Alcoólicas/metabolismo , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismoRESUMO
INTRODUCTION: Alcohol-induced thickening of the gut mucosal layer and increased expression of goblet cell gel-forming mucins, such as mucin-2 (MUC2) are associated with disruptions to the gut barrier in alcoholic liver disease (ALD). Interest in drugs that can target gut mucins in ALD has grown; however to date, no studies have examined the properties of drugs on expression of gut mucins in models of ALD. We previously demonstrated that at 10 mg/kg/day, the drug fenretinide (N-[4-hydroxyphenyl] retinamide [Fen]), a synthetic retinoid, mitigates alcohol-associated damage to the gut barrier and liver injury in a murine model of ALD. METHODS: In this study, we specifically sought to examine the effects of Fen on gut goblet cells, and expression of mucins, including MUC2 using a 25-day Lieber-DeCarli model of chronic alcohol intake. RESULTS: Our results show that chronic alcohol intake increased gut-mucosal thickening, goblet cell numbers, and mRNA and protein expression of MUC2 in both the ileum and colon. Alcohol intake was associated with marked decreases in ileal and colonic Notch signaling, levels of Notch ligands Dll1 and Dll4, and increases in the expression of Notch-associated genes indispensable for goblet cell specification, including Math1 and Spdef. Interestingly, ileal and colonic expression of KLF4, which is involved in terminal differentiation of goblet cells, was reduced in mice chronically fed alcohol. Coadministration of alcohol with Fen at 10 mg/kg/day significantly reduced alcohol-associated increases in ileal and colonic mucosal thickening, ileal Muc2, colonic Muc2, Muc5ac and Muc6 mRNAs, and goblet cell numbers. We also found that Fen strongly prevented alcohol-mediated suppression of the Notch ligand Dll1, Notch signaling, and alcohol-induced increases in expression of Notch-associated goblet cell specification genes in both the ileum and colon. In the absence of alcohol, Fen treatments alone at 10 mg/kg/day had no effects on any of the goblet cell-related endpoints. CONCLUSION: These data show for the first time that the drug Fen possesses mucosal layer-modulating properties in response to chronic alcohol abuse. These data warrant further preclinical examination of Fen given the need for anti-ALD drugs and emerging evidence of a role for intestinal goblet cell mucins in the progression of ALD.
Assuntos
Alcoolismo , Fenretinida , Alcoolismo/metabolismo , Animais , Colo/metabolismo , Fenretinida/metabolismo , Células Caliciformes/metabolismo , Mucosa Intestinal/metabolismo , Camundongos , Mucina-2/genética , Mucina-2/metabolismoRESUMO
The 2020 global outbreak of the novel coronavirus (SARS-CoV-2 or COVID-19) is a serious threat to international health, and thus, there is an urgent need for discovery of novel therapies or use of repurposed drugs that can make a significant impact on slowing the spread of the virus. Type 1 interferons (IFN-I) are a family cytokines of the early innate immune response to viruses that are being tested against SARS-CoV-2. However, coronaviruses similar to SARS-CoV-2 can suppress host IFN-I antiviral responses. Retinoids are a family molecules related to vitamin A that possess robust immune-modulating properties, including the ability to increase and potentiate the actions of IFN-I. Therefore, adjuvants such as retinoids, capable of increasing IFN-I-mediated antiviral responses, should be tested in combinations of IFN-I and antiviral drugs in pre-clinical studies of SARS-CoV-2.
Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Retinoides/uso terapêutico , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , COVID-19 , Ensaios Clínicos como Assunto/métodos , Infecções por Coronavirus/diagnóstico , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interferon Tipo I/farmacologia , Interferon Tipo I/uso terapêutico , Pandemias , Pneumonia Viral/diagnóstico , Retinoides/farmacologia , SARS-CoV-2 , Resultado do TratamentoRESUMO
Vitamin A (VA) and its derivatives, known as retinoids, play critical roles in renal development through retinoic acid receptor ß2 (RARß2). Disruptions in VA signaling pathways are associated with the onset of diabetic nephropathy (DN). Despite the known role of RARß2 in renal development, the effects of selective agonists for RARß2 in a high-fat diet (HFD) model of DN are unknown. Here we examined whether AC261066 (AC261), a highly selective agonist for RARß2, exhibited therapeutic effects in a HFD model of DN in C57BL/6 mice. Twelve weeks of AC261 administration to HFD-fed mice was well tolerated with no observable side effects. Compared with HFD-fed mice, HFD + AC261-treated mice had improved glycemic control and reductions in proteinuria and urine albumin-to-creatinine ratio. Several cellular hallmarks of DN were mitigated in HFD + AC261-treated mice, including reductions in tubule lipid droplets, podocyte (POD) effacement, endothelial cell collapse, mesangial expansion, and glomerular basement membrane thickening. Mesangial and tubule interstitial expression of the myofibroblast markers α-smooth muscle actin (α-SMA) and type IV collagen (Col-IV) was lower in HFD + AC261-treated mice compared with HFD alone. Ultrastructural and immunohistochemistry analyses showed that, compared with HFD-fed mice, HFD + AC261-treated mice showed preservation of POD foot process and slit-diaphragm morphology, an increase in the levels of slit-diagram protein podocin, and the transcription factor Wilms tumor-suppressor gene 1 in PODs. Given the need for novel DN therapies, our results warrant further studies of the therapeutic properties of AC261 in DN.
Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Receptores do Ácido Retinoico/agonistas , Actinas/metabolismo , Animais , Benzoatos/farmacologia , Colágeno Tipo IV/metabolismo , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Membrana Basal Glomerular/efeitos dos fármacos , Membrana Basal Glomerular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Tiazóis/farmacologiaRESUMO
We show that vitamin A (all-trans-retinol) (VA) is required both for the maintenance of pancreatic ß-cell and α-cell mass and for glucose-stimulated insulin secretion in adult mice. Dietary VA deprivation (VAD) causes greatly decreased pancreatic VA levels, hyperglycemia, and reduced insulin secretion. Adult mice fed VAD diets display remodeling of the endocrine pancreas, marked ß-cell apoptosis, shifts to smaller islet size distributions, decreased ß-cell mass, increased α-cell mass, and hyperglucagonemia. Importantly, although we induced VAD in the entire animal, the pancreatic ß-cells are exquisitely sensitive to VAD-associated apoptosis compared with other cell types in other organs. VAD causes major reductions in levels of the VA intracellular binding protein Crbp1 and the retinoic acid-metabolizing enzyme Cyp26a1 specifically in larger islets, suggesting the use of these proteins as biomarkers for early endocrine mass abnormalities. In the VAD mice, the reductions in pancreatic islet sizes and the associated aberrant endocrine functions, which show similarities to the phenotype in advanced type 2 diabetes, result from reductions in pancreatic VA signaling. Reintroduction of dietary VA to VAD mice restores pancreatic VA levels, glycemic control, normal islet size distributions, ß-cell to α-cell ratios, endocrine hormone profiles, and RARß2 and RARγ2 transcript levels. Restoration of ß-cell mass by reintroducing VA to VAD mice does not involve increased ß-cell proliferation or neogenesis. Pharmacologic modulation of pancreatic VA signaling should be explored for the preservation and/or restoration of pancreatic ß-cell mass and function in individuals with diabetes mellitus.
Assuntos
Apoptose , Hiperglicemia/patologia , Células Secretoras de Insulina/patologia , Deficiência de Vitamina A/patologia , Animais , Proliferação de Células , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Glucagon/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ácido Retinoico 4 Hidroxilase , Retinoides/metabolismo , Proteínas Celulares de Ligação ao Retinol/metabolismo , Transdução de SinaisRESUMO
Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether postnatal AE exacerbates metabolic deterioration resulting from prenatal AE. Choline is a semi-essential nutrient that has been demonstrated to mitigate the cognitive impairment of prenatal AE. This study investigated how maternal choline supplementation (CS) may modify the metabolic health of offspring with prenatal and postnatal AE (AE/AE). C57BL/6J female mice were fed either a Lieber-DeCarli diet with 1.4% ethanol between embryonic day (E) 9.5 and E17.5 or a control diet. Choline was supplemented with 4 × concentrations versus the control throughout pregnancy. At postnatal week 7, offspring mice were exposed to 1.4% ethanol for females and 3.9% ethanol for males for 4 weeks. AE/AE increased hepatic triglyceride accumulation in male offspring only, which was normalized by prenatal CS. Prenatal CS also improved glucose tolerance compared to AE/AE animals. AE/AE suppressed hepatic gene expression of peroxisome proliferator activated receptor alpha (Ppara) and low-density lipoprotein receptor (Ldlr), which regulate fatty acid catabolism and cholesterol reuptake, respectively, in male offspring. However, these changes were not rectified by prenatal CS. In conclusion, AE/AE led to an increased risk of steatosis and was partially prevented by prenatal CS in male mice.
Assuntos
Colina , Suplementos Nutricionais , Etanol , Fígado , Camundongos Endogâmicos C57BL , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Colina/administração & dosagem , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos , Fígado Gorduroso/prevenção & controle , Fígado Gorduroso/etiologia , Triglicerídeos/metabolismo , PPAR alfa/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Intolerância à Glucose/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacosRESUMO
Background: In response to the COVID-19 pandemic, telehealth digital applications (apps) permitted the delivery of health care to millions of individuals, including those with poor access to health services. Aim: To review a body of evidence demonstrating that telehealth and mobile health (mHealth) apps can promote clinically meaningful weight loss, and thus hold potential to increase access to treatment and weight loss care for individuals suffering from obesity. Results: Data from COVID-19 pandemic revealed that access to telehealth and mHealth remains a challenge for underserved communities that are disproportionately affected by obesity. Conclusions: The development of telehealth and mHealth for obesity treatment must be informed by the success and failures of telehealth during the COVID-19 pandemic. Failure to do so, risks alienating the very populations that stand most to benefit from telehealth and mHealth apps for obesity treatment.
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Sarcopenia and muscle wasting have many negative impacts on health and well-being. Evidence suggests that high rates of COVID-19 hospitalizations and lockdown conditions will lead to a marked increase in musculoskeletal disorders associated with sarcopenia in older adults. The molecular etiology of sarcopenia is complex, but physical inactivity, poor diet, and age diminished ability to stimulate muscle protein synthesis (MPS) remain important drivers. A body of evidence shows that, acting through the highly conserved nutrient sensor pathway mTORc1, the branch chain amino acid leucine can trigger and enhance MPS in older adults, and thus has a role in the medical management of sarcopenia. Whey protein-enriched enteral supplements are a low cost, easily accessible source of highly bioavailable leucine used clinically in older adults for preservation of lean body mass in long-term care setting. Therefore, given the evidence of leucine's ability to stimulate MPS in older adults, we argue that meal supplementation with whey-enriched enteral products, which can provide the 3-5 g of leucine necessary to trigger MPS in older adults, should be given serious consideration by medical and nutrition professionals to potentially mitigate muscle wasting and sarcopenia risk associated with prolonged COVID-19 lockdown measures.
Assuntos
COVID-19 , Sarcopenia , Idoso , Controle de Doenças Transmissíveis , Suplementos Nutricionais , Humanos , Leucina , Músculo Esquelético , SARS-CoV-2 , Sarcopenia/prevenção & controleRESUMO
Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARß, and RARγ, all-trans-retinoic acid, an active metabolite of VA, is a potent regulator of numerous biological pathways, including embryonic and somatic cellular differentiation, immune functions, and energy metabolism. The liver is the primary organ for retinoid storage and metabolism in humans. For reasons that remain incompletely understood, a body of evidence shows that reductions in liver retinoids, aberrant retinoid metabolism, and reductions in RAR signaling are implicated in numerous diseases of the liver, including hepatocellular carcinoma, non-alcohol-associated fatty liver diseases, and alcohol-associated liver diseases. Conversely, restoration of retinoid signaling, pharmacological treatments with natural and synthetic retinoids, and newer agonists for specific RARs show promising benefits for treatment of a number of these liver diseases. Here we provide a comprehensive review of the literature demonstrating a role for retinoids in limiting the pathogenesis of these diseases and in the treatment of liver diseases.
