title: Disruption of tumor suppressor gene Hint1 leads to remodeling of the lipid metabolic phenotype of mouse liver.
abstract: A lipidomic and metabolomic investigation of serum and liver from mice was performed to gain insight into the tumor suppressor gene Hint1. A major reprogramming of lipid homeostasis was found in both serum and liver of Hint1-null (Hint(-/-)) mice, with significant changes in the levels of many lipid molecules, as compared with gender-, age-, and strain-matched WT mice. In the Hint1(-/-) mice, serum total and esterified cholesterol were reduced 2.5-fold, and lysophosphatidylcholines (LPCs) and lysophosphatidic acids were 10-fold elevated in serum, with a corresponding fall in phosphatidylcholines (PCs). In the liver, MUFAs and PUFAs, including arachidonic acid (AA) and its metabolic precursors, were also raised, as was mRNA encoding enzymes involved in AA de novo synthesis. There was also a significant 50% increase in hepatic macrophages in the Hint1(-/-) mice. Several hepatic ceramides and acylcarnitines were decreased in the livers of Hint1(-/-) mice. The changes in serum LPCs and PCs were neither related to hepatic phospholipase A2 activity nor to mRNAs encoding lysophosphatidylcholine acetyltransferases 1-4. The lipidomic phenotype of the Hint1(-/-) mouse revealed decreased inflammatory eicosanoids with elevated proliferative mediators that, combined with decreased ceramide apoptosis signaling molecules, may contribute to the tumor suppressor activity of Hint1.
authors.affiliation: Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Diren
authors.initials: D
authors.lastname: Beyoğlu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Juliette
authors.initials: J
authors.lastname: Martin
authors.affiliation: Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Maurhofer
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Dorow
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Ceglarek
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
mesh_terms: D000818:Animals; D055786:Gene Knockout Techniques; D016147:Genes, Tumor Suppressor; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D010641:Phenotype
chemical_list: C489275:Hint1 protein, mouse; D008055:Lipids; D009419:Nerve Tissue Proteins
keywords: apoptosis; carcinogenesis; cholesterol; eicosanoids; lipidomics; mass spectrometry; metabolomics; phospholipids; proliferation