title: Liver-specific PGC-1beta deficiency leads to impaired mitochondrial function and lipogenic response to fasting-refeeding.
abstract: PGC-1β plays pleiotropic roles in regulating intermediary metabolism and has been shown to regulate both catabolic and anabolic processes in liver. We sought to evaluate the effects of PGC-1β on liver energy metabolism by generating mice with postnatal, liver-specific deletion of PGC-1β (LS-PGC-1β(-/-) mice). LS-PGC-1β(-/-) mice were outwardly normal, but exhibited a significant increase in hepatic triglyceride content at 6 weeks of age. Hepatic steatosis was due, at least in part, to impaired capacity for fatty acid oxidation and marked mitochondrial dysfunction. Mitochondrial DNA content and the expression of genes encoding multiple steps in mitochondrial fatty acid oxidation and oxidative phosphorylation pathways were significantly diminished in LS-PGC-1β(-/-) mice. Liquid chromatography mass spectrometry-based analyses also revealed that acetylcarnitine and butyrylcarnitine levels were depleted whereas palmitoylcarnitine content was increased in LS-PGC-1β(-/-) liver, which is consistent with attenuated rates of fatty acid oxidation. Interestingly, loss of PGC-1β also significantly impaired inducible expression of glycolytic and lipogenic enzymes that occurs with high carbohydrate diet refeeding after a prolonged fast. These results suggest that PGC-1β plays dual roles in regulating hepatic fatty acid metabolism by controlling the expression of programs of genes involved in both fatty acid oxidation and de novo fatty acid synthesis.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Kari T
authors.initials: KT
authors.lastname: Chambers
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crawford
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Fu
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D006019:Glycolysis; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides