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- Title
FoxO1 Deficiency in Liver Is Associated with Reduced Hepatic Fatty Acid Oxidation.
- Authors
D'Souza, Fiona M.; Qu, Shen; Su, Dongming; Meseck, Marcia; Dong, Henry
- Abstract
Fatty acid oxidation occurs in mitochondria and plays an important role in hepatic energy homeostasis. In response to fasting, augmented fatty acid oxidation provides fuel for hepatic gluconeogenesis. Fatty acid oxidation is sensitive to insulin inhibition. Loss of insulin inhibition results in unrestrained hepatic fatty acid oxidation in diabetes. This effect along with increased fatty acid influx into liver promotes excessive production of glucose and triglyceride-rich very low-density lipoproteins, contributing to hyperglycemia and hyperlipidemia. To better understand the mechanism of insulin-dependent regulation of fatty acid oxidation, we generated liver-specific FoxO1-deficient mice by siRNA-mediated gene silencing. FoxO1 is a transcription factor that plays a key role in insulin signaling. CD-1 mice were treated with control or FoxO1-siRNA adenovirus. This approach resulted in 50-80% reduction of FoxO1 expression levels in liver, as determined by real-time qRT-PCR and immunoblot assays. Mice with FoxO1 deficiency in liver exhibited relatively lower fasting blood glucose levels without alterations in plasma triglyceride, cholesterol and ketone levels. Fasting plasma insulin levels in FoxO1-deficient mice were also reduced, but not to a significant level when compared to control mice. In contrast, we detected a significant elevation in plasma free fatty acid levels in FoxO1-deficient mice. This raises the hypothesis that FoxO1 loss-of-function is associated with reduced hepatic fatty acid oxidation, resulting in elevated free fatty acid levels. Consistent with this hypothesis, hepatic FoxO1 activity is increased in diabetes. Thus, FoxO1 is a positive regulator of fatty acid oxidation in modulating hepatic energy homeostasis. ADA-Funded Research
- Publication
Diabetes, 2007, Vol 56, pA392
- ISSN
0012-1797
- Publication type
Academic Journal