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.
Highlights
Transcriptional coactivators are a class of proteins that regulate gene transcription by interacting with DNA-bound transcription factors
Hematoxylin and eosin staining of livers revealed increased numbers of very small lipid droplets in the livers of LS-PGC-1b2/2 mice compared to WT littermate control mice (Figure 1E)
The data presented are consistent with dual roles for PGC-1b in regulating intermediary fat metabolism and suggest that PGC-1b controls hepatic mitochondrial biogenesis and oxidative function as well as the capacity for lipogenesis under conditions of high lipogenic flux
Summary
Transcriptional coactivators are a class of proteins that regulate gene transcription by interacting with DNA-bound transcription factors. Three distinct lines of mice with constitutive knockout of PGC1b [9,10,12] and a fourth mouse line harboring a hypomorphic PGC-1b allele [11] have been generated and characterized Two of these models, including the PGC-1b hypomorph, were reported to exhibit hepatic steatosis and evidence for diminished mitochondrial oxidative metabolism [10,11]. The present data support dual roles for PGC-1b in regulating hepatic fatty acid homeostasis, since loss of PGC-1b blunted the increase in lipogenesis that occurs during refeeding after a prolonged fast. These findings demonstrate that PGC-1b is a critical regulator of these pathways in liver
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