Abstract
Transcription is tightly regulated to maintain energy homeostasis during periods of feeding or fasting, but the molecular factors that control these alternating gene programs are incompletely understood. Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched in the fed state and converges genome-wide with PPARa to potently suppress the induction of fasting transcription. Deletion of hepatocyte Bcl6 enhances lipid catabolism and ameliorates highfat- diet-induced steatosis. In Ppara-null mice, hepatocyte Bcl6 ablation restores enhancer activity at PPARa-dependent genes and overcomes defective fasting-induced fatty acid oxidation and lipid accumulation. Together, these findings identify BCL6 as a negative regulator of oxidative metabolism and reveal that alternating recruitment of repressive and activating transcription factors to shared cis-regulatory regions dictates hepatic lipid handling.
| Original language | English (US) |
|---|---|
| Article number | e43922 |
| Journal | eLife |
| Volume | 8 |
| DOIs | |
| State | Published - Apr 2019 |
Funding
We thank Joe Bass, Liming Pei, and Debabrata Chakravarti for helpful advice and discussion. We thank Northwestern University’s Comprehensive Metabolic Core and Mouse Histology and Phenotyping Laboratory (supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center) for services. This work was funded by NIH grants R01DK108987 (GB) and K08HL092298 (GB), American Diabetes Association Award 1–17-IBS-137 (GB), and NIH T32 GM008061 (MS).
ASJC Scopus subject areas
- General Neuroscience
- General Biochemistry, Genetics and Molecular Biology
- General Immunology and Microbiology
