title: CCAAT/enhancer binding protein β deletion increases mitochondrial function and protects mice from LXR-induced hepatic steatosis.
abstract: Drugs designed specifically to activate liver X receptors (LXRs) have beneficial effects on lowering cholesterol metabolism and inflammation but unfortunately lead to severe hepatic steatosis. The transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is an important regulator of liver gene expression but little is known about its involvement in LXR-based steatosis and cholesterol metabolism. The present study investigated the role of C/EBPβ expression in LXR agonist (T0901317)-mediated alteration of hepatic triglyceride (TG) and lipogenesis in mice. C/EBPβ deletion in mice prevented LXR agonist-mediated induction of lipogenic gene expression in liver in conjunction with significant reduction of liver TG accumulation. Surprisingly, C/EBPβ(-/-) mice showed a major increase in liver mitochondrial electron chain function compared to WT mice. Furthermore, LXR activation in C/EBPβ(-/-) mice increased the expression of liver ATP-binding cassette transporter ABCG1, a gene implicated in cholesterol efflux and reducing blood levels of total and LDL-cholesterol. Together, these findings establish a central role for C/EBPβ in the LXR-mediated steatosis and mitochondrial function, without impairing the influence of LXR activation on lowering LDL and increasing HDL-cholesterol. Inactivation of C/EBPβ might therefore be an important therapeutic strategy to prevent LXR activation-mediated adverse effects on liver TG metabolism without disrupting its beneficial effects on cholesterol metabolism.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA. rmizanoor@hotmail.com
authors.forename: Shaikh M
authors.initials: SM
authors.lastname: Rahman
authors.forename: Mahua
authors.initials: M
authors.lastname: Choudhury
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Janssen
authors.forename: Karalee C
authors.initials: KC
authors.lastname: Baquero
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics*; D008076:Cholesterol, HDL / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000235:genetics*; D017353:Gene Deletion; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000009:adverse effects*; D050155:Lipogenesis / Q000187:drug effects; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008930:Mitochondria, Liver / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D014280:Triglycerides / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000924:Anticholesteremic Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; D008076:Cholesterol, HDL; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; D014280:Triglycerides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides