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Principal pathways for membrane lipid synthesis. Acronyms in italics indicate genes encoding reaction-catalyzing enzymes. (a) Membrane lipid synthesis in mammals. Genes regulated by SREBP transcription factors are shown in red. (b) Membrane lipid synthesis in yeast. Known and putative target genes of Ino2p/Ino4p transcription factors are shown in red. In these simplified schematics several lipogenic pathways have been omitted for clarity, including the nonsterol branch of the mevalonate pathway, steps for ether phospholipid synthesis, and phospholipid turnover and remodeling (Lands cycle). CoA, coenzyme A; HMG, 3-hydroxy-3methylglutaryl; PA, phosphatidic acid; DAG, diacylglycerol; CDP-DAG, cytidine diphosphate-diacylglycerol; PI, phosphatidylinositol; PIP, PI phosphate; PG, phosphatidylglycerol; CL, cardiolipin; PE, phosphatidylethanolamine; PS, phosphatidylserine; PC, phosphatidylcholine; Glu-6-P, glucose-6-phosphate; Ins-3-P, inositol-3-phosphate; Ins, inositol; Etn, ethanolamine; P-Etn, phosphoethanolamine; CDP-Etn, cytidine diphosphate ethanolamine; Cho, choline; P-Cho, phosphocholine; CDP-Cho, cytidine diphosphate choline; α-HPC, α-hydroxyphytoceramide; IPC, inositol-phosphoceramide; MIPC, mannose-inositol-phosphoceramide; M(IP) 2 C, mannose-(inositol phosphate) 2-ceramide. Links to detailed gene information are available at http://www.ncbi.nlm.nih.gov/ gene and http://www.yeastgenome.org.
Source publication
Bilayer synthesis during membrane biogenesis involves the concerted assembly of multiple lipid species, requiring coordination of the level of lipid synthesis, uptake, turnover, and subcellular distribution. In this review, we discuss some of the salient conclusions regarding the coordination of lipid synthesis that have emerged from work in mammal...
Contexts in source publication
Context 1
... major routes for the de novo synthe- sis of membrane lipids in mammals and yeast are schematically outlined in Figure 1. Bulk carbon enters these pathways as acetyl CoA, whose utilization is split for the synthesis of cholesterol/ergosterol (mevalonate pathway), and fatty acids via acetoacetyl CoA and malonyl CoA, respectively. ...
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... carbon enters these pathways as acetyl CoA, whose utilization is split for the synthesis of cholesterol/ergosterol (mevalonate pathway), and fatty acids via acetoacetyl CoA and malonyl CoA, respectively. An important branch point intermediate in the mevalonate pathway is far- nesylpyrophosphate (not shown in Figure 1), which can be converted either to a number of nonsterol isoprenoids or via squalene to choles- terol (ergosterol in yeast). ...
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... genes in question, FDFT1 and CYP51A1, encode the enzymes farnesyldiphosphate farnesyl Model for cooperative cholesterol regulation by SREBP and LXR. transferase 1 (squalene synthase) and lanosterol 14α-demethylase (Figure 1). LXRα was found to block expression by binding directly to target sequences in the FDFT1 and CYP51A1 promoters. ...
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... synthesis of glycerophospholipids in S. cerevisiae is coordinated by a transcrip- tion factor consisting of the proteins Ino2p and Ino4p. Ino2p and Ino4p bind directly to a conserved upstream activating sequence (UAS Ino ) found in the promoters of multi- ple genes involved in the synthesis of fatty acids and glycerophospholipids (Figure 1b) (Carman & Henry 2007). Ino2p and Ino4p form heterodimers via basic helix-loop-helix motifs present in both proteins ( Dietz et al. 2003, Schwank et al. 1995). ...
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... critical control point for mammalian bulk phospholipid regulation is the synthesis of PC. PC is the most abundant phospholipid and serves as a precursor for sphingomyelin, gen- erally the major sphingolipid, as well as PS and PE (Vance 2002) (Figure 1). PC can be formed through the methylation of PE but, in most mammalian tissues, it is produced in a branch of the Kennedy pathway through the reaction of diacylglycerol and CDP-choline. ...
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... the broadest level of membrane lipid metabolism, cells must coordinate the levels of cholesterol and phospholipids (Figure 1). During phagocytosis-induced membrane bio- genesis, for example, the ratio of cholesterol to phospholipids remains fairly constant over time (Werb & Cohn 1972), suggesting that metabolic flux into different lipid species is syn- chronized throughout the synthetic process. ...
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... an alternative to the Kennedy path- way, PE is also generated through decarboxy- lation of PS, and PE can then be methylated to form PC (Figure 1b). In mammalian cells, PC is mainly produced through the Kennedy pathway, because most tissues lack the PE N- methyltransferase activity required for the syn- thesis of PC from PE ( Li & Vance 2008). ...
Citations
... Additionally, cholesterol, a vital component of mammalian cell membranes, plays a crucial role in cell growth. In the context of the eye lens, cholesterol, a major constituent of the cell plasma membrane, ensures membrane fluidity, orderliness, and lens transparency [54]. As one of the major components of the eye lens's cell plasma membrane, cholesterol ensures the fluidity and orderliness of eye lens's cell plasma membrane and maintains the transparency of the lens [55]. ...
Age-related cataract (ARC) is the predominant cause of global blindness, linked to the progressive aging of the lens, oxidative stress, perturbed calcium homeostasis, hydration irregularities, and modifications in crystallin proteins. Currently, surgical intervention remains the sole efficacious remedy, albeit carrying inherent risks of complications that may culminate in irreversible blindness. It is urgent to explore alternative, cost-effective, and uncomplicated treatment modalities for cataracts. Lanosterol has been widely reported to reverse cataracts, but the mechanism of action is not yet clear. In this study, we elucidated the mechanism through which lanosterol operates in the context of cataract reversal. Through the targeted suppression of sterol regulatory element-binding protein 2 (SREBP2) followed by lanosterol treatment, we observed the restoration of lipid metabolism disorders induced by SREBP2 knockdown in lens epithelial cells (LECs). Notably, lanosterol exhibited the ability to effectively counteract amyloid accumulation and cellular apoptosis triggered by lipid metabolism disorders. In summary, our findings suggest that lanosterol, a pivotal intermediate in lipid metabolism, may exert its therapeutic effects on cataracts by influencing lipid metabolism. This study shed light on the treatment and pharmaceutical development targeting Age-related Cataracts (ARC).
... The family of SREBPs includes SREBP1 and SREBP2, both of which bind to steroid regulatory elements (SREs) but prefer different promoters and have tissue-specific expression. SREBP1 primarily regulates genes associated with FA synthesis and is primarily expressed in the liver, while SREBP2 is primarily involved in cholesterol biosynthesis pathways 33,34 . In addition, Thomas et al. previously demonstrated that mTOR1 is required for SREBP1 activation (mSREBP1) and that rapamycin inhibits the mTOR-Akt-induced nuclear accumulation of mSREBP1 35 . ...
Abnormal lipid metabolism promotes hepatocellular carcinoma (HCC) progression, which engenders therapeutic difficulties owing to unclear mechanisms of the phenomenon. We precisely described a special steatotic HCC subtype with HBV-related cirrhosis and probed its drivers. Hematoxylin-eosin (HE) staining of 245 HCC samples revealed a special HCC subtype (41 cases) characterized by HBV-related cirrhosis and intratumoral steatosis without fatty liver background, defined as steatotic HCC with HBV-related cirrhosis (SBC-HCC). SBC-HCC exhibits a larger tumor volume and worse prognosis than non-SBC-HCC. Screening for driver genes promoting fatty acid (FA) biosynthesis in the Gao’s HBV-related cirrhosis HCC cases and GSE121248’ HBV-related HCC cases revealed that high expression of SOCS5 predicts increased FA synthesis and that SOCS5 is upregulated in SBC-HCC. Through proteomics, metabolomics, and both in vivo and in vitro experiments, we demonstrated that SOCS5 induces lipid accumulation to promote HCC metastasis. Mechanistically, through co-IP and GST-pulldown experiments, we found that the SOCS5-SH2 domain, especially the amino acids Y413 and D443, act as critical binding sites for the RBMX-RRM domain. SOCS5-RBMX costimulates the promoter of SREBP1, inducing de novo lipogenesis, while mutations in the SH2 domain, Y413, and D443 reverse this effect. These findings precisely identified SBC-HCC as a special steatotic HCC subtype and highlighted a new mechanism by which SOCS5 promotes SBC-HCC metastasis.
... Cells need adequate lipids to produce membranes in order to maintain their viability and growth. [1][2][3][4][5][6] Cholesterol acts as an essential structural component of membrane lipids, playing a critical role in the regulation of membrane integrity and function. 5 Cholesterol in the plasma membrane corresponds to ~70% of the total cellular cholesterol levels and accounts appreciable difference in free cholesterol levels between tumor and healthy tissues, but there was a marked prevalence of LDs and CE levels in the GBM tumor tissues but not in the healthy tissue ( Figure 1A, middle and bottom panels). ...
Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant presence of cholesteryl esters (CEs) in its lipid droplets (LDs). Mechanistically, SREBP-1 (sterol regulatory element-binding protein 1), a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A, and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked, GBM cells become quite sensitive to cholesterol deficiency with poor growth in vitro. Our study unravels an SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis while providing a potential therapeutic avenue for GBM.
... SREBP1 mainly regulates the genes involved in fatty acid (FA) synthesis, while SREBP2 controls the gene of the cholesterol biosynthesis pathway (Horton et al., 2003). When the cholesterol content is present in endoplasmic reticulum (ER) is low, SREBP2 activates the transcription and expression of the cholesterol biosynthetic enzymes HMGCR, increases the expression of the NPC1L1 and LDLR genes (Luo et al., 2020) to increase the de novo cholesterol synthesis (Nohturfft and Zhang, 2009;Cai et al., 2019). When cholesterol content in endoplasmic reticulum (ER) is high, the activation of SREBP2 and cholesterol synthesis are blocked. ...
Cholesterol and its metabolites have important biological functions. Cholesterol is able to maintain the physical properties of cell membrane, play an important role in cellular signaling, and cellular cholesterol levels reflect the dynamic balance between biosynthesis, uptake, efflux and esterification. Cholesterol metabolism participates in bile acid production and steroid hormone biosynthesis. Increasing evidence suggests a strict link between cholesterol homeostasis and tumors. Cholesterol metabolism in tumor cells is reprogrammed to differ significantly from normal cells, and disturbances of cholesterol balance also induce tumorigenesis and progression. Preclinical and clinical studies have shown that controlling cholesterol metabolism suppresses tumor growth, suggesting that targeting cholesterol metabolism may provide new possibilities for tumor therapy. In this review, we summarized the metabolic pathways of cholesterol in normal and tumor cells and reviewed the pre-clinical and clinical progression of novel tumor therapeutic strategy with the drugs targeting different stages of cholesterol metabolism from bench to bedside.
... Cholesterol is needed in cell membranes and for the synthesis of sex hormones and glucocorticoids [19]. Cells depend on increased cholesterol synthesis and uptake to proliferate at a high pace [20], and cholesterol has been shown to stimulate cell growth signaling in vitro [21]. Moreover, a genome wide association study indicated that cholesterol biosynthesis is important for fetal growth [22]. ...
... Non-fasting blood samples were obtained in mean (standard deviation [SD], min-max) gestational week 19 [1,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] among the mothers and 19 [2, among the fathers [34]. TC, LDL-C, HDL-C, triglycerides (TG), apoB, apoA1, apoB/apoA1 ratio, and glucose levels were measured in EDTA plasma samples by nuclear magnetic resonance spectroscopy at the accredited laboratory Nightingale Health in Finland [38]. ...
... Hence, maternal mid-pregnancy TC and HDL-C levels probably affect fetal TC and HDL-C levels but also possibly offspring TC and HDL-C later in childhood [48,49]. High offspring LDL-C level may increase and high offspring HDL-C level may decrease the supply of cholesterol to peripheral cells [50], which in theory may affect the offspring's development or epigenetic pattern, and subsequent body growth [5,[20][21][22]. This possible effect was mostly apparent from 9 months of age according to the data presented in the current study. ...
Background
Numerous intrauterine factors may affect the offspring’s growth during childhood. We aimed to explore if maternal and paternal prenatal lipid, apolipoprotein (apo)B and apoA1 levels are associated with offspring weight, length, and body mass index from 6 weeks to eight years of age. This has previously been studied to a limited extent.
Methods
This parental negative control study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. We included 713 mothers and fathers with or without self-reported hypercholesterolemia and their offspring. Seven parental metabolites were measured by nuclear magnetic resonance spectroscopy, and offspring weight and length were measured at 12 time points. Data were analyzed by linear spline mixed models, and the results are presented as the interaction between parental metabolite levels and offspring spline (age).
Results
Higher maternal total cholesterol (TC) level was associated with a larger increase in offspring body weight up to 8 years of age (0.03 ≤ Pinteraction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ Pinteraction ≤ 0.25). Higher maternal high-density lipoprotein cholesterol (HDL-C) and apoA1 levels were associated with a lower increase in offspring body weight up to 8 years of age (0.001 ≤ Pinteraction ≤ 0.005). Higher paternal HDL-C and apoA1 levels were associated with a lower increase in offspring body weight up to 5 years of age but a larger increase in offspring body weight from 5 to 8 years of age (0.01 ≤ Pinteraction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ Pinteraction ≤ 0.99).
