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1.
J Lipid Res ; 61(5): 707-721, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32086244

RESUMEN

Fatty liver involves ectopic lipid accumulation and dysregulated hepatic oxidative metabolism, which can progress to a state of elevated inflammation and fibrosis referred to as nonalcoholic steatohepatitis (NASH). The factors that control progression from simple steatosis to NASH are not fully known. Here, we tested the hypothesis that dietary vitamin E (VitE) supplementation would prevent NASH progression and associated metabolic alterations induced by a Western diet (WD). Hyperphagic melanocortin-4 receptor-deficient (MC4R-/-) mice were fed chow, chow+VitE, WD, or WD+VitE starting at 8 or 20 weeks of age. All groups exhibited extensive hepatic steatosis by the end of the study (28 weeks of age). WD feeding exacerbated liver disease severity without inducing proportional changes in liver triglycerides. Eight weeks of WD accelerated liver pyruvate cycling, and 20 weeks of WD extensively upregulated liver glucose and oxidative metabolism assessed by 2H/13C flux analysis. VitE supplementation failed to reduce the histological features of NASH. Rather, WD+VitE increased the abundance and saturation of liver ceramides and accelerated metabolic flux dysregulation compared with 8 weeks of WD alone. In summary, VitE did not limit NASH pathogenesis in genetically obese mice, but instead increased some indicators of metabolic dysfunction.


Asunto(s)
Dieta Occidental/efectos adversos , Análisis de Flujos Metabólicos , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Vitamina E/farmacología , Animales , Antioxidantes/química , Antioxidantes/farmacología , Interacciones Farmacológicas , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Solubilidad
2.
J Nutr ; 150(5): 994-1003, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32119738

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is a term used to characterize a range of disease states that involve the accumulation of fat in the liver but are not associated with excessive alcohol consumption. NAFLD is a prevalent disease that can progress to organ damage like liver cirrhosis and hepatocellular carcinoma. Many animal models have demonstrated that one-carbon metabolism is strongly associated with NAFLD. Phosphatidylcholine is an important phospholipid that affects hepatic lipid homeostasis and de novo synthesis of this phospholipid is associated with NAFLD. However, one-carbon metabolism serves to support all cellular methylation reactions and catabolism of methionine, serine, glycine, choline, betaine, tryptophan, and histidine. Several different pathways within one-carbon metabolism that play important roles in regulating energy metabolism and immune function have received less attention in the study of fatty liver disease and fibrosis. This review examines what we have learned about hepatic lipid metabolism and liver damage from the study of one-carbon metabolism thus far and highlights unexplored opportunities for future research.


Asunto(s)
Carbono/metabolismo , Dieta , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Humanos
3.
Biochim Biophys Acta ; 1841(11): 1639-46, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25205520

RESUMEN

Non-alcoholic fatty liver disease encompasses a wide spectrum of liver damage including steatosis, non-alcoholic steatohepatitis, fibrosis and cirrhosis. We have previously reported that creatine supplementation prevents hepatic steatosis and lipid peroxidation in rats fed a high-fat diet. In this study, we employed oleate-treated McArdle RH-7777 rat hepatoma cells to investigate the role of creatine in regulating hepatic lipid metabolism. Creatine, but not structural analogs, reduced cellular TG accumulation in a dose-dependent manner. Incubating cells with the pan-lipase inhibitor diethyl p-nitrophenylphosphate (E600) did not diminish the effect of creatine, demonstrating that the TG reduction brought about by creatine does not depend on lipolysis. Radiolabeled tracer experiments indicate that creatine increases fatty acid oxidation and TG secretion. In line with increased fatty acid oxidation, mRNA analysis revealed that creatine-treated cells had increased expression of PPARα and several of its transcriptional targets. Taken together, this study provides direct evidence that creatine reduces lipid accumulation in hepatocytes by the stimulation of fatty acid oxidation and TG secretion.

4.
Amino Acids ; 47(4): 839-46, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25577261

RESUMEN

The purpose of this study was to examine the effects of betaine supplementation on the regulation of one-carbon metabolism and liver lipid accumulation induced by a high-fat diet in rats. Rats were fed one of three different liquid diets: control diet, high-fat diet and high-fat diet supplemented with betaine. The control and high-fat liquid diets contained, respectively, 35 and 71 % of energy derived from fat. Betaine supplementation involved the addition of 1 % (g/L) to the diet. After three weeks on the high-fat diet the rats had increased total liver fat concentration, liver triglycerides, liver TBARS and plasma TNF-α. The high-fat diet decreased the hepatic S-adenosylmethionine concentration and the S-adenosylmethionine/S-adenosylhomocysteine ratio compared to the control as well as altering the expression of genes involved in one-carbon metabolism. Betaine supplementation substantially increased the hepatic S-adenosylmethionine concentration (~fourfold) and prevented fatty liver and hepatic injury induced by the high-fat diet. It was accompanied by the normalization of the gene expression of BHMT, GNMT and MGAT, which code for key enzymes of one-carbon metabolism related to liver fat accumulation. In conclusion, the regulation of the expression of MGAT by betaine supplementation provides an additional and novel mechanism by which betaine supplementation regulates lipid metabolism and prevents accumulation of fat in the liver.


Asunto(s)
Betaína/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos/análisis , Hígado Graso/tratamiento farmacológico , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Aciltransferasas/genética , Aciltransferasas/metabolismo , Animales , Carbono/metabolismo , Hígado Graso/etiología , Hígado Graso/genética , Hígado Graso/metabolismo , Glicina N-Metiltransferasa/genética , Glicina N-Metiltransferasa/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Triglicéridos/metabolismo
5.
J Nutr ; 144(3): 252-7, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24368431

RESUMEN

Dietary choline is required for proper structure and dynamics of cell membranes, lipoprotein synthesis, and methyl-group metabolism. In mammals, choline is synthesized via phosphatidylethanolamine N-methyltransferase (Pemt), which converts phosphatidylethanolamine to phosphatidylcholine. Pemt(-/-) mice have impaired VLDL secretion and developed fatty liver when fed a high-fat (HF) diet. Because of the reduction in plasma lipids, Pemt(-/-)/low-density lipoprotein receptor knockout (Ldlr(-/-)) mice are protected from atherosclerosis. The goal of this study was to investigate the importance of dietary choline in the metabolic phenotype of Pemt(-/-)/Ldlr(-/-) male mice. At 10-12 wk of age, Pemt(+/+)/Ldlr(-/-) (HF(+/+)) and half of the Pemt(-/-)/Ldlr(-/-) (HF(-/-)) mice were fed an HF diet with normal (1.3 g/kg) choline. The remaining Pemt(-/-)/Ldlr(-/-) mice were fed an HF diet supplemented (5 g/kg) with choline (HFCS(-/-) mice). The HF diet contained 60% of calories from fat and 1% cholesterol, and the mice were fed for 16 d. HF(-/-) mice lost weight and developed hepatomegaly, steatohepatitis, and liver damage. Hepatic concentrations of free cholesterol, cholesterol-esters, and triglyceride (TG) were elevated by 30%, 1.1-fold and 3.1-fold, respectively, in HF(-/-) compared with HF(+/+) mice. Choline supplementation normalized hepatic cholesterol, but not TG, and dramatically improved liver function. The expression of genes involved in cholesterol transport and esterification increased by 50% to 5.6-fold in HF(-/-) mice when compared with HF(+/+) mice. Markers of macrophages, oxidative stress, and fibrosis were elevated in the HF(-/-) mice. Choline supplementation normalized the expression of these genes. In conclusion, HF(-/-) mice develop liver failure associated with altered cholesterol metabolism when fed an HF/normal choline diet. Choline supplementation normalized cholesterol metabolism, which was sufficient to prevent nonalcoholic steatohepatitis development and improve liver function. Our data suggest that choline can promote liver health by maintaining cholesterol homeostasis.


Asunto(s)
Colesterol/metabolismo , Colina/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Ésteres del Colesterol/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Fosfatidiletanolamina N-Metiltransferasa/sangre , Receptores de LDL/sangre , Triglicéridos/metabolismo
6.
Br J Nutr ; 111(4): 571-7, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24103317

RESUMEN

Creatine is an important molecule involved in cellular energy metabolism. Creatine is spontaneously converted to creatinine at a rate of 1·7% per d; creatinine is lost in the urine. Creatine can be obtained from the diet or synthesised from endogenous amino acids via the enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT). The liver has high GAMT activity and the kidney has high AGAT activity. Although the pancreas has both AGAT and GAMT activities, its possible role in creatine synthesis has not been characterised. In the present study, we examined the enzymes involved in creatine synthesis in the pancreas as well as the synthesis of guanidinoacetate (GAA) and creatine by isolated pancreatic acini. We found significant AGAT activity and somewhat lower GAMT activity in the pancreas and that pancreatic acini had measurable activities of both AGAT and GAMT and the capacity to synthesise GAA and creatine from amino acids. Creatine supplementation led to a decrease in AGAT activity in the pancreas, though it did not affect its mRNA or protein abundance. This was in contrast with the reduction of AGAT activity and mRNA and protein abundance in the kidney, suggesting that the regulatory mechanisms that control the expression of this enzyme in the pancreas are different from those in the kidney. Dietary creatine increased the concentrations of GAA, creatine and phosphocreatine in the pancreas. Unexpectedly, creatine supplementation decreased the concentrations of S-adenosylmethionine, while those of S-adenosylhomocysteine were not altered significantly.


Asunto(s)
Amidinotransferasas/metabolismo , Aminoácidos/metabolismo , Creatina/biosíntesis , Glicina/análogos & derivados , Guanidinoacetato N-Metiltransferasa/metabolismo , Páncreas/metabolismo , Animales , Creatina/farmacología , Creatinina/metabolismo , Dieta , Suplementos Dietéticos , Glicina/biosíntesis , Riñón/metabolismo , Hígado/metabolismo , Masculino , Páncreas/enzimología , Fosfocreatina/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/metabolismo
7.
Can J Physiol Pharmacol ; 91(5): 362-8, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23656379

RESUMEN

There is functional zonation of metabolism across the liver acinus, with glutamine synthetase restricted to a narrow band of cells around the terminal hepatic venules. Portacaval anastomosis, where there is a major rerouting of portal blood flow from the portal vein directly to the vena cava bypassing the liver, has been reported to result in a marked decrease in the activity of glutamine synthetase. It is not known whether this represents a loss of perivenous hepatocytes or whether there is a specific loss of glutamine synthetase. To answer this question, we have determined the activity of glutamine synthetase and another enzyme from the perivenous compartment, ornithine aminotransferase, as well as the immunochemical localization of both glutamine synthetase and ornithine aminotransferase in rats with a portacaval shunt. The portacaval shunt caused a marked decrease in glutamine synthetase activity and an increase in ornithine aminotransferase activity. Immunohistochemical analysis showed that the glutamine synthetase and ornithine aminotransferase proteins maintained their location in the perivenous cells. These results indicate that there is no generalized loss of perivenous hepatocytes, but rather, there is a significant alteration in the expression of these proteins and hence metabolism in this cell population.


Asunto(s)
Glutamato-Amoníaco Ligasa/biosíntesis , Hepatocitos/enzimología , Ornitina-Oxo-Ácido Transaminasa/biosíntesis , Derivación Portocava Quirúrgica/métodos , Vena Porta/enzimología , Vena Porta/cirugía , Animales , Glutamato-Amoníaco Ligasa/metabolismo , Hepatocitos/metabolismo , Masculino , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Vena Porta/metabolismo , Ratas , Ratas Sprague-Dawley
8.
Nutrients ; 14(3)2022 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-35277060

RESUMEN

Creatine is an important energy metabolite that is concentrated in tissues such as the muscles and brain. Creatine is reversibly converted to creatine phosphate through a reaction with ATP or ADP, which is catalyzed by the enzyme creatine kinase. Dietary supplementation with relatively large amounts of creatine monohydrate has been proven as an effective sports supplement that can enhances athletic performance during acute high-energy demand physical activity. Some side effects have been reported with creatine monohydrate supplementation, which have stimulated research into new potential molecules that could be used as supplements to potentially provide bioavailable creatine. Recently, a popular supplement, creatyl-l-leucine, has been proposed as a potential dietary ingredient that may potentially provide bioavailable creatine. This study tests whether creatyl-l-leucine is a bioavailable compound and determines whether it can furnish creatine as a dietary supplement. Rats were deprived of dietary creatine for a period of two weeks and then given one of three treatments: a control AIN-93G creatine-free diet, AIN-93G supplemented with creatine monohydrate or AIN-93G with an equimolar amount of creatyl-l-leucine supplement in the diet for one week. When compared to the control and the creatine monohydrate-supplemented diet, creatyl-l-leucine supplementation resulted in no bioaccumulation of either creatyl-l-leucine or creatine in tissue.


Asunto(s)
Creatina , Suplementos Dietéticos , Animales , Encéfalo/metabolismo , Creatina/metabolismo , Leucina/farmacología , Músculo Esquelético/metabolismo , Ratas
9.
Life Sci ; 310: 121064, 2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36220368

RESUMEN

AIMS: This work investigated the effects of creatine supplementation on different pathways related to the pathogenesis of non-alcoholic fatty liver disease and alcoholic liver disease. MAIN METHODS: To induce alcoholic liver disease, male Swiss mice were divided into three groups: control, ethanol and ethanol supplemented with creatine. To induce non-alcoholic fatty liver disease, mice were divided into three groups: control, high-fat diet and high-fat diet supplemented with creatine. Each group consisted of eight animals. In both cases, creatine monohydrate was added to the diets (1 %; weight/vol). KEY FINDINGS: Creatine supplementation prevented high-fat diet-induced non-alcoholic fatty liver disease progression, demonstrated by attenuated liver fat accumulation and liver damage. On the other hand, when combined with ethanol, creatine supplementation up-regulated key genes related to ethanol metabolism, oxidative stress, inflammation and lipid synthesis, and exacerbated ethanol-induced liver steatosis and damage, demonstrated by increased liver fat accumulation and histopathological score, as well as elevated oxidative damage markers and inflammatory mediators. SIGNIFICANCE: Our results clearly demonstrated creatine supplementation exerts different outcomes in relation to non-alcoholic fatty liver disease and alcoholic liver disease, namely it protects against high-fat diet-induced non-alcoholic fatty liver disease but exacerbates ethanol-induced alcoholic liver disease. The exacerbating effects of the creatine and ethanol combination appear to be related to oxidative stress and inflammation-mediated up-regulation of ethanol metabolism.


Asunto(s)
Hígado Graso Alcohólico , Hepatopatías Alcohólicas , Enfermedad del Hígado Graso no Alcohólico , Masculino , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Creatina/farmacología , Hígado Graso Alcohólico/etiología , Hígado Graso Alcohólico/prevención & control , Hígado/metabolismo , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Hepatopatías Alcohólicas/patología , Etanol/toxicidad , Etanol/metabolismo , Estrés Oxidativo , Inflamación/patología
10.
Lancet Glob Health ; 10(5): e705-e714, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35427527

RESUMEN

BACKGROUND: Pellagra is caused by niacin (vitamin B3) deficiency and patients with pellagra present with a characteristic rash. Isoniazid disrupts intracellular niacin synthesis and might induce niacin deficiency. In 2017, Malawi scaled up continuous isoniazid preventive treatment (IPT) for tuberculosis prevention among people living with HIV. In addition, an under-diversified diet based on subsistence maize, as is commonly the case in Malawi, is a risk factor for pellagra. We aimed to investigate whether large-scale isoniazid exposure in Malawi contributed to the cumulative risk for pellagra in a nutritionally vulnerable population. METHODS: We did a matched case-control study to evaluate the association between daily, continuous isoniazid exposure and pellagra. We matched sequentially enrolled patients with pellagra each with four control participants by sex and age from referral dermatology centres in three IPT scale-up districts in Malawi (Lilongwe, Blantyre, and Zomba) to evaluate isoniazid as a risk for pellagra using multivariable conditional logistic regression. We established a community clinic referral system surrounding the dermatology clinic in each district to enhance case-finding and included all patients with pellagra, regardless of referral status. The primary outcome was dermatologist-diagnosed pellagra. We calculated the interval between isoniazid initiation and rash onset and assessed 30-day clinical outcomes after multi-B vitamin treatment containing 300 mg nicotinamide daily. FINDINGS: Between Feb 5 and Aug 9, 2019, we enrolled 197 patients with pellagra and 781 matched controls. Isoniazid exposure was associated with an increased risk of pellagra (adjusted odds ratio 42·6 [95% CI 13·3-136·6]). Significant covariates included HIV infection, referral status, food insecurity, underweight, excess alcohol consumption, and, among women, lactation. The median time from isoniazid initiation to rash onset was shorter during the season of food scarcity (5 months [IQR 3-7]) compared with the harvest season (9 months [8-11]; hazard ratio 7·2 [95% CI 3·2-16·2], log-rank p<0·0001). Those with isoniazid-associated pellagra who discontinued isoniazid and adhered to multi-B vitamin treatment showed 30-day clinical improvement. INTERPRETATION: Continuous IPT scale-up and the annual period of food scarcity both increased the risk of pellagra in Malawi. Use of shorter rifamycin-based regimens for tuberculosis prevention and food fortification in populations with undernutrition might reduce this risk. Niacin-containing multi-B vitamin co-administration with isoniazid as pellagra prevention is worth exploring further. FUNDING: This study was supported by the President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention under project 7173.


Asunto(s)
Antituberculosos , Infecciones por VIH , Isoniazida , Pelagra , Tuberculosis , Antituberculosos/efectos adversos , Estudios de Casos y Controles , Exantema/inducido químicamente , Exantema/tratamiento farmacológico , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Isoniazida/efectos adversos , Masculino , Niacina/uso terapéutico , Pelagra/inducido químicamente , Pelagra/complicaciones , Pelagra/tratamiento farmacológico , Tuberculosis/complicaciones , Tuberculosis/tratamiento farmacológico , Tuberculosis/epidemiología , Complejo Vitamínico B/uso terapéutico
11.
J Nutr ; 141(10): 1799-804, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21880953

RESUMEN

The aim of the present study was to examine the effects of creatine supplementation on liver fat accumulation induced by a high-fat diet in rats. Rats were fed 1 of 3 different diets for 3 wk: a control liquid diet (C), a high-fat liquid diet (HF), or a high-fat liquid diet supplemented with creatine (HFC). The C and HF diets contained, respectively, 35 and 71% of energy derived from fat. Creatine supplementation involved the addition of 1% (wt:v) of creatine monohydrate to the liquid diet. The HF diet increased total liver fat concentration, liver TG, and liver TBARS and decreased the hepatic S-adenosylmethionine (SAM) concentration. Creatine supplementation normalized all of these perturbations. Creatine supplementation significantly decreased the renal activity of l-arginine:glycine amidinotransferase and plasma guanidinoacetate and prevented the decrease in hepatic SAM concentration in rats fed the HF diet. However, there was no change in either the phosphatidylcholine:phosphatidylethanolamine (PE) ratio or PE N-methyltransferase activity. The HF diet decreased mRNA for PPARα as well as 2 of its targets, carnitine palmitoyltransferase and long-chain acylCoA dehydrogenase. Creatine supplementation normalized these mRNA levels. In conclusion, creatine supplementation prevented the fatty liver induced by feeding rats a HF diet, probably by normalization of the expression of key genes of ß-oxidation.


Asunto(s)
Creatina/uso terapéutico , Grasas de la Dieta/efectos adversos , Suplementos Dietéticos , Hígado Graso/prevención & control , Metabolismo de los Lípidos , Hígado/metabolismo , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Amidinotransferasas/metabolismo , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Creatina/sangre , Hígado Graso/sangre , Hígado Graso/metabolismo , Hígado Graso/patología , Regulación de la Expresión Génica , Glicina/análogos & derivados , Glicina/sangre , Riñón/enzimología , Peroxidación de Lípido , Hígado/patología , Masculino , PPAR alfa/genética , PPAR alfa/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , S-Adenosilmetionina/metabolismo
12.
Amino Acids ; 40(5): 1325-31, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21387089

RESUMEN

Creatine synthesis is required in adult animals to replace creatine that is spontaneously converted to creatinine and excreted in the urine. Additionally, in growing animals it is necessary to provide creatine to the expanding tissue mass. Creatine synthesis requires three amino acids: glycine, methionine and arginine, and three enzymes: L-arginine:glycine amidinotransferase (AGAT), methionine adenosyltransferase (MAT) and guanidinoacetate methyltransferase (GAMT). The entire glycine molecule is consumed in creatine synthesis but only the methyl and amidino groups, respectively, from methionine and arginine. Creatinine loss averages approximately 2 g (14.6 mmol) for 70 kg males in the 20- to 39-year age group. Creatinine loss is lower in females and in older age groups because of lower muscle mass. Approximately half of this creatine lost to creatinine can be replaced, in omnivorous individuals, by dietary creatine. However, since dietary creatine is only provided in animal products, principally in meat and fish, virtually all of the creatine loss in vegetarians must be replaced via endogenous synthesis. Creatine synthesis does not appear to place a major burden on glycine metabolism in adults since this amino acid is readily synthesized. However, creatine synthesis does account for approximately 40% of all of the labile methyl groups provided by S-adenosylmethionine (SAM) and, as such, places an appreciable burden on the provision of such methyl groups, either from the diet or via de novo methylneogenesis. Creatine synthesis consumes some 20-30% of arginine's amidino groups, whether provided in the diet or synthesized within the body. Creatine synthesis is, therefore, a quantitatively major pathway in amino acid metabolism and imposes an appreciable burden on the metabolism of methionine and of arginine.


Asunto(s)
Creatina/metabolismo , Animales , Humanos
13.
Mol Immunol ; 132: 1-7, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33524770

RESUMEN

Macrophages perform the fundamental function of sensing cellular damage, initiating and mediating immune response and tissue repair. Adenine nucleotides are in relatively high abundance in cells and are released from cells during tissue damage that are converted to adenosine in the extracellular environment. The A1, A2A, A2B and A3 adenosine receptors serve to regulate immune function. Despite characterization of the adenosine receptors, a comprehensive examination of adenosine receptor signaling in THP-1 macrophage cells has not been done. Moreover, previous studies employed chemical agonists and antagonists that have the potential for off-target affects. Here we systematically knockdown each of the four known adenosine receptors in THP-1 macrophages using validated siRNA and investigated their function under LPS stimulation. We demonstrate that the A1 receptor is required for adenosine-stimulated IL-10 and IL-1ß secretion indicating an important role of this receptor during resolution of inflammation and tissue repair in these cells. The A1 and A3 receptor were required for IL-6 and IL-1ß secretion showing a net pro-inflammatory role for these receptors. Finally, we present the novel finding that THP-1 macrophages lacking the A2B receptor undergo pyroptosis when exposed to LPS, demonstrating a novel role of the A2B receptor in regulation of programmed cell death during inflammation. This work underscores the fundamental importance of adenosine signaling and provides insight into the independent roles of the adenosine receptors in modulating cytokine signaling.


Asunto(s)
Citocinas/metabolismo , Macrófagos/metabolismo , Piroptosis/inmunología , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2B/metabolismo , Receptor de Adenosina A3/metabolismo , Adenosina/farmacología , Células Cultivadas , Técnicas de Silenciamiento del Gen , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Piroptosis/efectos de los fármacos , Piroptosis/genética , ARN Interferente Pequeño , Receptor de Adenosina A1/genética , Receptor de Adenosina A2A/genética , Receptor de Adenosina A2B/genética , Receptor de Adenosina A3/genética , Receptores Purinérgicos P1/genética , Receptores Purinérgicos P1/metabolismo , Transducción de Señal/inmunología
14.
Physiol Rep ; 8(18): e14576, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32951289

RESUMEN

Fatty liver disease is increasing along with the prevalence of obesity and type-2 diabetes. Hepatic fibrosis is a major health complication for which there are no efficacious treatment options available. A better understanding of the fundamental mechanisms that contribute to the accumulation of fibrosis is needed. Glycine-N-methyltransferase (GNMT) is a critical enzyme in one-carbon metabolism that serves to regulate methylation and remethylation reactions. GNMT knockout (GNMT-/- ) mice display spontaneous hepatic fibrosis and later develop hepatocellular carcinoma. Previous literature supports the idea that hypermethylation as a consequence of GNMT deletion contributes to the hepatic phenotype observed. However, limited metabolomic information is available and the underlying mechanisms that contribute to hepatic fibrogenesis in GNMT-/- mice are still incomplete. Therefore, our goals were to use dietary intervention to determine whether increased lipid load exacerbates steatosis and hepatic fibrosis in this model and to employ both targeted and untargeted metabolomics to further understand the metabolic consequences of GNMT deletion. We find that GNMT mice fed high-fat diet do not accumulate more lipid or fibrosis in the liver and are in fact resistant to weight gain. Metabolomics analysis confirmed that pan-hypermethylation occurs in GNMT mice resulting in a depletion of nicotinamide intermediate metabolites. Further, there is a disruption in tryptophan catabolism that prevents adequate immune cell activation in the liver. The chronic cellular damage cannot be appropriately cleared due to a lack of immune checkpoint activation. This mouse model is an excellent example of how a disruption in small molecule metabolism can significantly impact immune function.


Asunto(s)
Glicina N-Metiltransferasa/deficiencia , Metaboloma , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Animales , Dieta Alta en Grasa/efectos adversos , Fibrosis , Glicina N-Metiltransferasa/genética , Glicina N-Metiltransferasa/metabolismo , Metabolismo de los Lípidos , Masculino , Metaloproteinasa 12 de la Matriz/genética , Metaloproteinasa 12 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/patología , Vinculina/genética , Vinculina/metabolismo , Aumento de Peso
15.
J Nutr Biochem ; 81: 108381, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32422424

RESUMEN

One-carbon metabolism is a collection of metabolic cycles that supports methylation and provides one-carbon bound folates for the de novo synthesis of purine and thymidine nucleotides. The methylation of phosphatidylethanolamine to form choline has been extensively studied in the context of fatty liver disease. However, the role of one-carbon metabolism in supporting nucleotide synthesis during liver damage has not been addressed. The objective of this study is to determine how the disruption of one-carbon metabolism influences nucleotide metabolism in the liver after dietary methionine and choline restriction. Mice (n=8) were fed a methionine-choline-deficient or control diet for 3 weeks. We treated mice with the compound alloxazine (0.5 mg/kg), a known adenosine receptor antagonist, every second day during the final week of feeding to probe the function of adenosine signaling during liver damage. We found that concentrations of several hepatic nucleotides were significantly lower in methionine- and choline-deficient mice vs. controls (adenine: 13.9±0.7 vs. 10.1±0.6, guanine: 1.8±0.1 vs. 1.4±0.1, thymidine: 0.0122±0.0027 vs. 0.0059±0.0027 nmol/mg dry tissue). Treatment of alloxazine caused a specific decrease in thymidine nucleotides, decrease in mitochondrial content in the liver and exacerbation of steatohepatitis as shown by the increased hepatic lipid content and altered macrophage morphology. This study demonstrates a role for one-carbon metabolism in supporting de novo nucleotide synthesis and mitochondrial function during liver damage.


