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FASEB J. 2016 Mar;30(3):1207-17. doi: 10.1096/fj.15-271999. Epub 2015 Dec 7.

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

Author information

1
*Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
2
*Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA varman.samuel@yale.edu.

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:

Wnt pathway; lipid-induced insulin resistance; nonalcoholic fatty liver disease

PMID:
26644352
PMCID:
PMC4750414
[Available on 2017-03-01]
DOI:
10.1096/fj.15-271999
[Indexed for MEDLINE]
Free PMC Article

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