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Metabolic coessentiality mapping identifies C12orf49 as a regulator of SREBP processing and cholesterol metabolism.
Bayraktar EC, La K, Karpman K, Unlu G, Ozerdem C, Ritter DJ, Alwaseem H, Molina H, Hoffmann HH, Millner A, Atilla-Gokcumen GE, Gamazon ER, Rushing AR, Knapik EW, Basu S, Birsoy K
(2020) Nat Metab 2: 487-498
MeSH Terms: Animals, Cell Line, Cell Proliferation, Cholesterol, Gene Expression Regulation, Golgi Apparatus, Humans, Hyperlipidemias, Lipid Metabolism, Membrane Proteins, Proprotein Convertases, Serine Endopeptidases, Sterol Regulatory Element Binding Proteins, Zebrafish
Show Abstract · Added September 9, 2020
Coessentiality mapping has been useful to systematically cluster genes into biological pathways and identify gene functions. Here, using the debiased sparse partial correlation (DSPC) method, we construct a functional coessentiality map for cellular metabolic processes across human cancer cell lines. This analysis reveals 35 modules associated with known metabolic pathways and further assigns metabolic functions to unknown genes. In particular, we identify C12orf49 as an essential regulator of cholesterol and fatty acid metabolism in mammalian cells. Mechanistically, C12orf49 localizes to the Golgi, binds membrane-bound transcription factor peptidase, site 1 (MBTPS1, site 1 protease) and is necessary for the cleavage of its substrates, including sterol regulatory element binding protein (SREBP) transcription factors. This function depends on the evolutionarily conserved uncharacterized domain (DUF2054) and promotes cell proliferation under cholesterol depletion. Notably, c12orf49 depletion in zebrafish blocks dietary lipid clearance in vivo, mimicking the phenotype of mbtps1 mutants. Finally, in an electronic health record (EHR)-linked DNA biobank, C12orf49 is associated with hyperlipidaemia through phenome analysis. Altogether, our findings reveal a conserved role for C12orf49 in cholesterol and lipid homeostasis and provide a platform to identify unknown components of other metabolic pathways.
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14 MeSH Terms
Proprotein Convertase Processing Enhances Peroxidasin Activity to Reinforce Collagen IV.
Colon S, Bhave G
(2016) J Biol Chem 291: 24009-24016
MeSH Terms: Basement Membrane, Collagen Type IV, Extracellular Matrix Proteins, HEK293 Cells, Humans, Peroxidase, Proprotein Convertases, Protein Domains
Show Abstract · Added March 3, 2020
The basement membrane (BM) is a form of extracellular matrix that underlies cell layers in nearly all animal tissues. Type IV collagen, a major constituent of BMs, is critical for tissue development and architecture. The enzyme peroxidasin (Pxdn), an extracellular matrix-associated protein, catalyzes the formation of structurally reinforcing sulfilimine cross-links within the collagen IV network, an event essential to basement membrane integrity. Although the catalytic function of Pxdn is known, the regulation of its activity remains unclear. In this work we show through N-terminal sequencing, pharmacologic studies, and mutational analysis that proprotein convertases (PCs) proteolytically process human Pxdn at Arg-1336, a location relatively close to its C terminus. PC processing enhances the enzymatic activity of Pxdn and facilitates the formation of sulfilimine cross-links in collagen IV. Thus, PC processing of Pxdn is a key regulatory step that contributes to its function and, therefore, supports BM integrity and homeostasis.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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MeSH Terms
Local effects of human PCSK9 on the atherosclerotic lesion.
Giunzioni I, Tavori H, Covarrubias R, Major AS, Ding L, Zhang Y, DeVay RM, Hong L, Fan D, Predazzi IM, Rashid S, Linton MF, Fazio S
(2016) J Pathol 238: 52-62
MeSH Terms: Animals, Atherosclerosis, Disease Models, Animal, Flow Cytometry, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Immunoprecipitation, Macrophages, Peritoneal, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Serine Endopeptidases, Transplantation Chimera
Show Abstract · Added February 3, 2017
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptor (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque is unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition, independently of changes in serum cholesterol levels, we generated chimeric mice expressing hPCSK9 exclusively from macrophages, using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE(-/-) and LDLR(-/-) mice, which were then placed on a high-fat diet (HFD) for 8 weeks. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPMs from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE(-/-) recipient mice, while increasing the infiltration of Ly6C(hi) inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b- and Ly6C(hi) -positive cell numbers in spleens of apoE(-/-) mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent, as PCSK9 protein was not detected in lesions of LDLR(-/-) recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction.
Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
1 Communities
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18 MeSH Terms
Response to letter regarding article, "Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms".
Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S
(2015) Circulation 131: e428
MeSH Terms: Animals, Apolipoproteins B, Enterocytes, Humans, Hypertriglyceridemia, Proprotein Convertases, Receptors, LDL, Serine Endopeptidases, Triglycerides
Added April 10, 2018
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PCSK9 is a critical regulator of the innate immune response and septic shock outcome.
Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, Christie JD, Nakada TA, Fjell CD, Thair SA, Cirstea MS, Boyd JH
(2014) Sci Transl Med 6: 258ra143
MeSH Terms: Animals, Disease Models, Animal, Genetic Variation, Hep G2 Cells, Humans, Immunity, Innate, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Knockout, Proprotein Convertase 9, Proprotein Convertases, Serine Endopeptidases, Shock, Septic
Show Abstract · Added January 20, 2015
A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of low-density lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.
Copyright © 2014, American Association for the Advancement of Science.
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14 MeSH Terms
Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms.
Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S
(2014) Circulation 130: 431-41
MeSH Terms: Animals, Apolipoproteins B, Caco-2 Cells, Cell Survival, Enterocytes, Humans, Hypertriglyceridemia, Intestinal Mucosa, Intestines, Mice, Inbred C57BL, Mice, Knockout, Proprotein Convertase 9, Proprotein Convertases, RNA, Small Interfering, Receptors, LDL, Serine Endopeptidases, Transcription, Genetic, Triglycerides
Show Abstract · Added February 12, 2015
BACKGROUND - Proprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein (LDL) receptor (LDLR), and its deficiency in humans results in low plasma LDL cholesterol and protection against coronary heart disease. Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins, another important coronary heart disease risk factor. Here, we studied the effects of physiological levels of PCSK9 on intestinal triglyceride-rich apoB lipoprotein production and elucidated for the first time the cellular and molecular mechanisms involved.
METHODS AND RESULTS - Treatment of human enterocytes (CaCo-2 cells) with recombinant human PCSK9 (10 μg/mL for 24 hours) increased cellular and secreted apoB48 and apoB100 by 40% to 55% each (P<0.01 versus untreated cells), whereas short-term deletion of PCSK9 expression reversed this effect. PCSK9 stimulation of apoB was due to a 1.5-fold increase in apoB mRNA (P<0.01) and to enhanced apoB protein stability through both LDLR-dependent and LDLR-independent mechanisms. PCSK9 decreased LDLR protein (P<0.01) and increased cellular apoB stability via activation of microsomal triglyceride transfer protein. PCSK9 also increased levels of the lipid-generating enzymes FAS, SCD, and DGAT2 (P<0.05). In mice, human PCSK9 at physiological levels increased intestinal microsomal triglyceride transfer protein levels and activity regardless of LDLR expression.
CONCLUSIONS - PCSK9 markedly increases intestinal triglyceride-rich apoB production through mechanisms mediated in part by transcriptional effects on apoB, microsomal triglyceride transfer protein, and lipogenic genes and in part by posttranscriptional effects on the LDLR and microsomal triglyceride transfer protein. These findings indicate that targeted PCSK9-based therapies may also be effective in the management of postprandial hypertriglyceridemia.
© 2014 American Heart Association, Inc.
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18 MeSH Terms
Response to Duell et al.
Tavori H, Giunzioni I, Linton MF, Fazio S
(2014) Circ Res 115: e5
MeSH Terms: Blood Component Removal, Humans, Hyperlipoproteinemia Type II, Lipoproteins, LDL, Proprotein Convertases, Serine Endopeptidases
Added February 12, 2015
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6 MeSH Terms
Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis.
Tavori H, Giunzioni I, Linton MF, Fazio S
(2013) Circ Res 113: 1290-5
MeSH Terms: Apoptosis, Blood Component Removal, HEK293 Cells, Humans, Hyperlipoproteinemia Type II, Lipoproteins, LDL, Proprotein Convertase 9, Proprotein Convertases, Serine Endopeptidases
Show Abstract · Added May 27, 2014
RATIONALE - Lipoprotein apheresis (LA) reduces low-density lipoprotein (LDL) levels in patients with severe familial hypercholesterolemia (FH). We have recently reported that >30% of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL.
OBJECTIVE - Pre- and post-apheresis plasma from 6 patients with familial hypercholesterolemia on 3 consecutive treatment cycles was used to determine changes in PCSK9 levels.
METHODS AND RESULTS - LA drastically reduced plasma LDL (by 77 ± 4%). Concomitantly, PCSK9 levels fell by 52 ± 5%, strongly correlating with the LDL drop (P=0.0322; r(2)=0.26), but not with decreases in triglyceride (49 ± 13%) or high-density lipoprotein levels (18 ± 2%). Levels of albumin, creatinine, and CK-MB did not show significant changes after LA. Similar to LDL, PCSK9 levels returned to pretreatment values between cycles (2-week intervals). Fractionation of pre- and post-apheresis plasma showed that 81 ± 11% of LDL-bound PCSK9 and 48 ± 14% of apolipoprotein B-free PCSK9 were removed. Separation of whole plasma, purified LDL, or the apolipoprotein B-free fraction through a scaled-down, experimental dextran sulfate cellulose beads column produced similar results.
CONCLUSIONS - Our results show, for the first time, that modulation of LDL levels by LA directly affects plasma PCSK9 levels, and suggest that PCSK9 reduction is an additional benefit of LA. Because the loss of PCSK9 could contribute to the LDL-lowering effect of LA, then (1) anti-PCSK9 therapies may reduce frequency of LA in patients currently approved for therapy, and (2) LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden.
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9 MeSH Terms
Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation.
Tavori H, Fan D, Blakemore JL, Yancey PG, Ding L, Linton MF, Fazio S
(2013) Circulation 127: 2403-13
MeSH Terms: Animals, Cells, Cultured, Cholesterol, Disease Models, Animal, Humans, Hypercholesterolemia, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Serine Endopeptidases, Transfection
Show Abstract · Added December 10, 2013
BACKGROUND - Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels. However, dysfunctional LDLR causes hypercholesterolemia without affecting PCSK9 clearance from the circulation.
METHODS AND RESULTS - To study the reciprocal effects of PCSK9 and LDLR and the resultant effects on serum cholesterol, we produced transgenic mice expressing human (h) PCSK9. Although hPCSK9 was expressed mainly in the kidney, LDLR degradation was more evident in the liver. Adrenal LDLR levels were not affected, likely because of the impaired PCSK9 retention in this tissue. In addition, hPCSK9 expression increased hepatic secretion of apolipoprotein B-containing lipoproteins in an LDLR-independent fashion. Expression of hPCSK9 raised serum murine PCSK9 levels by 4.3-fold in wild-type mice and not at all in LDLR(-/-) mice, in which murine PCSK9 levels were already 10-fold higher than in wild-type mice. In addition, LDLR(+/-) mice had a 2.7-fold elevation in murine PCSK9 levels and no elevation in cholesterol levels. Conversely, acute expression of human LDLR in transgenic mice caused a 70% decrease in serum murine PCSK9 levels. Turnover studies using physiological levels of hPCSK9 showed rapid clearance in wild-type mice (half-life, 5.2 minutes), faster clearance in human LDLR transgenics (2.9 minutes), and much slower clearance in LDLR(-/-) recipients (50.5 minutes). Supportive results were obtained with an in vitro system. Finally, up to 30% of serum hPCSK9 was associated with LDL regardless of LDLR expression.
CONCLUSIONS - Our results support a scenario in which LDLR represents the main route of elimination of PCSK9 and a reciprocal regulation between these 2 proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.
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17 MeSH Terms
Proprotein convertase subtilisin/kexin type 9 as transducer of physiologic influences on cellular cholesterol: a case for resistin.
Fazio S, Linton MF
(2012) J Am Coll Cardiol 59: 1706-8
MeSH Terms: Dyslipidemias, Hepatocytes, Humans, Proprotein Convertases, Receptors, LDL, Resistin, Subtilisin
Added December 10, 2013
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7 MeSH Terms