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Flavin-Containing Monooxygenase 3 Reduces Endoplasmic Reticulum Stress in Lipid-Treated Hepatocytes

Abstract

Isoforms of flavin-containing monooxygenase (FMO) are involved in xenobiotic metabolism, but have also been implicated in the regulation of glucose and lipid homeostasis and in the development of atherosclerosis. However, we have recently shown that improved insulin action is associated with increased FMO expression in livers of protein kinase C (PKC)-deficient mice. Here we investigated whether FMO3 expression affected insulin signalling, glucose metabolism and ER stress in hepatocytes. HepG2 and IHH hepatocytes were transfected with FMO3 cDNA for overexpression, or small interfering RNA for knockdown. Cells were treated with palmitate to induce insulin resistance and insulin signalling, phosphoenolpyruvate carboxykinase (PEPCK) gene expression and ER stress markers were examined by immunoblotting and RT-PCR. Glycogen synthesis was measured using [14C]glucose. Palmitate treatment reduced insulin signalling at the level of Akt phosphorylation and glycogen synthesis, which were little affected by FMO3 overexpression. However, the fatty acid also increased the levels of several endoplasmic reticulum (ER) stress markers and activation of caspase 3, which were counteracted by FMO3 overexpression and exacerbated by FMO3 knockdown. While FMO3 expression did not reverse lipid effects on protein thiol redox in hepatocytes, it did prevent upregulation of the gluconeogenic enzyme PEPCK by pharmacological ER stress inducers or by palmitate. ER stress and PEPCK levels were also reduced in livers of fat-fed PKCdelta-deficient mice. Our data indicate that FMO3 can contribute to the regulation of glucose metabolism in the liver by reducing lipid-induced ER stress and the expression of PEPCK, independently of insulin signal transduction.

Type Journal
ISBN 1944-9917 (Electronic) 0888-8809 (Linking)
Authors Liao, B. M.1, McManus, S. A.1, Hughes, W. E.1,2, Schmitz-Peiffer, C.1,2 1 Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, New South Wales, 2010, Australia; 2 St. Vincent?s Hospital Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, 2052, Australia
Publisher Name MOL ENDOCRINOL
Published Date 2016-04-01 00:00:00
Published Volume 30
Published Issue 4
Published Pages 417-28
URL http://www.ncbi.nlm.nih.gov/pubmed/26886171
Status Published in-print