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Cell Rep. 2016 Jun 28;16(1):9-18. doi: 10.1016/j.celrep.2016.05.086. Epub 2016 Jun 16.

Cholesterol-Independent SREBP-1 Maturation Is Linked to ARF1 Inactivation.

Author information

1
Program in Molecular Medicine, UMASS Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
2
Metabolite Profiling Facility, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
3
Program in Molecular Medicine, UMASS Medical School, 373 Plantation Street, Worcester, MA 01605, USA. Electronic address: amy.walker@umassmed.edu.

Abstract

Lipogenesis requires coordinated expression of genes for fatty acid, phospholipid, and triglyceride synthesis. Transcription factors, such as SREBP-1 (Sterol regulatory element binding protein), may be activated in response to feedback mechanisms linking gene activation to levels of metabolites in the pathways. SREBPs can be regulated in response to membrane cholesterol and we also found that low levels of phosphatidylcholine (a methylated phospholipid) led to SBP-1/SREBP-1 maturation in C. elegans or mammalian models. To identify additional regulatory components, we performed a targeted RNAi screen in C. elegans, finding that both lpin-1/Lipin 1 (which converts phosphatidic acid to diacylglycerol) and arf-1.2/ARF1 (a GTPase regulating Golgi function) were important for low-PC activation of SBP-1/SREBP-1. Mechanistically linking the major hits of our screen, we find that limiting PC synthesis or LPIN1 knockdown in mammalian cells reduces the levels of active GTP-bound ARF1. Thus, changes in distinct lipid ratios may converge on ARF1 to increase SBP-1/SREBP-1 activity.

PMID:
27320911
PMCID:
PMC4934023
DOI:
10.1016/j.celrep.2016.05.086
[Indexed for MEDLINE]
Free PMC Article

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