Assuntos
Hepatopatias , Receptores do Ácido Retinoico , Retinoides , Humanos , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Receptores do Ácido Retinoico/metabolismo , Retinoides/metabolismo , Tretinoína/uso terapêutico , Vitamina A/uso terapêuticoRESUMO
Alcohol abuse reduces hepatic vitamin A (retinoids), reductions that are associated with progression of alcohol liver disease (ALD). Restoring hepatic retinoids through diet is contraindicated in ALD due to the negative effects of alcohol on retinoid metabolism. There are currently no drugs that can both mitigate alcohol-driven hepatic retinoid losses and progression of ALD. Using a mouse model of alcohol intake, we examined if an agonist for the retinoic acid (RA) receptor ß2 (RARß2), AC261066 (AC261) could prevent alcohol-driven hepatic retinoid losses and protect against ALD. Our results show that mice co-treated with AC261 and alcohol displayed mitigation of ALD, including reduced macro, and microvesicular steatosis, and liver damage. Alcohol intake led to increases in hepatic centrilobular levels of ALDH1A1, a rate-limiting enzyme in RA synthesis, and co-localization of ALDH1A1 with the alcohol-metabolizing enzyme CYP2E1, and 4-HNE, a marker of oxidative stress; expression of these targets was abrogated in mice co-treated with AC261 and alcohol. By RNA sequencing technology, we found that AC261 treatments opposed alcohol modulation of 68 transcripts involved in canonical retinoid metabolism. Alcohol modulation of these transcripts, including CES1D, CES1G, RBP1, RDH10, and CYP26A1, collectively favor hepatic retinoid hydrolysis and catabolism. However, despite this, co-administration of AC261 with alcohol did not mitigate alcohol-mediated depletions of hepatic retinoids, but did reduce alcohol-driven increases in serum retinol. Our data show that AC261 protected mice against ALD, even though AC261 did not prevent alcohol-mediated reductions in hepatic retinoids. These data warrant further studies of the anti-ALD properties of AC261.
Assuntos
Fígado , Receptores do Ácido Retinoico , Metabolismo dos Lipídeos , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Retinoides/genética , Retinoides/metabolismo , Retinoides/farmacologia , Tretinoína/metabolismo , Tretinoína/farmacologia , Vitamina A/farmacologiaRESUMO
Very low-calorie diets (VLCD) are hypocaloric dietary regimens of approximately 400-800 kcal/day that result in 20-30% reductions in body weight, sometimes in just 12-16 weeks. A body of evidence demonstrates that adherence to VLCD in adults with type 2 diabetes (T2D) can result in marked improvements to glycemic control and even full T2D remission, challenging the convention that T2D is a lifelong disease. Although these data are promising, the majority of VLCD studies have focused on weight loss and not T2D remission as a primary endpoint. Moreover, there is a wide range of VLCD protocols and definitions of T2D remission used across these hypocaloric studies. Together the large degree of heterogeneity in VLCD studies, and how T2D remission is defined, leave many gaps in knowledge to efficacy and durability of VLCD approaches for T2D remission. This narrative review examines findings from a body of data from VLCD studies that specifically sought to investigate T2D remission, and discusses the efficacy of VLCD compared to other hypocaloric approaches, and who is likely to benefit from VLCD approaches for T2D remission.
Assuntos
Restrição Calórica/métodos , Diabetes Mellitus Tipo 2/dietoterapia , Peso Corporal , Ingestão de Energia , Índice Glicêmico , Humanos , Obesidade/dietoterapia , Redução de PesoRESUMO
Alcohol liver disease (ALD) is a major cause of liver-related mortality globally, yet there remains an unmet demand for approved ALD drugs. The pathogenesis of ALD involves perturbations to the intestinal barrier and subsequent translocation of bacterial endotoxin that, acting through toll-like receptor 4 (TLR4), promotes hepatic inflammation and progression of ALD. In the present study we investigated the ability of fenretinide (Fen) [N-(4-hydroxyphenyl) retinamide], a synthetic retinoid with known anti-cancer and anti-inflammatory properties, to modulate intestinal permeability and clinical hallmarks of ALD in a mouse model of chronic ethanol (EtOH) exposure. Our results show that EtOH-treated mice had reductions in mRNA and protein expression of intestinal tight junction proteins, including claudin one and occludin, and increases in intestinal permeability and endotoxemia compared to pair-fed mice. Also, EtOH-treated mice had marked increases in hepatic steatosis, liver injury, and expression of pro-inflammatory mediators, including TNF-α, and TLR4-positive macrophages, Kupffer cells, and hepatocytes in the intestines and liver, respectively. In contrast, EtOH + Fen-treated mice were resistant to the effects of EtOH on promoting intestinal permeability and had higher intestinal protein levels of claudin one and occludin. Also, EtOH + Fen-treated mice had significantly lower plasma levels of endotoxin, and reductions in expression of TNF-α and TLR4 positive macrophages, Kupffer cells, and hepatocytes in the intestine and liver. Lastly, we found that EtOH + Fen-treated mice exhibited major reductions in hepatic triglycerides, steatosis, and liver injury compared to EtOH-treated mice. Our findings are the first to demonstrate that Fen possesses anti-ALD properties, potentially through modulation of the intestinal barrier function, endotoxemia, and TLR4-mediated inflammation. These data warrant further pre-clinical investigations of Fen as a potential anti-ALD drug.
