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.