Journal
JOURNAL OF LIPID RESEARCH
Volume 62, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jlr.2021.100051
Keywords
oxysterol; SREBP1c; liver-X-Receptor; de-novo-lipogenesis; lipid droplets; insulin
Categories
Funding
- National Institutes of Health [R01GM127763, R01GM130995, R01 HL067773]
- National Niemann-Pick foundation postdoctoral fellowship
- Taylor Family Institute for Innovative Psychiatric Research
- UCSF Liver Center [P30 DK026743]
Ask authors/readers for more resources
4β-hydroxycholesterol (4β-HC) is a potent and selective inducer of the master lipogenic transcription factor SREBP1c, acting as an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.
Oxysterols are oxidized derivatives of cholesterol that play regulatory roles in lipid biosynthesis and homeostasis. How oxysterol signaling coordinates different lipid classes such as sterols and triglycerides remains incompletely understood. Here, we show that 4 beta-hydroxycholesterol (HC) (4 beta-HC), a liver and serum abundant oxysterol of poorly defined functions, is a potent and selective inducer of the master lipogenic transcription factor, SREBP1c, but not the related steroidogenic transcription factor SREBP2. By correlating tracing of lipid synthesis with lipogenic gene expression profiling, we found that 4 beta-HC acts as a putative agonist for the liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of the LXR, 4 beta-HC induced expression of the lipogenic program downstream of SREBP1c and triggered de novo lipogenesis both in primary hepatocytes and in the mouse liver. In addition, 4 beta-HC acted in parallel to insulin-PI3K-dependent signaling to stimulate triglyceride synthesis and lipid-droplet accumulation. Thus, 4 beta-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available