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The roles of retinoids in nonalcoholic fatty liver disease (NAFLD) remain unclear and a better understanding may lead to therapies that prevent or limit NAFLD progression. We examined the actions of retinoic acid receptor (RAR) agonists- AM80 for RARα and AC261066 for RARß2- in a murine model of NAFLD. We fed wild type C57Bl/6 mice a chow or a 45% high fat diet (HFD) for 12 weeks, followed by 4 additional weeks with the HFD+AM80; HFD+AC261066; or HFD. The HFD+AM80 group showed greater hyperglycemia and glucose intolerance compared to other groups. Histopathological evaluation of the livers showed the highest degree of steatosis, triglycerides levels, and inflammation, assessed by F4/80 staining, in the HFD+AM80-treated compared to the HFD, the HFD+AC261066, and chow-fed mice. Liver vitamin A (retinol (ROL)) and retinyl palmitate levels were markedly lower in all HFD groups compared to chow-fed controls. HFD+AC261066-treated mice showed higher levels of a key intracellular ROL transporter, retinol-binding protein-1 (RBP1) compared to the HFD and HFD+AM80 groups. In conclusion, these data demonstrate that the selective RARα agonist AM80 exacerbates HFD-induced NAFLD and hyperglycemia. These findings should inform future studies examining the therapeutic potential of RAR agonists in HFD-related disorders.
Assuntos
Benzoatos/farmacologia , Gorduras na Dieta/efeitos adversos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica , Tetra-Hidronaftalenos/farmacologia , Tiazóis/farmacologia , Animais , Gorduras na Dieta/farmacologia , Intolerância à Glucose/induzido quimicamente , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/metabolismo , Proteínas Celulares de Ligação ao Retinol/metabolismo , Triglicerídeos/metabolismo , Vitamina A/metabolismoRESUMO
Previous gene array data from our laboratory identified the retinoic acid (RA) biosynthesis enzyme aldehyde dehydrogenase 1A3 (ALDH1A3) as a putative androgen-responsive gene in human prostate cancer epithelial (LNCaP) cells. In the present study, we attempted to identify if any of the three ALDH1A/RA synthesis enzymes are androgen responsive and how this may affect retinoid-mediated effects in LNCaP cells. We demonstrated that exposure of LNCaP cells to the androgen dihydrotestosterone (DHT) results in a 4-fold increase in ALDH1A3 mRNA levels compared with the untreated control. The mRNA for two other ALDH1A family members, ALDH1A1 and ALDH1A2, were not detected and not induced by DHT in LNCaP cells. Inhibition of androgen receptor (AR) with both the antiandrogen bicalutamide and small interfering RNA for AR support that ALDH1A3 regulation by DHT is mediated by AR. Furthermore, specific inhibition of the extracellular signal-regulated kinase and Src family of kinases with PD98059 and PP1 supports that AR's regulation of ALDH1A3 occurs by the typical AR nuclear-translocation cascade. Consistent with an increase in ALDH1A3 mRNA, DHT-treated LNCaP cells showed an 8-fold increase in retinaldehyde-dependent NAD(+) reduction compared with control. Lastly, treatment of LNCaP with all-trans retinal (RAL) in the presence of DHT resulted in significant up-regulation of the RA-inducible, RA-metabolizing enzyme CYP26A1 mRNA compared with RAL treatment alone. Taken together, these data suggest that (i) the RA biosynthesis enzyme ALDH1A3 is androgen responsive and (ii) DHT up-regulation of ALDH1A3 can increase the oxidation of retinal to RA and indirectly affect RA bioactivity and metabolism.
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Aldeído Desidrogenase/genética , Androgênios/farmacologia , Di-Hidrotestosterona/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/genética , Estradiol/farmacologia , Flavonoides/farmacologia , Humanos , Isoenzimas/genética , Masculino , Metribolona/farmacologia , Neoplasias da Próstata , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Retinaldeído/farmacologia , Ácido Retinoico 4 Hidroxilase , Tretinoína/metabolismo , Quinases da Família src/antagonistas & inibidoresRESUMO
Hepatic stellate cells (HSCs) are an important cellular target for the development of novel pharmacological therapies to prevent and treat nonalcoholic fatty liver diseases (NAFLD). Using a high fat diet (HFD) model of NAFLD, we sought to determine if synthetic selective agonists for retinoic acid receptor ß2 (RARß2) and RARγ can mitigate HSC activation and HSC relevant signaling pathways during early stages of NAFLD, before the onset of liver injury. We demonstrate that the highly selective RARß2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of α-smooth muscle actin (α-SMA), in mice with HFD-induced NAFLD. Livers of HFD-fed mice treated with AC261066 exhibited reduced steatosis, oxidative stress, and expression of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFα), interleukin 1ß (IL-1ß), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-ß1 (TGF-ß1), which plays a critical role in early HSC activation, was markedly reduced in AC261066-treated, HFD-fed mice. In contrast, HFD-fed mice treated with an RARγ agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-ß1 levels. In conclusion, our data demonstrate that RARß2 is an attractive target for development of NAFLD therapies. KEY MESSAGES: ⢠Hepatic stellate cells (HSCs) are an important pharmacological target for the prevention of nonalcoholic fatty liver diseases (NAFLD). ⢠Retinoids and retinoic acid receptors (RARs) possess favorable metabolic modulating properties. ⢠We show that an agonist for retinoic acid receptor-ß2 (RARß2), but not RARγ, mitigates HSC activation and NAFLD.
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Benzoatos/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores do Ácido Retinoico/agonistas , Tiazóis/uso terapêutico , Animais , Benzoatos/farmacologia , Citocinas/genética , Dieta Hiperlipídica , Células Estreladas do Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Naftóis/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Tiazóis/farmacologia , Receptor gama de Ácido RetinoicoRESUMO
Vitamin A has a critical role in embryonic development, immunity and the visual cycle. In recent years, evidence has demonstrated that vitamin A can also regulate metabolic pathways implicated in the pathogenesis of obesity and diabetes. This has increased interest in the possible antiobesity and antidiabetic properties of natural and synthetic vitamin A derivatives. However, whether vitamin A deficiency or aberrations in vitamin A metabolism contribute to the pathogenesis of diabetes is not known. This perspective article will review what is currently known and new data regarding the link between vitamin A and the clinical manifestations of common and atypical forms of diabetes.
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Obesity negatively affects multiple metabolic pathways, but little is known about the impact of obesity on vitamin A (VA)[retinol (ROL)], a nutrient that regulates expression of genes in numerous pathways essential for human development and health. We demonstrate that obese mice, generated from a high fat diet (HFD) or by genetic mutations (i.e., ob/ob; db/db), have greatly reduced ROL levels in multiple organs, including liver, lungs, pancreas, and kidneys, even though their diets have adequate VA. However, obese mice exhibit elevated serum VA. Organs from obese mice show impaired VA transcriptional signaling, including reductions in retinoic acid receptor (RARα, RARß2 and RARγ) mRNAs and lower intracellular ROL binding protein Crbp1 (RBP1) levels in VA-storing stellate cells. Reductions in organ VA signaling in obese mice correlate with increasing adiposity and fatty liver (steatosis), while with weight loss VA levels and signaling normalize. Consistent with our findings in obese mice, we show that increasing severity of fatty liver disease in humans correlates with reductions in hepatic VA, VA transcriptional signaling, and Crbp1 levels in VA storing stellate cells. Thus, obesity causes a "silent" VA deficiency marked by reductions in VA levels and signaling in multiple organs, but not detected by serum VA.
