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

Abstract

Summary 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 (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 levels of active GTP-bound ARF1. Thus, changes in distinct lipid ratios may converge on ARF1 to increase SBP-1/SREBP-1 activity.

Emerging Roles for the Lysosome in Lipid Metabolism

“…Conversely, when cholesterol levels drop, SCAP undergoes a conformational change that causes its dissociation from Insig and allows SREBP to be loaded onto COPII vesicles (Radhakrishnan et al, 2008). In addition to cholesterol, SREBP1 integrates information about other lipid species, such as phosphatidylcholine (PC), to fine-tune cellular lipid balance (Smulan et al, 2016, Walker et al, 2011). …”

1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver

“…While it was difficult to directly target PC to identify mechanistic links, proteins whose activity could be changed by membrane properties or PC availability could be analyzed. An RNAi screen in C. elegans identified factors that were necessary and sufficient for low-PC activation of SBP-1/SREBP-1 and determined which of these candidates was also relevant to low-PC processing in mammals [50]. Interestingly, it was found that depletion of lpin-1 /LPIN1 and arf-1.2 /ARF1 was sufficient to activate SBP-1 in C. elegans or SREBP-1 in mammalian liver-derived cells.…”

Roles of silent information regulator 1–serine/arginine-rich splicing factor 10–lipin 1 axis in the pathogenesis of alcohol fatty liver disease

“…1,39 In hepatocytes, ethanol may interdict lipin1 nuclear entry and upregulate SREBP-1 activity via triggering mammalian target of rapamycin complex 1-phosphorylated lipin1 signaling. 1,36,40 Moreover, lipin-1-PAP activity plays important role on SREBP-1 activation and the exacerbation of hepatic lipid accumulation. 1,8 Paradoxically, chronic ethanol consumption to lipin1 LKO mice, which can abrogate the elevation of ethanol-induced intrahepatic PAP activity, has showed a significantly augmented lipid accumulation in liver, suggesting that lipin1 PAP activity might prevent from AFLD.…”

“…Lipin1a and lipin1b both participate in lipid synthesis by regulating SREBP-1 signaling and mitochondrial medium-chain acyl-CoA dehydrogenase, acyl-CoA synthetase, acyl-CoA oxidase, carnitine palmitoyl transferase I, and fatty acid binding protein. 38 Furthermore, lipin1a restrains SREBP-1 expression and activity, resulting in weakened hepatic lipogenesis by downregulating lipid and cholesterol biosynthetic enzymes expression, 1,35,36 including FAS, mitochondrial glycerol-3-phosphate acyltransferase1, ACC, stearoyl-CoA desaturase, ATP citrate lyase, and malic enzyme. 1,39 In hepatocytes, ethanol may interdict lipin1 nuclear entry and upregulate SREBP-1 activity via triggering mammalian target of rapamycin complex 1-phosphorylated lipin1 signaling.…”

“…1,8 For another, lipin1 serves as a transcriptional co-activator associating with PGC-1a, PPARa, or SREBP-1 to regulate the lipid metabolism. 8,35,36 LPIN1 gene can encode three diverse isoforms, namely lipin-1 a, b, and g, by alternative splicing of pre-mRNA in human. 1,37 Lipin-1a and lipin-1b have been found principally settling in liver and skeletal muscle, while lipin-1g primarily in brain tissue regulating lipid metabolism.…”