@article{8aa9cb2d57ba46c4a1556b6f1ea65bb4,
title = "Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids",
abstract = "Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of 13C-alanine into newly synthesized glucose by hepatocytes. In vivo Gpt2 knockdown or knockout in liver has no effect on glucose concentrations in lean mice, but Gpt2 suppression alleviates hyperglycemia in db/db mice. These data suggest that ALT2 plays a significant role in hepatic gluconeogenesis from amino acids in diabetes.",
keywords = "ATF4, CP: Metabolism, GPT2, amino acids, gluconeogenesis, liver",
author = "Martino, {Michael R.} and Manuel Guti{\'e}rrez-Aguilar and Yiew, {Nicole K.H.} and Lutkewitte, {Andrew J.} and Singer, {Jason M.} and Kyle McCommis and Daniel Ferguson and Liss, {Kim H.H.} and Jun Yoshino and Renkemeyer, {M. Katie} and Smith, {Gordon I.} and Kevin Cho and Fletcher, {Justin A.} and Samuel Klein and Patti, {Gary J.} and Burgess, {Shawn C.} and Finck, {Brian N.}",
note = "Funding Information: This work was funded by NIH grant R01 DK117657 (to B.N.F.). The Core services of the Diabetes Research Center ( P30 DK020579 ) and the Nutrition Obesity Research Center ( P30 DK56341 ) at the Washington University School of Medicine also supported this work. N.K.H.Y. was supported by a training grant ( T32 HL134635-05 ). K.S.M. was supported by ( R00 HL136658 ). M.G.-A. was supported by Direcci{\'o}n General de Asuntos del Personal Acad{\'e}mico , Programa de Apoyo a Proyectos de Investigaci{\'o}n e Innovaci{\'o}n Tecnol{\'o}gica (PAPIIT) IA208121 , UNAM, and UNAM-FQ-PAIP 5000-9171 . K.H.H.L. is supported by the Dean's Scholars Program which is in part funded from a grant from the Burroughs Wellcome Fund ( 1020047 ). S.C.B. and J.A.F. were supported by R01 DK078184 and a Robert A. Welch Foundation grant I-1804 . Some metabolic analyses were supported by NIH grant R35 ES028365 (to G.J.P.). We thank Michael A. Cooper for assistance with animal experiments and Mitchell R. McGill with assistance in ALT assays. Funding Information: This work was funded by NIH grant R01 DK117657 (to B.N.F.). The Core services of the Diabetes Research Center (P30 DK020579) and the Nutrition Obesity Research Center (P30 DK56341) at the Washington University School of Medicine also supported this work. N.K.H.Y. was supported by a training grant (T32 HL134635-05). K.S.M. was supported by (R00 HL136658). M.G.-A. was supported by Direcci{\'o}n General de Asuntos del Personal Acad{\'e}mico, Programa de Apoyo a Proyectos de Investigaci{\'o}n e Innovaci{\'o}n Tecnol{\'o}gica (PAPIIT) IA208121, UNAM, and UNAM-FQ-PAIP 5000-9171. K.H.H.L. is supported by the Dean's Scholars Program which is in part funded from a grant from the Burroughs Wellcome Fund (1020047). S.C.B. and J.A.F. were supported by R01 DK078184 and a Robert A. Welch Foundation grant I-1804. Some metabolic analyses were supported by NIH grant R35 ES028365 (to G.J.P.). We thank Michael A. Cooper for assistance with animal experiments and Mitchell R. McGill with assistance in ALT assays. M.R.M. M.G.-A. N.K.H.Y. D.F. K.H.H.L. J.Y. G.I.S. K.C. and J.A.F. designed and performed the experiments, interpreted the data, and wrote and edited the manuscript. A.J.L. and K.S.McC. performed data analysis and wrote and edited the manuscript. J.M.S. and M.K.R. performed the experiments, collected the data, and wrote and edited the manuscript. S.K. G.J.P. S.C.B. and B.N.F. designed and performed the experiments, interpreted the data, and wrote and edited the manuscript. The authors declare no competing interests. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = apr,
day = "26",
doi = "10.1016/j.celrep.2022.110733",
language = "English",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
number = "4",
}