title: Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition.
abstract: 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 [(3)H]-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.
authors.affiliation: Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Karavia
authors.affiliation: Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Hatziri
authors.affiliation: Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Kalogeropoulou
authors.affiliation: Anatomy, Histology and Embryology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Nikolaos I
authors.initials: NI
authors.lastname: Papachristou
authors.affiliation: Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Eva
authors.initials: E
authors.lastname: Xepapadaki
authors.affiliation: Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Caterina
authors.initials: C
authors.lastname: Constantinou
authors.affiliation: Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Natsos
authors.affiliation: Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Peristera-Ioanna
authors.initials: PI
authors.lastname: Petropoulou
authors.affiliation: Institute for Drug Research, Department of Pharmacology, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Sasson
authors.affiliation: Anatomy, Histology and Embryology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece.
authors.forename: Dionysios J
authors.initials: DJ
authors.lastname: Papachristou
authors.affiliation: Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece. Electronic address: kkypreos@med.upatras.gr.
authors.forename: Kyriakos E
authors.initials: KE
authors.lastname: Kypreos
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency* / Q000235:genetics; D001786:Blood Glucose / Q000032:analysis*; D002784:Cholesterol / Q000097:blood; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000378:metabolism / Q000473:pathology; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D014280:Triglycerides; D008687:Metformin; D002784:Cholesterol
keywords: Apolipoprotein A-I; Glucose intolerance; HDL lipoprotein; Metformin; Nonalcoholic fatty liver disease; Obesity