Cholesterol-Independent SREBP-1 Maturation Is Linked to ARF1 Inactivation.
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.
Program in Molecular Medicine, UMASS Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Lorissa J
LJ
Smulan
Program in Molecular Medicine, UMASS Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Wei
W
Ding
Metabolite Profiling Facility, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Elizaveta
E
Freinkman
Program in Molecular Medicine, UMASS Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Sharvari
S
Gujja
Program in Molecular Medicine, UMASS Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Yvonne J K
YJK
Edwards
Program in Molecular Medicine, UMASS Medical School, 373 Plantation Street, Worcester, MA 01605, USA. Electronic address: amy.walker@umassmed.edu.
Amy K
AK
Walker
D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D004075:Diglycerides; D010712:Phosphatidic Acids; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; C513283:SBP-1 protein, C elegans; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D002784:Cholesterol; C000607011:ARF-1.2 protein, C elegans; D020558:GTP Phosphohydrolases; D020823:ADP-Ribosylation Factor 1