Dietäärisen SFA.n vaikutus NLRP3 inflammasomiin ja Il-1B statukseen.
https://www.cell.com/cell-reports/fulltext/S2211-1247(16)30174-7
torsdag 18 oktober 2018
onsdag 8 augusti 2018
Plasmalogeenit sammaleläinlajissa . Plasmalogeenikardiomyosyytissä.
Sammaleläinlajista Pectinella magnifica löytyy hyvin runsans PUDFA- happojohdannasi sisältö plasmalogeenimuotoisina.
2.
2.
Řezanka T, Vítová M, Lukavský J, Sigler K.
Lipids. 2018 Apr;53(4):413-427. doi: 10.1002/lipd.12039. Epub 2018 Apr 30.
- PMID:
- 29709080
5
DaTorre SD, Creer MH.
J Lipid Res. 1991 Jul;32(7):1159-72.
- PMID:
- 1940640
fredag 3 augusti 2018
Histoni- K- krotonylaatio - vasta keksitty modifikaatio . SIRT 3 on dekrotonylaasi.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920150/
Dis Model Mech. 2016 Jun 1; 9(6): 633–645.
doi: 10.1242/dmm.024455
PMCID: PMC4920150
PMID: 27125278
Histone lysine crotonylation during acute kidney injury in mice
K-krotonylaatio
http://www.mcponline.org/content/early/2018/07/18/mcp.RA118.000640
Global involvement of lysine crotonylation in protein modification and transcription regulation in rice
- 1Yangzhou University, China
- 2Nanjing Agricultural University, China
- 3Jingjie PTM Biolabs (Hangzhou) Co. Ltd
- 4Fujian Agriculture and Forestry University, China
- ↵* Corresponding Author:
Zhiyun Gong, Yangzhou University, China. E-mail: zygong{at}yzu.edu.cn
Abstract
Lysine crotonylation (Kcr) is a newly discovered post-translational modification (PTM) existing in mammals.
A global crotonylome
analysis was undertaken in rice (Oryza sativa L. japonica)
using high accuracy nano-LC-MS/MS in combination with crotonylated
peptide enrichment. A total of 1,265 lysine crotonylation
sites were identified on 690 proteins in rice
seedlings. Subcellular localization analysis revealed that 51% of the
crotonylated
proteins identified were localized in chloroplasts.
The photosynthesis-associated proteins were also mostly enriched in
total
crotonylated proteins.
In addition, a genomic
localization analysis of histone Kcr by ChIP-seq was performed to assess
the
relevance between histone Kcr and the genome. Of
the 10,923 identified peak regions, the majority (86.7%) of the enriched
peaks were located in gene body, especially exons.
Furthermore, the degree of histone Kcr modification was positively
correlated
with gene expression in genic regions. Compared
with other published histone modification data, the Kcr was co-located
with
the active histone modifications. Interestingly,
histone Kcr facilitated expression of genes with existing active histone
modifications. In addition, 77% of histone Kcr
modifications overlapped with DNase hypersensitive sites (DHSs) in
intergenic
regions of the rice genome, and might mark other
cis-regulatory DNA elements which are different from IPA1, a
transcription
activator in rice seedlings.
Overall, our results
provide a comprehensive understanding of the biological functions of the
crotonylome and new active histone modification in
transcriptional regulation in plants.
Proteiinien K-asylaatiosta yleensä
2018
https://www.ncbi.nlm.nih.gov/pubmed/29887264
Xu JY, Xu Y, Xu Z, Zhai LH, Ye Y, Zhao Y, Chu X, Tan M, Ye BC.
Cell Chem Biol. 2018 May 21. pii: S2451-9456(18)30152-1. doi: 10.1016/j.chembiol.2018.05.005. [Epub ahead of print] PMID: 29887264
2.
Revealing the protein propionylation activity of the histone acetyltransferase MOF (males absent on the first). Han
Z, Wu H, Kim S, Yang X, Li Q, Huang H, Cai H, Bartlett MG, Dong A, Zeng
H, Brown PJ, Yang XJ, Arrowsmith CH, Zhao Y, Zheng YG.
J Biol Chem. 2018 Mar 2;293(9):3410-3420. doi: 10.1074/jbc.RA117.000529. Epub 2018 Jan 10. PMID: 29321206
3.
Liu X, Wei W, Liu Y, Yang X, Wu J, Zhang Y, Zhang Q, Shi T, Du JX, Zhao Y, Lei M, Zhou JQ, Li J, Wong J. Cell Discov. 2017 May 23;3:17016. doi: 10.1038/celldisc.2017.16. eCollection 2017. PMID:28580166
".. Recent studies indicate that histones are subjected to various types of
acylation including acetylation, propionylation and crotonylation."
4.
Nie L, Shuai L, Zhu M, Liu P, Xie ZF, Jiang S, Jiang HW, Li J, Zhao Y, Li JY, Tan M.
Mol Cell Proteomics. 2017 Jul;16(7):1324-1334. doi: 10.1074/mcp.M117.067553. Epub 2017 Apr 27.PMID:28450421
".. Type 2 diabetes (T2D) is a major chronic healthcare concern worldwide.
Emerging evidence suggests that a histone-modification-mediated
epigenetic mechanism underlies T2D."
5.
Li QQ, Hao JJ, Zhang Z, Krane LS, Hammerich KH, Sanford T, Trepel JB, Neckers L, Agarwal PK.
