Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition

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• 作者：Eleni A. Karavia^a ; ¹ ; Aikaterini Hatziri^a ; ¹ ; Christina Kalogeropoulou^a ; ¹ ; Nikolaos I Papachristou^b ; Eva Xepapadaki^a ; Caterina Constantinou^a ; Anastasios Natsos^a ; Peristera-Ioanna Petropoulou^a ; Shlomo Sasson^c ; Dionysios J Papachristou^b ; Kyriakos E. Kypreos^a ; ^{kkypreos@med.upatras.gr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ABCA1 ; ATP-binding cassette sub-family A member 1 ; ABCG1 ; ATP-binding cassette sub-family G member 1 ; AMPK ; adenosine monophosphate-activated protein kinase ; apoa1-/- ; apoa1 deficient mice ; ApoA-I ; apolipoprotein A-I ; apoe ; apolipoprotein e gene ; ApoE ; apolipoprotein E ; AUC ; area under the curve ; CETP ; cholesterylester transfer protein ; dgat-1 ; diacylglycerol acyltransferase isoform 1 gene ; fasn ; fatty acid synthase gene ; FFA ; free fatty acids ; GTT ; glucose tolerance test ; HDL-C ; HDL cholesterol
• 刊名：European Journal of Pharmacology
• 出版年：2015
• 出版时间：5 November 2015
• 年：2015
• 卷：766
• 期：Complete
• 页码：76-85
• 全文大小：6340 K

文摘

Recently, we showed that deficiency in apolipoprotein A-I (ApoA-I) sensitizes mice to diet-induced obesity, glucose intolerance and NAFLD. Here we investigated the potential involvement of ApoA-I in the pharmacological effects of metformin on glucose intolerance and NAFLD development. Groups of apoa1-deficient (apoa1^-/-) and C57BL/6 mice fed western-type diet were either treated with a daily dose of 300 mg/kg metformin for 18 weeks or left untreated for the same period. Then, histological and biochemical analyses were performed. Metformin treatment led to a comparable reduction in plasma insulin levels in both C57BL/6 and apoa1^-/- mice following intraperitoneal glucose tolerance test. However, only metformin-treated C57BL/6 mice maintained sufficient peripheral insulin sensitivity to effectively clear glucose following the challenge, as indicated by a [³H]-2-deoxy-D-glucose uptake assay in isolated soleus muscle. Similarly, deficiency in ApoA-I ablated the effect of metformin on hepatic lipid deposition and NAFLD development. Gene expression analysis indicated that the effects of ApoA-I on metformin treatment may be independent of adenosine monophosphate-activated protein kinase (AMPK) activation and de novo lipogenesis. Interestingly, metformin treatment reduced mitochondrial oxidative phosphorylation function only in apoa1^-/- mice. Our data show that the role of ApoA-I in diabetes extends to the modulation of the pharmacological actions of metformin, a common drug for the treatment of type 2 diabetes.