Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1864, Issue 9, Pages 2881-2889Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2018.05.022
Keywords
Transcriptional regulation; Brg1; SREBP; Epigenetics; Hepatocyte; Steatosis
Funding
- Natural Science Foundation of China [81725001]
- 2016333 Project Award of Jiangsu Province
- 2013 Qinglan Project of the Young and Middle-Aged Academic Leader of Jiangsu College and University
- Major Fundamental Research Program of the Natural Science Foundation of the Jiangsu Higher Education Institutions of China [13KJA180001]
- Cultivate National Science Fund for Distinguished Young Scholars of Jiangsu Normal University
- Priority Academic Program Developmentof Jiangsu Higher Education Institutions (PAPD)
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Alteration of hepatic lipid metabolism contributes to a range of human diseases including steatosis. Sterol response element binding protein (SREBP) is the master regulator of lipid metabolism. The epigenetic mechanism whereby SREBP activity is regulated remains incompletely understood. We have previously shown that systemic knockdown of brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuates steatosis in mice by down-regulating the synthesis of pro-inflammatory mediators. Here we show that hepatocyte conditional Brg1 knockout (HepcKO) mice were largely protected from high-fat diet (HFD) induced steatosis as evidenced by decelerated weight gains, improved insulin sensitivity, ameliorated steatotic injuries, and diminished hepatic inflammation. Brg1 contributed to lipid metabolism by trans-activating the genes involved in fatty acid esterification. Mechanistically, Brg1 interacted with and was recruited by sterol response element binding protein (SREBP1c) to the promoters of SREBP target genes and optimized the chromatin structure to facilitate SREBP1c binding. Therefore, our data have identified a previously unrecognized role for Brg1 in hepatic lipid metabolism by portraying Brg1 as an essential epigenetic co-factor for SREBP1c.
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