A Conserved SREBP-1/Phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans

Abstract

Summary Sterol Regulatory Element-Binding Proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids, and therefore are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can result in excess stored fat and contribute to obesity, fatty liver disease and insulin resistance, hallmarks of metabolic syndrome. Our studies identify a conserved regulatory circuit in which SREBP-1 controls production of the methyl donor S-adenosylmethionine (SAMe). Methylation is critical for synthesis of phosphatidylcholine (PC), a major membrane component, and we find that blocking SAMe or PC synthesis in C. elegans, mouse liver and human cells causes elevated SREBP-1-dependent transcription and lipid droplet accumulation. Distinct from negative regulation of SREBP-2 by cholesterol, our data suggest a mechanism where maturation of nuclear, transcriptionally active SREBP-1 is controlled by levels of PC. Thus, nutritional or genetic conditions limiting SAMe or PC production may activate SREBP-1, contributing to human metabolic disorders.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

“…Knockdown of PCYT1A expression in Caenorhabditis elegans and in human hepatocytes was shown to reduce PC levels, activate SREBP1c, and increase de novo lipogenesis and LD/triacylglycerol accumulation (17). These findings are consistent with the presence of steatosis in liver-specific Pcyt1a knockout mice (18) and in our patients.…”

“…insight was recently provided by Walker et al (17) in a series of experiments suggesting that PC levels act as a rheostat for the activation of SREBP1c, a transcription factor known to induce expression of all of the key enzymes involved in fatty acid synthesis. Knockdown of PCYT1A expression in Caenorhabditis elegans and in human hepatocytes was shown to reduce PC levels, activate SREBP1c, and increase de novo lipogenesis and LD/triacylglycerol accumulation (17).…”

Liver and plasma lipid changes induced by cyclic fatty acid monomers from heated vegetable oil in the rat

“…Because the increases of both hepatic CFAM and TAG were closely associated with hepatic PC, it was plausible that the levels of increased TAG by CFAM in our experimental conditions were partly dictated by decreased PC concentrations. Decreased PC levels can trigger the relocation of SREBP‐activating proteases resulting in the activation of SREBP‐1 and transition to the nucleus, and the upregulation of lipogenesis (Walker et al., 2011). However, in the present study, no significant effect of CFAM was noted on hepatic PEMT activity and CT‐α protein, suggesting that the decrease in liver PC levels observed in the present study was independent of PC biosynthesis pathways.…”

The membrane anchor of the transcriptional activator SREBP is characterized by intrinsic conformational flexibility

“…Certainly, as derived from the different tilt angles in MD simulations of different membrane thickness, the flexure of the S2P substrate and all derived consequences will be directly influenced by the characteristics of the lipid membrane. Work by Walker et al concluded from cell biological studies on Caenorhabditis elegans previously that membrane composition and curvature play a significant role for SREBP-1 cleavage in vivo, which could be related to the SREBP flexing (10).…”

“…Site-1 protease (S1P) and S2P, located in the Golgi, in turn exert release of the active transcription factor (2). SREBP-1, which is linked to regulation of fatty acid, phospholipid, and triacylglycerol synthesis, can be activated by retrograde transport of the respective proteases from the Golgi into the ER (10). Cleavage of the SREBP precursor molecule arises in two steps.…”