Asunto(s)
Carbono/metabolismo , Hígado Graso/metabolismo , Macrófagos/metabolismo , Mitocondrias/metabolismo , Nucleótidos/metabolismo , Adenosina/metabolismo , Animales , Colina/farmacología , Deficiencia de Colina/metabolismo , Dieta , Modelos Animales de Enfermedad , Flavinas/farmacología , Guanidina/metabolismo , Inflamación/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Metionina/deficiencia , Metionina/farmacología , Ratones , Ratones Endogámicos C57BL , Antagonistas de Receptores Purinérgicos P1/farmacología , Timidina/metabolismo
16.
Front Public Health ; 8: 551308, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33324593

RESUMEN

Background: Pellagra is caused by niacin (vitamin B3) deficiency and manifested by a distinctive dermatitis. Isoniazid is critical for treating tuberculosis globally and is a component of most regimens to prevent tuberculosis. Isoniazid may contribute to pellagra by disrupting intracellular niacin synthesis. In 2017, Malawian clinicians recognized a high incidence of pellagra-like rashes after scale-up of isoniazid preventive treatment (IPT) to people living with HIV (PLHIV). This increase in pellagra incidence among PLHIV coincided with a seasonal period of sustained food insecurity in the region, which obscured epidemiological interpretations. Although isoniazid has been implicated as a secondary cause of pellagra for decades, no hypothesis-driven epidemiological study has assessed this relationship in a population exposed to isoniazid. We developed this case-control protocol to assess the association between large-scale isoniazid distribution and pellagra in Malawi. Methods: We measure the relative odds of having pellagra among isoniazid-exposed people compared to those without exposure while controlling for other pellagra risk factors. Secondary aims include measuring time from isoniazid initiation to onset of dermatitis, comparing niacin metabolites 1-methylnicotinamide (1-MN), and l-methyl-2-pyridone-5-carboxamide (2-PYR) in urine as a proxy for total body niacin status among subpopulations, and describing clinical outcomes after 30-days multi-B vitamin (containing 300 mg nicotinamide daily) therapy and isoniazid cessation (if exposed). We aim to enroll 197 participants with pellagra and 788 age- and sex-matched controls (1:4 ratio) presenting at three dermatology clinics. Four randomly selected community clinics within 3-25 km of designated dermatology clinics will refer persons with pellagra-like symptoms to one of the study enrollment sites for diagnosis. Trained study dermatologists will conduct a detailed exposure questionnaire and perform anthropometric measurements. A subset of enrollees will provide a casual urine specimen for niacin metabolites quantification and/or point-of-care isoniazid detection to confirm whether participants recently ingested isoniazid. We will use conditional logistic regression, matching age and sex, to estimate odds ratios for the primary study aim. Discussion: The results of this study will inform the programmatic scale-up of isoniazid-containing regimens to prevent tuberculosis.


Asunto(s)
Pelagra , Tuberculosis , Estudios de Casos y Controles , Humanos , Isoniazida/efectos adversos , Malaui/epidemiología , Tuberculosis/epidemiología
18.
J Nutr Biochem ; 50: 46-53, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29031242

RESUMEN

Recent studies have shown that dietary creatine supplementation can prevent lipid accumulation in the liver. Creatine is a small molecule that plays a large role in energy metabolism, but since the enzyme creatine kinase is not present in the liver, the classical role in energy metabolism does not hold in this tissue. Fat accumulation in the liver can lead to the development of nonalcoholic fatty liver disease (NAFLD), a progressive disease that is prevalent in humans. We have previously reported that creatine can directly influence lipid metabolism in cell culture to promote lipid secretion and oxidation. Our goal in the current study was to determine whether similar mechanisms that occur in cell culture were present in vivo. We also sought to determine whether dietary creatine supplementation could be effective in reversing steatosis. Sprague-Dawley rats were fed a high-fat diet or a high-fat diet supplemented with creatine for 5 weeks. We found that rats supplemented with creatine had significantly improved rates of lipoprotein secretion and alterations in mitochondrial function that were consistent with greater oxidative capacity. We also find that introducing creatine into a high-fat diet halted hepatic lipid accumulation in rats with fatty liver. Our results support our previous report that liver cells in culture with creatine secrete and oxidize more oleic acid, demonstrating that dietary creatine can effectively change hepatic lipid metabolism by increasing lipoprotein secretion and oxidation in vivo. Our data suggest that creatine might be an effective therapy for NAFLD.