Conclusions
Maternal compared to paternal TC, HDL-C, and apoA1 levels were more strongly and consistently associated with offspring body weight during childhood, supporting a direct intrauterine effect.
... There, it might have an additional structural function for the initial germline development upon dauer exit. As the germline develops rapidly during the transition into reproductive mode and many cell divisions take place, worms potentially use the stored cholesterol as building blocks within new cell membranes [41]. Along these lines, the sequestration and absence of cholesterol during dauer might be an effective . ...
Recovery from the quiescent developmental stage called dauer is an essential process in C. elegans and provides an excellent model to understand how metabolic transitions contribute to developmental plasticity. We here show that the depletion of sterol-binding proteins SCL-12 and SCL-13 is the key change in the C. elegans proteome in early dauer recovery. This process releases a cholesterol store that is sequestered in the gut lumen during the dauer state to facilitate the transition into reproductive development. First, the stored cholesterol undergoes endocytosis into the lysosomes of the intestinal cells, where it activates mTOR to promote protein synthesis and growth. Second, it is used for the production of dafachronic acids that switch metabolic programs at the transcriptional level. These processes are essential for population fitness and survival, as loss of SCL-12 and SCL-13, depletion of sterols, and loss of mTOR precludes quiescence exit, ultimately leading to the expiration of the entire population.
... As an essential building block for membrane biosynthesis, cholesterol is irreplaceable for rapidly proliferating cells to sustain their growth 4,5 . In addition, cholesterol drives the mechanistic target of rapamycin complex 1 (mTORC1) activation and growth signaling 6,7 . ...
Cholesterol sulfate, produced by hydroxysteroid sulfotransferase 2B1 (SULT2B1), is highly abundant in the intestine. Herein, we study the functional role and underlying intestinal epithelial repair mechanisms of cholesterol sulfate in ulcerative colitis. The levels of cholesterol and cholesterol sulfate, as well as the expression of Sult2b1 and genes involved in cholesterol biosynthesis, are significantly higher in inflamed tissues from patients with ulcerative colitis than in intestinal mucosa from healthy controls. Cholesterol sulfate in the gut and circulation is mainly catalyzed by intestinal epithelial SULT2B1. Specific deletion of the Sult2b1 gene in the intestinal epithelial cells aggravates dextran sulfate sodium-induced colitis; however, dietary supplementation with cholesterol sulfate ameliorates this effect in acute and chronic ulcerative colitis in mice. Cholesterol sulfate promotes cholesterol biosynthesis by binding to Niemann-Pick type C2 protein and activating sterol regulatory element binding protein 2 in colonic epithelial cells, thereby alleviates ulcerative colitis. In conclusion, cholesterol sulfate contributes to the healing of the mucosal barrier and exhibits therapeutic efficacy against ulcerative colitis in mice. New treatment strategies are required for ulcerative colitis. Here the authors show in mouse models that cholesterol sulfate, an endogenous active cholesterol derivative, contributes to the healing of the mucosal barrier by promoting cholesterol biosynthesis in colonic epithelial cells and exhibits therapeutic efficacy against ulcerative colitis.
... L ipids form the basic structure of the plasma membrane and of all cellular organelle membranes, which makes gaining sufficient lipids a precondition for cell growth and proliferation [1][2][3][4] . Under physiological conditions, lipid levels are mainly regulated by SREBPs, a family of transcription factors that include three isoforms, SREBP-1a, SREBP-1c and SREBP-2 (refs. ...
... b, Western blot analysis of whole lysates of cells cultured in serum-free medium with or without the presence of glucose (5 mM), glutamine (4 mM), glutamate (4 mM), lactate (10 mM) or NH 4 Cl (4 mM) for 12 h. c,d, Western blot analysis of whole lysates from cells after NH 4 Cl stimulation at the indicated doses for 12 h (c) or over time after 4 mM NH 4 Cl stimulation (d). e, Representative IF images of anti-SREBP-1 staining (red) in cells with or without NH 4 Cl (4 mM) stimulation for 12 h. ...
