Identification of IQ motif–containing GTPase-activating protein 1 as a regulator of long-term ketosis
Hanna L. Erickson, Sayeepriyadarshini Anakk
Hanna L. Erickson, Sayeepriyadarshini Anakk
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e99866. https://doi.org/10.1172/jci.insight.99866.
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Research Article Hepatology Metabolism

Identification of IQ motif–containing GTPase-activating protein 1 as a regulator of long-term ketosis

Abstract

IQ motif–containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that integrates multiple cellular processes, including motility, adhesion, and proliferation, but its role in metabolism is unknown. Here, we show that IQGAP1 is induced upon fasting and regulates β-oxidation of fatty acids and synthesis of ketone bodies in the liver. IQGAP1-null (Iqgap1–/–) mice exhibit reduced hepatic PPARα transcriptional activity, as evidenced during fasting, after ketogenic diet, and upon pharmacological activation. Conversely, we found that the activity of fed-state sensor mTORC1 is enhanced in Iqgap1–/– livers, but acute inhibition of mTOR in Iqgap1–/– mice was unable to rescue the defect in ketone body synthesis. However, reexpressing IQGAP1 in the livers of Iqgap1–/– mice was sufficient to promote ketone body synthesis, increase PPARα signaling, and suppress mTORC1 activity. Taken together, we uncover what we believe to be a previously unidentified role for IQGAP1 in regulating PPARα activity and ketogenesis.

Authors

Hanna L. Erickson, Sayeepriyadarshini Anakk

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Figure 2

Iqgap1–/– mice accumulate excess hepatic fat when challenged with ketogenic diet.

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Iqgap1–/– mice accumulate excess hepatic fat when challenged with ketog...
WT and Iqgap1–/– mice were fed ketogenic diet (KD) for 4 weeks and fasted overnight (n = 6 mice per group). Control mice were fed normal chow ad libitum (n = 9–10 mice per group). (A) Liver weight normalized to total body weight. (B) Gross appearance of livers from KD-fed WT and Iqgap1–/– mice. Scale bar: 1 cm. (C) Representative images of H&E-stained and Oil red O–stained liver sections from KD-fed mice (n = 6 mice per group). Scale bar: 50 μm; 10 μm (inset). (D) Hepatic triglyceride was measured in Iqgap1–/– and WT mice (n = 6 mice per group). (E and F) Serum NEFA and triglyceride levels (n = 3–8 mice per group). Values are displayed as mean ± SD. Two-way ANOVA with Bonferroni multiple comparisons test was used to determine significance between 2 groups under 2 conditions. *P < 0.05, **P < 0.01, ***P < 0.001.