Asunto(s)
Creatina/uso terapéutico , Suplementos Dietéticos , Lipoproteínas/metabolismo , Lipotrópicos/uso terapéutico , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Triglicéridos/metabolismo , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Ésteres del Colesterol/sangre , Ésteres del Colesterol/metabolismo , Creatina/efectos adversos , Citocinas/sangre , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos/efectos adversos , Represión Enzimática , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Gotas Lipídicas/metabolismo , Gotas Lipídicas/patología , Lipoproteínas/sangre , Lipotrópicos/efectos adversos , Hígado/inmunología , Hígado/patología , Mitocondrias Hepáticas/inmunología , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , ATPasas de Translocación de Protón Mitocondriales/antagonistas & inhibidores , ATPasas de Translocación de Protón Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Tamaño de los Órganos , Oxidación-Reducción , Distribución Aleatoria , Ratas Sprague-Dawley , Triglicéridos/sangre , Canales Aniónicos Dependientes del Voltaje/antagonistas & inhibidores , Canales Aniónicos Dependientes del Voltaje/genética , Canales Aniónicos Dependientes del Voltaje/metabolismo
19.
Lipids ; 51(1): 95-104, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26526060

RESUMEN

Carbohydrate response element binding protein (ChREBP) regulates insulin-independent de novo lipogenesis. Recently, a novel ChREBPß isoform was identified. The purpose of the current study was to define the effect of dietary carbohydrates (CHO) and obesity on the transcriptional activity of ChREBP isoforms and their respective target genes. Mice were subjected to fasting-refeeding of high-CHO diets. In all three CHO-refeeding groups, mice failed to induce ChREBPα, yet ChREBPß increased 10- to 20-fold. High-fat fed mice increased hepatic ChREBPß mRNA expression compared to chow-fed along with increased protein expression. To better assess the independent effect of fructose on ChREBPα/ß activity, HepG2 cells were treated with fructose ± a fructose-1,6-bisphosphatase inhibitor to suppress gluconeogenesis. Fructose treatment in the absence of gluconeogenesis resulted in increased ChREBP activity. To confirm the existence of ChREBPß in human tissue, primary hepatocytes were incubated with high-glucose and the expression of ChREBPα and -ß was determined. As with the animal models, glucose induced ChREBPß expression while ChREBPα was decreased. Taken together, ChREBPß is more responsive to changes in dietary CHO availability than the -α isoform. Diet-induced obesity increases basal expression of ChREBPß, which may increase the risk of developing hepatic steatosis, and fructose-induced activation is independent of gluconeogenesis.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carbohidratos de la Dieta/efectos adversos , Proteínas Nucleares/genética , Obesidad/metabolismo , Factores de Transcripción/genética , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Dieta , Carbohidratos de la Dieta/administración & dosificación , Fructosa/farmacología , Perfilación de la Expresión Génica , Gluconeogénesis/efectos de los fármacos , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/metabolismo , Obesidad/inducido químicamente , Especificidad de Órganos/efectos de los fármacos , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas
20.
J Nutr Biochem ; 26(10): 1077-83, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26092371

RESUMEN

Choline is a precursor to phosphatidylcholine (PC), a structural molecule in cellular membranes that is crucial for cell growth and function. PC is also required for the secretion of lipoprotein particles from liver and intestine. Choline requirements are increased during lactation when maternal choline is supplied to the offspring through breast milk. To investigate the effect of dietary choline on intestinal lipid metabolism during lactation, choline-supplemented (CS), phosphatidylcholine-supplemented (PCS) or choline-deficient (CD) diets were fed to dams during the suckling period. CD dams had lower plasma triacylglycerol, cholesterol and apoB in the fasted state and following a fat-challenge (P < .05). There was a higher content of neutral lipids and lower content of PC in the intestine of CD dams, compared with CS and PCS fed animals (P < .05). In addition, there was lower (P < .05) villus height in CD dams, which indicated a reduced absorptive surface area in the intestine. Choline is critical for the absorption of fat in lactating rats and choline deficiency alters intestinal morphology and impairs chylomicron secretion by limiting the supply of PC.


Asunto(s)
Deficiencia de Colina/fisiopatología , Mucosa Intestinal/metabolismo , Lactancia/fisiología , Metabolismo de los Lípidos/fisiología , Animales , Colina/administración & dosificación , Colina/fisiología , Dieta , Esterificación , Ácidos Grasos/metabolismo , Femenino , Mucosa Intestinal/fisiopatología , Yeyuno/química , Lípidos/análisis , Lípidos/sangre , Lipoproteínas/metabolismo , Periodo Posprandial , Embarazo , Ratas , Ratas Sprague-Dawley , Pérdida de Peso
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