PIMT regulates hepatic gluconeogenesis in mice

Bandish Kapadia; Soma Behera; Sireesh T Kumar; Tapan Shah; Rebecca Kristina Edwin; Phanithi Prakash Babu; Partha Chakrabarti; Kishore V L Parsa; Parimal Misra

doi:10.1016/j.isci.2023.106120

PIMT regulates hepatic gluconeogenesis in mice

iScience. 2023 Feb 2;26(3):106120. doi: 10.1016/j.isci.2023.106120. eCollection 2023 Mar 17.

Authors

Bandish Kapadia¹, Soma Behera¹, Sireesh T Kumar², Tapan Shah³, Rebecca Kristina Edwin¹, Phanithi Prakash Babu², Partha Chakrabarti⁴, Kishore V L Parsa¹, Parimal Misra¹

Affiliations

¹ Center for Innovation in Molecular and Pharmaceutical Sciences, Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad, TG 500046, India.
² Department of Biotechnology, University of Hyderabad, Hyderabad 500046, India.
³ Department of Biochemistry, Saurashtra University, Rajkot 360005, India.
⁴ Indian Institute of Chemical Biology, Jadavpur, Kolkata 700032, India.

Abstract

The physiological and metabolic functions of PIMT/TGS1, a third-generation transcriptional apparatus protein, in glucose homeostasis sustenance are unclear. Here, we observed that the expression of PIMT was upregulated in the livers of short-term fasted and obese mice. Lentiviruses expressing Tgs1-specific shRNA or cDNA were injected into wild-type mice. Gene expression, hepatic glucose output, glucose tolerance, and insulin sensitivity were evaluated in mice and primary hepatocytes. Genetic modulation of PIMT exerted a direct positive impact on the gluconeogenic gene expression program and hepatic glucose output. Molecular studies utilizing cultured cells, in vivo models, genetic manipulation, and PKA pharmacological inhibition establish that PKA regulates PIMT at post-transcriptional/translational and post-translational levels. PKA enhanced 3'UTR-mediated translation of TGS1 mRNA and phosphorylated PIMT at Ser656, increasing Ep300-mediated gluconeogenic transcriptional activity. The PKA-PIMT-Ep300 signaling module and associated PIMT regulation may serve as a key driver of gluconeogenesis, positioning PIMT as a critical hepatic glucose sensor.

Keywords: Hepatology; Human metabolism; Molecular biology.