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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Categories: 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 1

Hepatic IQGAP1 is induced by fasting and is crucial for the fasting response.

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Hepatic IQGAP1 is induced by fasting and is crucial for the fasting resp...
Mice were fed ad libitum or fasted for 24 hours. (A) Immunoblots of WT liver extracts indicate increased IQGAP1 expression with fasting. Each lane is a mixture of liver extracts from 2 mice (n = 6 mice per group). (B) Quantification of average relative IQGAP1 protein per mouse, measured from 7 Western blots. IQGAP1 levels were normalized to GAPDH using densitometry. Each dot represents a single mouse. (C) Representative images of H&E staining of liver sections and Oil red O staining of frozen liver sections from Iqgap1–/– and WT mice (n = 5–6 mice per group). Scale bar: 50 μm; 10 μm (inset). (D) Serum β-hydroxybutyrate levels (n = 3 mice per group). (E) Schematic depicting the workflow for measuring ketogenic potential. (F) Serum ketone body levels measured before and after sodium octanoate treatment (n = 6–8 mice per group). (G–I) Hepatic gene expression of (G) Acadm, (H) Ehhadh, and (I) Fgf21 normalized to Gapdh expression in WT and Iqgap1–/– mice (n = 6–10 mice per group). (J) Serum FGF21 levels were measured by ELISA (n = 6–7 mice per group). Values are displayed as mean ± SD. Two-tailed unpaired t test was used to determine significance between 2 groups. 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 < 0.0001. See complete unedited blots in Supplemental Figure 7.