Interactions Between Nuclear receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice, Gastroenterology. 2015 Feb 18, Tsuchiya H1, Costa KA2, Lee S3, Renga B4, Jaeschke H5, Yang Z6, Orena SJ2, Goedken MJ7, Zhang Y5, Bo K8, Lebofsky M5, Rudraiah S3, Smalling R1, Guo G8, Fiorucci S4, Zeisel SH2, Wang L9.
- Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132.
- 2Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Kannapolis, NC 28081.
- 3Department of Physiology and Neurobiology, and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269.
- 4Dipartimento di Scienze Chirurgiche e Biomediche Piazza L. Severi 1, University of Perugia, Perugia 06100, Italy.
- 5Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160.
- 6Department of Physiology and Neurobiology, and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269; Department of Pharmacology and Toxicology of School of Pharmacy, Rutgers University, Piscataway, NJ 08854.
- 7Translational Sciences, Rutgers University, Piscataway, NJ 08854.
- 8Department of Pharmacology and Toxicology of School of Pharmacy, Rutgers University, Piscataway, NJ 08854.
- 9Department of Physiology and Neurobiology, and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269; Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516; Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06520. Electronic address: email@example.com.
BACKGROUND & AIMS:
Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediateoscillatory control of homocysteine homeostasis in mice.
We studied mice with disruptions in Nr0b2 (called SHP-null mice) Bhmt, or both genes (BHMT-null/SHP-null mice), along with mice with wild-type copies of these genes (controls). Hyperhomocysteinemia was induced by feeding mice alcohol (the NIAAA binge model) or chow diets along with water containing 0.18% DL-homocysteine. Some mice were placed on diets containing cholic acid (1%) or cholestyramine (2%), or high-fat diets (60%). Serum and livers were collected over a 24 hr light-dark cycle and analyzed by RNA-seq, metabolomic, and quantitative PCR, immunoblot, and chromatin immunoprecipitation assays.
SHP-null mice had altered timing in expression of genes that regulate homocysteine metabolism, compared with control mice. Oscillatoryproduction of S-adenosylmethionine, betaine, choline, phosphocholine, glyceophosphocholine, cystathionine, cysteine, hydrogen sulfide, glutathione disulfide, and glutathione, differed between SHP-null mice and control mice. SHP inhibited transcriptional activation of Bhmt and Cth by FOXA1. Expression of Bhmt and Cth was decreased when mice were fed cholic acid but increased when they were placed on diets containing cholestyramine or high-fat content. Diets containing ethanol or homocysteine induced hyperhomocysteinemia and glucose intolerance in control but not SHP-nullmice. In BHMT-null and BHMT-null/SHP-null mice fed a control liquid, lipid vacuoles were observed in livers. Ethanol feeding induced accumulation of macrovesicular lipid vacuoles to the greatest extent in BHMT-null and BHMT-null/SHP-null mice.
Disruption of Shp in mice alters timing of expression of genes that regulate homocysteine metabolism and the liver responses to ethanol and homocysteine. SHP inhibits the transcriptional activation of Bhmt and Cth by FOXA1.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Nuclear receptor; circadian regulation; liver disease model; metabolism
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