Summary of project PR001993
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001993. The data can be accessed directly via it's Project DOI: 10.21228/M83T6C This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001993 |
| Project DOI: | doi: 10.21228/M83T6C |
| Project Title: | Selective remodeling of the translatome underlies ketogenesis and diet associated tumor growth |
| Project Summary: | Fasting is associated with a range of health benefits, including increased longevity, enhanced brain function, and improved metabolism. How fasting signals elicit changes in the proteome to establish metabolic programs that underlie lipid catabolism and the production of ketone bodies, an essential alternative fuel of energy, remain poorly understood. Here we show that paradoxically, while global translation is downregulated during fasting, hepatocytes selectively remodel the translatome to sustain lipid metabolism and ketogenesis. We discovered that phosphorylation of the major cap binding protein, eukaryotic translation initiation factor (P-eIF4E), is induced during fasting. By employing genome-wide unbiased polysome sequencing, we show that P-eIF4E is responsible for controlling the translation of the entire ketogenesis pathway, including the master regulator of fatty acid oxidation in the liver, peroxisome proliferator-activated receptor alpha (PPAR-alpha). Importantly, P-eIF4E regulates those mRNAs through a specific translation regulatory element within their 5’ untranslated regions. Genetic inhibition of P-eIF4E interrupts ketogenesis and fatty acid oxidation upon fasting. In addition, our findings reveal a new signaling property of fatty acids (FAs) derived from adipose tissue lipolysis, which are elevated during fasting. We uncovered that FAs bind and induce AMPK kinase activity that in turn enhances the phosphorylation of the kinase that phosphorylates eIF4E, the mitogen-activated protein kinase-interacting kinase (MNK). The AMPK-MNK axis controls ketogenesis revealing a new lipid-mediated kinase signaling pathway that links ketogenesis to translation control. We further show that genetically inhibiting P-eIF4E also impairs ketogenesis in response to a ketogenic diet. Certain types of cancers, such as pancreatic cancers use ketone bodies as an energy source which may rely on P-eIF4E suggesting a novel point of vulnerability. Our findings reveal that upon a ketogenic diet, treatment with eFT508 (a clinic P-eIF4E inhibitor) restrains pancreatic tumor growth in vivo. Importantly, restoring circulating β-hydroxybutyrate (BHB) or overexpression of PPAR-alpha in tumor cells ablate the effect of eFT508, demonstrating a systemic and tumor intrinsic role of P-eIF4E during tumorigenesis in response to a ketogenic diet. Thus, our findings unveil a novel fatty acid-induced signaling pathway that activates selective translation, which underlies the rapid cellular response to fasting and ketogenesis and provides a tailored diet intervention therapy for cancer. |
| Institute: | University of Chicago |
| Last Name: | Shah |
| First Name: | Hardik |
| Address: | 900 E 57th street |
| Email: | hardikshah@uchicago.edu |
| Phone: | 7738348830 |
Summary of all studies in project PR001993
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003199 | Metabolite profiling in the liver from fasted eIF4ES209A (S209A) mice compared to fasted wild type (WT) mice | Mus musculus | University of Chicago | MS | 2024-08-14 | 1 | 6 | Uploaded data (68.3M)* |