Assuntos
Obesidade/metabolismo , Deficiência de Vitamina A/metabolismo , Vitamina A/metabolismo , Adiposidade/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos/metabolismoAssuntos
Aciltransferases/metabolismo , Pulmão/metabolismo , Tuberculose/metabolismo , Vitamina A/metabolismo , Aciltransferases/genética , Animais , Cromatografia Líquida de Alta Pressão , Imuno-Histoquímica , Fígado/enzimologia , Fígado/metabolismo , Pulmão/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Retinoides/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Liver X receptors (LXR) play an integral role in cholesterol metabolism and the inflammatory response. High-fat (HF) diets and microbial infection can antagonize the LXR pathway leading to accumulation of cholesteryl-esters (CE) and increased expression of pro-inflammatory mediators in macrophages. The probiotic bacteria Lactobacillus paracasei possesses cholesterol lowering and immune modulating properties. Therefore, the present study sought to model whether daily feeding of L. paracasei to juvenile Ossabaw pigs fed a HF diet could modulate cholesterol metabolism and the LXR/inflammatory axis in lipopolysacharide (LPS)-stimulated alveolar macrophages (AM). The results showed that AM from pigs fed a HF diet had significantly higher concentrations of CE compared to AM from pigs fed a control (C) diet, but not in pigs fed a HF diet with L. paracasei (HFPB). Ex vivo LPS stimulation of AM opposed LXR agonist-mediated transcription of cholesterol metabolism related genes: ABCA1, CH25H and PPARγ in pigs on the C diet, and LXRα, ABCA1, ABCG1, CH25H and PPARγ in pigs on the HF diet. This effect was abrogated for all these genes except LXRα in AM from pigs given L. paracasei. Protein analysis of culture supernatants revealed that AM from HFPB-fed pigs had significantly lower LPS-induced protein expression of IL-1ß than AM from HF-fed pigs. Moreover, AM from pigs fed the C diet and given L. paracasei, had significantly higher mRNA levels of IL-8, and IL-6, in response to LPS. These data demonstrated a role for L. paracasei in modulating AM cholesterol metabolism and the response to LPS.
Assuntos
Colesterol/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/fisiologia , Receptores Nucleares Órfãos/antagonistas & inibidores , Probióticos/farmacologia , Animais , Colesterol/sangue , Dieta Hiperlipídica , Expressão Gênica , Interleucina-1beta/biossíntese , Lactobacillus/metabolismo , Receptores X do Fígado , Macrófagos Alveolares/efeitos dos fármacos , Receptores Nucleares Órfãos/metabolismo , Suínos , Porco MiniaturaRESUMO
Recent evidence suggests that the liver X receptor (LXR) is a potential anticancer target in prostate carcinoma. There is little characterization, however, of which of the two LXR isoforms, LXRalpha or LXRbeta, regulates the LXR-responsive genes ATP-binding cassette subfamily members A1 (ABCA1) and G1 (ABCG1) in transformed prostatic epithelial cells. In this study, small interfering RNA (siRNA) was used to determine whether LXRalpha or LXRbeta is involved in regulating ABCA1 and ABCG1 mRNA expression in LNCaP and PC-3 cells. Treatment of both cell lines with the synthetic LXR ligand T0901317 and oxysterols: 25-hydroxycholesterol (25HC) and 24(S), 25-epoxycholesterol (24,25EC), resulted in more than a 10-fold increase of ABCA1 and ABCG1 mRNA expression. Transfection of LNCaP cells with siRNA against either LXRbeta or LXRalpha failed to inhibit T0901317 and 25HC-mediated increase of ABCA1 mRNA. siRNA silencing of LXRbeta did, however, inhibit ABCA1 mRNA expression in 24,25EC-treated LNCaP cells. In contrast, LXRbeta siRNA inhibited T0901317, 25HC, and 24,25EC induction of ABCA1 mRNA in PC-3 cells and ABCG1 mRNA in both LNCaP and PC-3 cells. Additional experiments revealed that T0901317 and 25HC induction of ABCA1 mRNA expression was significantly inhibited by the p38 stress kinase antagonist SB202190 and PKA inhibitor H89. Our study is the first to show that LXRbeta, but not LXRalpha, is the major regulatory isoform of ABCG1 mRNA expression in LNCaP and PC-3 cells. Our study also reveals that ABCA1 gene expression is differentially regulated by synthetic and natural LXR ligands, possibly involving kinase mediated signal transduction.