Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Ther ; 26(8): 1983-1995, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29914758

RESUMO

Primary hyperoxalurias (PHs) are autosomal recessive disorders caused by the overproduction of oxalate leading to calcium oxalate precipitation in the kidney and eventually to end-stage renal disease. One promising strategy to treat PHs is to reduce the hepatic production of oxalate through substrate reduction therapy by inhibiting liver-specific glycolate oxidase (GO), which controls the conversion of glycolate to glyoxylate, the proposed main precursor to oxalate. Alternatively, diminishing the amount of hepatic lactate dehydrogenase (LDH) expression, the proposed key enzyme responsible for converting glyoxylate to oxalate, should directly prevent the accumulation of oxalate in PH patients. Using RNAi, we provide the first in vivo evidence in mammals to support LDH as the key enzyme responsible for converting glyoxylate to oxalate. In addition, we demonstrate that reduction of hepatic LDH achieves efficient oxalate reduction and prevents calcium oxalate crystal deposition in genetically engineered mouse models of PH types 1 (PH1) and 2 (PH2), as well as in chemically induced PH mouse models. Repression of hepatic LDH in mice did not cause any acute elevation of circulating liver enzymes, lactate acidosis, or exertional myopathy, suggesting further evaluation of liver-specific inhibition of LDH as a potential approach for treating PH1 and PH2 is warranted.


Assuntos
Hiperoxalúria Primária/terapia , L-Lactato Desidrogenase/antagonistas & inibidores , Oxalatos/metabolismo , Interferência de RNA/fisiologia , Animais , Modelos Animais de Doenças , Inativação Gênica , Humanos , Hiperoxalúria Primária/genética , Hiperoxalúria Primária/metabolismo , L-Lactato Desidrogenase/genética , Fígado/enzimologia , Camundongos
2.
Mol Ther ; 26(7): 1771-1782, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29784585

RESUMO

Glycogen storage diseases (GSDs) of the liver are devastating disorders presenting with fasting hypoglycemia as well as hepatic glycogen and lipid accumulation, which could lead to long-term liver damage. Diet control is frequently utilized to manage the potentially dangerous hypoglycemia, but there is currently no effective pharmacological treatment for preventing hepatomegaly and concurrent liver metabolic abnormalities, which could lead to fibrosis, cirrhosis, and hepatocellular adenoma or carcinoma. In this study, we demonstrate that inhibition of glycogen synthesis using an RNAi approach to silence hepatic Gys2 expression effectively prevents glycogen synthesis, glycogen accumulation, hepatomegaly, fibrosis, and nodule development in a mouse model of GSD III. Mechanistically, reduction of accumulated abnormally structured glycogen prevents proliferation of hepatocytes and activation of myofibroblasts as well as infiltration of mononuclear cells. Additionally, we show that silencing Gys2 expression reduces hepatic steatosis in a mouse model of GSD type Ia, where we hypothesize that the reduction of glycogen also reduces the production of excess glucose-6-phosphate and its subsequent diversion to lipid synthesis. Our results support therapeutic silencing of GYS2 expression to prevent glycogen and lipid accumulation, which mediate initial signals that subsequently trigger cascades of long-term liver injury in GSDs.


Assuntos
Doença de Depósito de Glicogênio Tipo III/genética , Glicogênio Sintase/genética , Glicogênio/genética , Cirrose Hepática/genética , Cirrose Hepática/patologia , Fígado/patologia , Interferência de RNA/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Fibroblastos/patologia , Glucose-6-Fosfato/genética , Doença de Depósito de Glicogênio Tipo III/patologia , Hepatócitos/patologia , Hepatomegalia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...