@article{dbcd7a96eb7d4e9bbc8f3aaedd5599ea,
title = "Defining the mammalian coactivation of hepatic 12-h clock and lipid metabolism",
abstract = "The 12-h clock coordinates lipid homeostasis, energy metabolism, and stress rhythms via the transcriptional regulator XBP1. However, the biochemical and physiological bases for integrated control of the 12-h clock and diverse metabolic pathways remain unclear. Here, we show that steroid receptor coactivator SRC-3 coactivates XBP1 transcription and regulates hepatic 12-h cistrome and gene rhythmicity. Mice lacking SRC-3 show abnormal 12-h rhythms in hepatic transcription, metabolic functions, systemic energetics, and rate-limiting lipid metabolic processes, including triglyceride, phospholipid, and cardiolipin pathways. Notably, 12-h clock coactivation is not only preserved, with its cistromic activation priming ahead of the zeitgeber cue of light, but concomitant with rhythmic remodeling in the absence of food. These findings reveal that SRC-3 integrates the mammalian 12-h clock, energy metabolism, and membrane and lipid homeostasis and demonstrates a role for the 12-h clock machinery as an active transcriptional mechanism in anticipating physiological and metabolic energy needs and stresses.",
keywords = "12-h clock, 12-h gene oscillations, SRC-3, XBP1, XBP1s, cardiolipin, cistromic reprogramming, energy metabolism, fasting regimen, lipid homeostasis, lipid metabolism, metabolic diseases, metabolic stresses, phospholipid, rhythmic remodeling, steroid receptor coactivator, stress rhythms, transcriptional coactivation, transcriptional coregulator, triglyceride, Lipids, Liver/metabolism, Energy Metabolism/genetics, Lipid Metabolism, Mammals, Animals, Mice",
author = "Huan Meng and Gonzales, {Naomi M.} and Jung, {Sung Yun} and Yue Lu and Nagireddy Putluri and Bokai Zhu and Dacso, {Clifford C.} and Lonard, {David M.} and O'Malley, {Bert W.}",
note = "Funding Information: The human pan-cancer prognostic results here are based upon data obtained from the TCGA Research Network: https://www.cancer.gov/tcga . We thank Vasanta Putluri in the Metabolomics Core at Baylor College of Medicine (BCM) supported by the CPRIT Core Facility Support Award RP170005 and RP210227 , NCI Cancer Center Support Grant P30CA125123 , NIH /NCI R01CA220297 , and R01CA216426 , and the Helis Foundation . We thank P.K. Saha and the MMPC core at BCM supported by NIH funds R01DK114356 and UM1HG006348 . We thank the ADA award 1-18-JDF-025 , NIGMS DP2GM140924 , and NIDDK P30DK120531 to B.Z. We also thank the Science Park NGS Core at the MD Anderson Cancer Center, supported by CPRIT Core Facility Support Grant RP170002 . This research work was supported by grants from the National Institutes of Health 1P01DK113954 and NICHD 5R01HD007857 and 5R01HD08188 to B.W.O. and Pilot Project Program under Award Number P30ES030285 to B.W.O. and H.M. Funding Information: The human pan-cancer prognostic results here are based upon data obtained from the TCGA Research Network: https://www.cancer.gov/tcga. We thank Vasanta Putluri in the Metabolomics Core at Baylor College of Medicine (BCM) supported by the CPRIT Core Facility Support Award RP170005 and RP210227, NCI Cancer Center Support Grant P30CA125123, NIH/NCI R01CA220297, and R01CA216426, and the Helis Foundation. We thank P.K. Saha and the MMPC core at BCM supported by NIH funds R01DK114356 and UM1HG006348. We thank the ADA award 1-18-JDF-025, NIGMS DP2GM140924, and NIDDK P30DK120531 to B.Z. We also thank the Science Park NGS Core at the MD Anderson Cancer Center, supported by CPRIT Core Facility Support Grant RP170002. This research work was supported by grants from the National Institutes of Health 1P01DK113954 and NICHD 5R01HD007857 and 5R01HD08188 to B.W.O. and Pilot Project Program under Award Number P30ES030285 to B.W.O. and H.M. B.W.O. and H.M. supervised the project. B.W.O. H.M. and B.Z. conceptualized the research. H.M. designed, performed, and analyzed most of the experiments, with N.M.G.?s and B.Z.?s technical assistance. H.M. conducted the NGS bioinformatics, lipidomics analysis, and rhythmic mathematic modeling. The mouse liver lipidomics was conducted by N.P. at the Metabolomics Core at BCM. The protein mass spectrometry analysis was conducted by S.Y.J. at BCM. The NGS sequencing was conducted by Y.L. at the Science Park NGS Core at the MD Anderson Cancer Center. B.W.O. C.C.D. and D.M.L. provided resource and editing during the manuscript preparation. H.M. wrote the paper. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = mar,
day = "8",
doi = "10.1016/j.celrep.2022.110491",
language = "English (US)",
volume = "38",
pages = "110491",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}