Tumorigenesis is associated with elevated glucose and glutamine consumption, but how cancer cells can sense their levels to activate lipid synthesis is unknown. Here, we reveal that ammonia, released from glutamine, promotes lipogenesis via activation of sterol regulatory element-binding proteins (SREBPs), endoplasmic reticulum-bound transcription factors that play a central role in lipid metabolism. Ammonia activates the dissociation of glucose-regulated, N-glycosylated SREBP-cleavage-activating protein (SCAP) from insulin-inducible gene protein (Insig), an endoplasmic reticulum-retention protein, leading to SREBP translocation and lipogenic gene expression. Notably, 25-hydroxycholesterol blocks ammonia to access its binding site on SCAP. Mutating aspartate D428 to alanine prevents ammonia binding to SCAP, abolishes SREBP-1 activation and suppresses tumour growth. Our study characterizes the unknown role, opposite to sterols, of ammonia as a key activator that stimulates SCAP–Insig dissociation and SREBP-1 activation to promote tumour growth and demonstrates that SCAP is a critical sensor of glutamine, glucose and sterol levels to precisely control lipid synthesis.
... Osh protein elimination increased the post-translational expression of Tcb3p, despite that TCB1-TCB3 and IST2 transcription is reduced 2-3-fold in osh4-1 ts oshΔ cells. Although gene and protein expression do not always directly correlate, negative feedback loops are common modes to reassert homeostatic control of membrane maintenance [68]. Another possibility is that rESR-mediated global transcriptional decreases tether gene expression, which in osh4-1 ts oshΔ cells is offset by increased stability of Tcb3p in ER-MCSs. ...
In yeast, at least seven proteins (Ice2p, Ist2p, Scs2/22p, Tcb1-Tcb3p) affect cortical endoplasmic reticulum (ER) tethering and contact with the plasma membrane (PM). In Δ-super-tether (Δ-s-tether) cells that lack these tethers, cortical ER-PM association is all but gone. Yeast OSBP homologue (Osh) proteins are also implicated in membrane contact site (MCS) assembly, perhaps as subunits for multicomponent tethers, though their function at MCSs involves intermembrane lipid transfer. Paradoxically, when analyzed by fluorescence and electron microscopy, the elimination of the OSH gene family does not reduce cortical ER-PM association but dramatically increases it. In response to the inactivation of all Osh proteins, the yeast E-Syt (extended-synaptotagmin) homologue Tcb3p is post-transcriptionally upregulated thereby generating additional Tcb3p-dependent ER-PM MCSs for recruiting more cortical ER to the PM. Although the elimination of OSH genes and the deletion of ER-PM tether genes have divergent effects on cortical ER-PM association, both elicit the Environmental Stress Response (ESR). Through comparisons of transcriptomic profiles of cells lacking OSH genes or ER-PM tethers, changes in ESR expression are partially manifested through the induction of the HOG (high-osmolarity glycerol) PM stress pathway or the ER-specific UPR (unfolded protein response) pathway, respectively. Defects in either UPR or HOG pathways also increase ER-PM MCSs, and expression of extra “artificial ER-PM membrane staples” rescues growth of UPR mutants challenged with lethal ER stress. Transcriptome analysis of OSH and Δ-s-tether mutants also revealed dysregulation of inositol-dependent phospholipid gene expression, and the combined lethality of osh4 Δ and Δ-s-tether mutations is suppressed by overexpression of the phosphatidic acid biosynthetic gene, DGK1 . These findings establish that the Tcb3p tether is induced by ER and PM stresses and ER-PM MCSs augment responses to membrane stresses, which are integrated through the broader ESR pathway.
... Regulation of lipid metabolism via engineering ER and LDs was reported to improve the production of sterols (Arendt et al. 2017;Fei et al. 2008). In phospholipid synthesis pathway, diacylglycerol (DAG) is formed from phosphatidic acid (PA) which is one of the membrane lipids under catalysis of phosphatidic acid phosphatase (Pah1p), and the deletion of PAH1 led to PA accumulation which caused the drastic proliferation of the outer nuclear membrane and the ER (Arendt et al. 2017;Nohturfft and Zhang 2009). The expansion of ER has been successfully used for the functional overproduction of ER-localized proteins which may be beneficial to the production of corresponding metabolites (Arendt et al. 2017). ...
Steroidal compounds are of great interest in the pharmaceutical field, with steroidal drugs as the second largest category of medicine in the world. Advances in synthetic biology and metabolic engineering have enabled de novo biosynthesis of sterols and steroids in yeast, which is a green and safe production route for these valuable steroidal compounds. In this review, we summarize the metabolic engineering strategies developed and employed for improving the de novo biosynthesis of sterols and steroids in yeast based on the regulation mechanisms, and introduce the recent progresses in de novo synthesis of some typical sterols and steroids in yeast. The remaining challenges and future perspectives are also discussed.
