title: Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c.
abstract: Two treatments, fasting/refeeding and administration of liver X receptor (LXR) agonists, elevate the mRNA for sterol regulatory element-binding protein-1c (SREBP-1c) and enhance lipid synthesis in liver. These treatments do not affect the mRNA for SREBP-1a, an alternative transcript from the same gene. Through homologous recombination, we eliminated the exon encoding SREBP-1c from the mouse genome, leaving the SREBP-1a transcript intact. On a normal diet, livers of SREBP-1c(-/-) mice manifested reductions in multiple mRNAs encoding enzymes of fatty acid and triglyceride synthesis, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In contrast, SREBP-1c(-/-) livers showed a compensatory increase in hepatic SREBP-2 mRNA, accompanied by increased mRNA levels for cholesterol biosynthetic enzymes. In fasted/refed animals, ACC and FAS mRNAs rose, but not to the same extent as in wild-type livers. The refeeding-induced increase in SREBP-1c(-/-) mice was greater than in mice lacking SREBP cleavage-activating protein (SCAP), in which all nuclear SREBPs are absent. Thus, SREBP-2 and/or SREBP-1a can substitute partially for SREBP-1c in permitting an insulin-mediated increase in ACC and FAS mRNAs. In contrast, mRNAs for several other lipogenic enzymes (glucose-6-phosphate dehydrogenase, malic enzyme, glycerol-3-phosphate acyltransferase, and stearoyl-CoA desaturase-1) showed a complete failure of the normal inductive response to refeeding, indicating specific reliance on SREBP-1c. Moreover, these mRNAs, as well as multiple other lipogenic mRNAs, showed a markedly blunted response to the LXR agonist T090137, indicating an essential role of SREBP-1c in the LXR response.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liang
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Goldstein
authors.forename: Michael S
authors.initials: MS
authors.lastname: Brown
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D017667:Adipocytes / Q000502:physiology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005215:Fasting; D064429:Fatty Acid Synthases / Q000235:genetics; D006845:Hydrocarbons, Fluorinated; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013449:Sulfonamides; D014157:Transcription Factors / Q000502:physiology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000103:Acetyl-CoA Carboxylase; D000924:Anticholesteremic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D064429:Fatty Acid Synthases; D006845:Hydrocarbons, Fluorinated; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D000071518:Liver X Receptors; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013449:Sulfonamides; D014157:Transcription Factors; C102196:SREBP cleavage-activating protein; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides