title: Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice.
abstract: OBJECTIVE
  Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice.
  
  
  METHODS
  We studied mice with disruptions in Nr0b2 (called small heterodimer partner [SHP]-null mice), betaine-homocysteine S-methyltransferase (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 (National Institute on Alcohol Abuse and Alcoholism 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 during a 24-hour light-dark cycle and analyzed by RNA-seq, metabolomic, and quantitative polymerase chain reaction, immunoblot, and chromatin immunoprecipitation assays.
  
  
  RESULTS
  SHP-null mice had altered timing in expression of genes that regulate homocysteine metabolism compared with control mice. Oscillatory production 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 cystathionine γ-lyase by FOXA1. Expression of Bhmt and cystathionine γ-lyase 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-null, mice. 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.
  
  
  CONCLUSIONS
  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 cystathionine γ-lyase by FOXA1.
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.affiliation: Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, North Carolina.
authors.forename: Kerry-Ann
authors.initials: KA
authors.lastname: da Costa
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, University of Perugia, Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, North Carolina.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Orena
authors.affiliation: Translational Sciences, Rutgers University, Piscataway, New Jersey.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology of School of Pharmacy, Rutgers University, Piscataway, New Jersey.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Margitta
authors.initials: M
authors.lastname: Lebofsky
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut.
authors.forename: Swetha
authors.initials: S
authors.lastname: Rudraiah
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Rana
authors.initials: R
authors.lastname: Smalling
authors.affiliation: Department of Pharmacology and Toxicology of School of Pharmacy, Rutgers University, Piscataway, New Jersey.
authors.forename: Grace
authors.initials: G
authors.lastname: Guo
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, University of Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.affiliation: Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, North Carolina.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Zeisel
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut. Electronic address: li.wang@uconn.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002792:Cholestyramine Resin; D019826:Cholic Acid; D002940:Circadian Rhythm; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D000431:Ethanol; D015971:Gene Expression Regulation, Enzymologic; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D006706:Homeostasis; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008099:Liver / Q000378:metabolism*; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation
chemical_list: D001786:Blood Glucose; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D006710:Homocysteine; D002792:Cholestyramine Resin; D000431:Ethanol; D050940:Betaine-Homocysteine S-Methyltransferase; C494549:Bhmt protein, mouse; D003542:Cystathionine gamma-Lyase; D019826:Cholic Acid
keywords: Circadian Regulation; Liver Disease Model; Metabolism; Nuclear Receptor