RESUMO
Glycogen storage disease type Ia (GSD Ia) is caused by autosomal mutations in glucose-6-phosphatase α catalytic subunit (G6PC) and can present with severe hypoglycemia, lactic acidosis and hypertriglyceridemia. In both children and adults with GSD Ia, there is over-accumulation of hepatic glycogen and triglycerides that can lead to steatohepatitis and a risk for hepatocellular adenoma or carcinoma. Here, we examined the effects of the commonly used peroxisomal proliferated activated receptor α agonist, fenofibrate, on liver and kidney autophagy and lipid metabolism in 5-day-old G6pc -/- mice serving as a model of neonatal GSD Ia. Five-day administration of fenofibrate decreased the elevated hepatic and renal triglyceride and hepatic glycogen levels found in control G6pc -/- mice. Fenofibrate also induced autophagy and promoted ß-oxidation of fatty acids and stimulated gene expression of acyl-CoA dehydrogenases in the liver. These findings show that fenofibrate can rapidly decrease hepatic glycogen and triglyceride levels and renal triglyceride levels in neonatal G6pc -/- mice. Moreover, since fenofibrate is an FDA-approved drug that has an excellent safety profile, our findings suggest that fenofibrate could be a potential pharmacological therapy for GSD Ia in neonatal and pediatric patients as well as for adults. These findings may also apply to non-alcoholic fatty liver disease, which shares similar pathological and metabolic changes with GSD Ia.
Assuntos
Fenofibrato/farmacologia , Glucose-6-Fosfatase/metabolismo , Doença de Depósito de Glicogênio Tipo I/metabolismo , Glicogênio/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Acil-CoA Desidrogenases/metabolismo , Animais , Animais Recém-Nascidos , Autofagossomos/efeitos dos fármacos , Autofagossomos/patologia , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Ácidos Graxos/metabolismo , Fenofibrato/administração & dosagem , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio Tipo I/enzimologia , Doença de Depósito de Glicogênio Tipo I/genética , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/enzimologia , Fígado/patologia , Fígado/ultraestrutura , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , PPAR alfa/genética , PPAR alfa/metabolismo , Triglicerídeos/metabolismoRESUMO
Glucose-6-phosphatase α (G6Pase) deficiency, also known as von Gierke's Disease or Glycogen storage disease type Ia (GSD Ia), is characterized by decreased ability of the liver to convert glucose-6-phosphate to glucose leading to glycogen accumulation and hepatosteatosis. Long-term complications of GSD Ia include hepatic adenomas and carcinomas, in association with the suppression of autophagy in the liver. The G6pc-/- mouse and canine models for GSD Ia were treated with the pan-peroxisomal proliferator-activated receptor agonist, bezafibrate, to determine the drug's effect on liver metabolism and function. Hepatic glycogen and triglyceride concentrations were measured and western blotting was performed to investigate pathways affected by the treatment. Bezafibrate decreased liver triglyceride and glycogen concentrations and partially reversed the autophagy defect previously demonstrated in GSD Ia models. Changes in medium-chain acyl-CoA dehydrogenase expression and acylcarnintine flux suggested that fatty acid oxidation was increased and fatty acid synthase expression associated with lipogenesis was decreased in G6pc-/- mice treated with bezafibrate. In summary, bezafibrate induced autophagy in the liver while increasing fatty acid oxidation and decreasing lipogenesis in G6pc-/- mice. It represents a potential therapy for glycogen overload and hepatosteatosis associated with GSD Ia, with beneficial effects that have implications for non-alcoholic fatty liver disease.
Assuntos
Bezafibrato/farmacologia , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Bezafibrato/metabolismo , Modelos Animais de Doenças , Cães , Glucose/metabolismo , Glucose-6-Fosfatase/metabolismo , Glucose-6-Fosfato/metabolismo , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo I/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Knockout , Triglicerídeos/metabolismoRESUMO
INTRODUCTION: We aimed to understand clinician views regarding gene therapy as a future treatment for Alzheimer's disease (AD) and potential barriers and facilitators to its use. METHODS: We interviewed ten clinicians who treat patients with AD. Clinicians helped design a semi-structured interview including the following domains: establishing understanding, cost/access, quality of life, and religion/spirituality. Transcripts were analyzed by a coding team using descriptive content analysis with inductive approach. RESULTS: Clinicians identified three main areas of concern: 1) potential clinician and patient understanding of gene therapy and Alzheimer's disease 2) consideration of inequity (i.e., care access, disease awareness along with education level, family support, trust in care systems); and 3) considerations in decision-making (i.e., religious/spiritual beliefs and method of treatment delivery as a decision-making tools). DISCUSSION AND CONCLUSION: Findings highlight areas for knowledge-building for patients and clinicians alike. Clinicians must be aware of patient/family educational needs and gaps in their own clinical knowledge before engaging patients/families with new technology. Allowing time for questions is crucial to building rapport and trust.