[PMID]: | 29272360 |
[Au] Autor: | Hasan MK; Friedman TC; Sims C; Lee DL; Espinoza-Derout J; Ume A; Chalfant V; Lee ML; Sinha-Hikim I; Lutfy K; Liu Y; Mahata SK; Sinha-Hikim AP |
[Ad] Endereço: | Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California. |
[Ti] Título: | α7-Nicotinic Acetylcholine Receptor Agonist Ameliorates Nicotine Plus High-Fat Diet-Induced Hepatic Steatosis in Male Mice by Inhibiting Oxidative Stress and Stimulating AMPK Signaling. |
[So] Source: | Endocrinology;159(2):931-944, 2018 02 01. |
[Is] ISSN: | 1945-7170 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | α7-Nicotinic acetylcholine receptor (α7nAChR) agonists confer protection against a wide variety of cytotoxic insults and suppress oxidative stress and apoptosis in various cell systems, including hepatocytes. We recently demonstrated that nicotine, when combined with a high-fat diet (HFD), triggers oxidative stress, activates hepatocyte apoptosis, and exacerbates HFD-induced hepatic steatosis in male mice. This study evaluates whether PNU-282987 (PNU), a specific α7nAChR agonist, is effective in preventing nicotine plus HFD-induced hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice-daily intraperitoneal injections of 0.75 mg/kg body weight (BW) of nicotine, PNU (0.26 mg/kg BW), PNU plus nicotine, or saline for 10 weeks. PNU treatment was effective in attenuating nicotine plus HFD-induced increase in hepatic triglyceride levels, hepatocyte apoptosis, and hepatic steatosis. The preventive effects of PNU on nicotine plus HFD-induced hepatic steatosis were mediated by suppression of oxidative stress and activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) together with inhibition of its downstream target sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-coenzyme A-carboxylase (ACC). We conclude that the α7nAChR agonist PNU protects against nicotine plus HFD-induced hepatic steatosis in obese mice. PNU appears to work at various steps of signaling pathways involving suppression of oxidative stress, activation of AMPK, and inhibition of SREBP1c, FAS, and ACC. α7nAChR agonists may be an effective therapeutic strategy for ameliorating fatty liver disease, especially in obese smokers. |
[Mh] Termos MeSH primário: |
Benzamidas/farmacologia Compostos Bicíclicos com Pontes/farmacologia Fígado Gorduroso/tratamento farmacológico Estresse Oxidativo/efeitos dos fármacos
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[Mh] Termos MeSH secundário: |
Proteínas Quinases Ativadas por AMP/metabolismo Animais Benzamidas/uso terapêutico Compostos Bicíclicos com Pontes/uso terapêutico Dieta Hiperlipídica/efeitos adversos Fígado Gorduroso/etiologia Fígado Gorduroso/metabolismo Fígado Gorduroso/patologia Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Obesos Nicotina/toxicidade Transdução de Sinais/efeitos dos fármacos Receptor Nicotínico de Acetilcolina alfa7/agonistas
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL |
[Nm] Nome de substância:
| 0 (Benzamides); 0 (Bridged Bicyclo Compounds); 0 (PNU-282987); 0 (alpha7 Nicotinic Acetylcholine Receptor); 6M3C89ZY6R (Nicotine); EC 2.7.11.31 (AMP-Activated Protein Kinases) |
[Em] Mês de entrada: | 1802 |
[Cu] Atualização por classe: | 180215 |
[Lr] Data última revisão:
| 180215 |
[Sb] Subgrupo de revista: | AIM; IM |
[Da] Data de entrada para processamento: | 171223 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1210/en.2017-00594 |
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