Transcriptional Control of Oscillatory Homocysteine Homeostasis by Nuclear Receptor SHP

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[Purpose]Hyperhomocysteinemia (HHcy) is often associated with metabolic diseases. This study aims at identifying transcriptional control of oscillatory homocysteine homeostasis.[Methods]Wild‐type (WT), Shp‐/‐, Bhmt‐/‐, and Bhmt‐/‐Shp‐/‐mice were used. HHcy was induced by alcohol‐ binge or chow diet supplied with drinking water containing 0.18% of DL‐Hcy. Serum and livers were collected over a 24h light/dark cycle. Assays: RNA‐seq, metabolomics (LC/MS, GC/MS), qPCR, adenovirus transduction, transfection, luciferase reporter assay, ChIP assay, Co‐IP, Western blots, and enzymatic assays.[Results]Loss of small heterodimer partner (SHP) induced a robust expression of betaine‐homocysteine S‐methyltransferase (Bhmt) and cystathionine γ‐lyase (Cth), and caused rhythmic alterations of other genes in the Hcy metabolic pathway. The induction of Bhmt and Cthwas blocked by Shp reexpression in Shp‐/‐liver. Consequently, the oscillatory productions of betaine, choline, cystathionine, cysteine, SAH and SAM, GSSG and GSH, were modulated by Shp‐deficiency or Shp‐reexpression. Forkhead box A1 (FoxA1) activated Bhmt and Cth promoter activities and expression, which was inhibited by Shp. Ethanol‐binge or homocysteine induced HHcy, glucose intolerance and ER stress response in WT mice, which was diminished in Shp‐/‐mice. However, ethanol‐binge triggered macrovesicular fatty changes in Bhmt‐/‐ and Bhmt‐/‐/Shp‐/‐ mice, but not in Shp‐/‐ mice.ConclusionsThe study sheds light on a new regulatory module to control one‐carbon metabolism in the liver, which may have significant clinical implications.[Grant support]NIH DK080440, AHA 13GRNT14700043, VA Merit Award 1I01BX002634.