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Title

Second-generation antisense oligonucleotides against β-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance

Authors
Popov, Violeta B
Akgul, Emin O
Kanda, Shoichi
Jurczak, Michael J
Zhang, Dongyan
Abudukadier, Abulizi
Majumdar, Sachin K
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Published in FASEB Journal. 2016, vol. 30, no. 3, p. 1207-1217
Abstract Although mutations in the Wnt/β-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High-fat-fed male C57BL/6 mice were treated for 4 wk with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of β-catenin. β-Catenin mRNA decreased by ≈80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. β-Catenin ASO improved hepatic insulin sensitivity and increased insulin-stimulated whole body glucose metabolism, as assessed during hyperinsulinemic-euglycemic clamp in awake mice. β-Catenin ASO altered hepatic lipid composition in high-fat-fed mice. There were reductions in hepatic triglyceride (44%, P < 0.05) and diacylglycerol content (60%, P < 0.01) but a 30% increase in ceramide content (P < 0.001). The altered lipid content was attributed to decreased expression of sn-1,2 diacylglycerol acyltransferase and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase and an increase in serine palmitoyl transferase. The decrease in cellular diacyglycerol was associated with a 33% decrease in PKCε activation (P < 0.05) and 64% increase in Akt2 phosphorylation (P < 0.05). In summary, Reducing β-catenin expression decreases expression of enzymes involved in hepatic fatty acid esterification, ameliorates hepatic steatosis and lipid-induced insulin resistance.
Keywords Adipose Tissue, White/drug effects/metabolismAnimalsDietary Fats/metabolismDiglycerides/metabolismFatty Acids/metabolismFatty Liver/drug therapy/genetics/metabolism/prevention & controlGlucose/metabolismInsulin/metabolismInsulin Resistance/physiologyLipids/physiologyLiver/drug effects/metabolismMaleMiceMice, Inbred C57BLOligonucleotides, Antisense/genetics/pharmacologyProtective Agents/pharmacologyTriglycerides/metabolismbeta Catenin/metabolism
Identifiers
PMID: 26644352
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POPOV, Violeta B et al. Second-generation antisense oligonucleotides against β-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance. In: FASEB Journal, 2016, vol. 30, n° 3, p. 1207-1217. https://archive-ouverte.unige.ch/unige:96956

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Deposited on : 2017-09-22

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