title: Nuclear lactate dehydrogenase modulates histone modification in human hepatocytes.
abstract: It is becoming increasingly apparent that the nucleus harbors metabolic enzymes that affect genetic transforming events. Here, we describe a nuclear isoform of lactate dehydrogenase (nLDH) and its ability to orchestrate histone deacetylation by controlling the availability of nicotinamide adenine dinucleotide (NAD(+)), a key ingredient of the sirtuin-1 (SIRT1) deacetylase system. There was an increase in the expression of nLDH concomitant with the presence of hydrogen peroxide (H2O2) in the culture medium. Under oxidative stress, the NAD(+) generated by nLDH resulted in the enhanced deacetylation of histones compared to the control hepatocytes despite no discernable change in the levels of SIRT1. There appeared to be an intimate association between nLDH and SIRT1 as these two enzymes co-immunoprecipitated. The ability of nLDH to regulate epigenetic modifications by manipulating NAD(+) reveals an intricate link between metabolism and the processing of genetic information.
authors.affiliation: Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Castonguay
authors.affiliation: Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Auger
authors.affiliation: Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Thomas
authors.affiliation: Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada.
authors.forename: M'hamed
authors.initials: M
authors.lastname: Chahma
authors.affiliation: Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada. Electronic address: vappanna@laurentian.ca.
authors.forename: Vasu D
authors.initials: VD
authors.lastname: Appanna
mesh_terms: D000107:Acetylation; D002467:Cell Nucleus / Q000378:metabolism; D044127:Epigenesis, Genetic; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D009243:NAD; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Epigenetics; Lactate dehydrogenase; Metabolism; Oxidative stress; Sirtuin