Sci Rep. 2017 Mar 15;7(1):201. doi: 10.1038/s41598-017-00143-6. PMID: 28298630
".. Furthermore, quantitative proteome studies identified 14 types of PTMs
with 93 marks on the core histones, including 34 novel histone marks of
butyrylation, citrullination, 2-hydroxyisobutyrylation, methylation,
O-GlcNAcylation, propionylation, and succinylation in AUY922- and
ganetespib-treated 5637 cells".
6.
Pelletier N, Grégoire S, Yang XJ.
Curr Protoc Protein Sci. 2017 Feb 2;87:14.11.1-14.11.18. doi: 10.1002/cpps.26. PMID:28150880
".. Lysine acetylation refers to addition of an acetyl moiety to the
epsilon-amino group of a lysine residue and is important for regulating
protein functions in various organisms from bacteria to humans. This is a
reversible and precisely controlled covalent modification that either
serves as an on/off switch or participates in a codified manner with
other post-translational modifications to regulate different cellular
and developmental processes in normal and pathological states. This unit
describes methods for in vitro and in vivo determination of lysine
acetylation. Such methods can be easily extended for analysis of other
acylations (such as propionylation, butyrylation, crotonylation, and
succinylation) that are also present in histones and many other
proteins."
2016
7.
Sabari BR, Zhang D, Allis CD, Zhao Y.
Nat Rev Mol Cell Biol. 2017 Feb;18(2):90-101. doi: 10.1038/nrm.2016.140. Epub 2016 Dec 7. Review. PMID: 27924077
" Eight types of short-chain Lys acylations have recently been identified
on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation,
succinylation, malonylation, glutarylation, crotonylation and
β-hydroxybutyrylation. Emerging evidence suggests that these histone
modifications affect gene expression and are structurally and
functionally different from the widely studied histone Lys acetylation.
In this Review, we discuss the regulation of non-acetyl histone
acylation by enzymatic and metabolic mechanisms, the acylation 'reader'
proteins that mediate the effects of different acylations and their
physiological functions, which include signal-dependent gene activation,
spermatogenesis, tissue injury and metabolic stress. We propose a model
to explain our present understanding of how differential histone
acylation is regulated by the metabolism of the different acyl-CoA
forms, which in turn modulates the regulation of gene expression".
8.
Sun M, Xu J, Wu Z, Zhai L, Liu C, Cheng Z, Xu G, Tao S, Ye BC, Zhao Y, Tan M.
J Proteome Res. 2016 Dec 2;15(12):4696-4708. Epub 2016 Nov 10.PMID:27804304
", we identified 1467 lysine propionylation sites in 603 proteins in E.
coli. Quantitative propionylome analysis further revealed that global
lysine propionylation level was drastically increased in response to
propionate treatment,.."
9.
Xiong X, Panchenko T, Yang S, Zhao S, Yan P, Zhang W, Xie W, Li Y, Zhao Y, Allis CD, Li H.
Nat Chem Biol. 2016 Dec;12(12):1111-1118. doi: 10.1038/nchembio.2218. Epub 2016 Oct 24. PMID: 27775714
".. Recognition of histone covalent modifications by 'reader' modules
constitutes a major mechanism for epigenetic regulation. A recent
upsurge of newly discovered histone lysine acylations, such as
crotonylation (Kcr), butyrylation (Kbu), and propionylation (Kpr),
greatly expands the coding potential of histone lysine modifications.
Here we demonstrate that the histone acetylation-binding double PHD
finger (DPF) domains of human MOZ (also known as KAT6A) and DPF2 (also
known as BAF45d) accommodate a wide range of histone lysine acylations
with the strongest preference for Kcr.
10.
Li Y, Sabari BR, Panchenko T, Wen H, Zhao D, Guan H, Wan L, Huang H, Tang Z, Zhao Y, Roeder RG, Shi X, Allis CD, Li H.Mol Cell. 2016 Apr 21;62(2):181-193. doi: 10.1016/j.molcel.2016.03.028.PMID: 27105114Free PMC Article
" Recognition of histone covalent modifications by chromatin-binding
protein modules ("readers") constitutes a major mechanism for epigenetic
regulation, typified by bromodomains that bind acetyllysine. Non-acetyl
histone lysine acylations (e.g., crotonylation, butyrylation,
propionylation) have been recently identified, but readers that prefer
these acylations have not been characterized. Here we report that the
AF9 YEATS domain displays selectively higher binding affinity for
crotonyllysine over acetyllysine."
2014
11.
Wu Z, Cheng Z, Sun M, Wan X, Liu P, He T, Tan M, Zhao Y.
Mol Cell Proteomics. 2015 Feb;14(2):329-39. doi: 10.1074/mcp.M114.044255. Epub 2014 Dec 11.PMID:25505155
12.
Tooley JG, Schaner Tooley CE.
Protein Sci. 2014 Dec;23(12):1641-9. doi: 10.1002/pro.2547. Epub 2014 Sep 26. Review.PMID:25209108
".. Historically considered static regulators of protein stability,
additional functional roles for N-terminal PTMs are now beginning to be
elucidated. New findings show that N-terminal methylation, along with
N-terminal acetylation, is an important regulatory modification with
significant roles in development and disease progression.There are also emerging studies on the enzymology and functional roles
of N-terminal ubiquitylation and N-terminal propionylation.
13.
Lee S.Toxicol Res. 2013 Jun;29(2):81-6. doi: 10.5487/TR.2013.29.2.081. Review. PMID:24278632
".. Post-translational modification (PTM) alters the three-dimensional (3D)
structure of proteins by covalently binding small molecules to them and
therefore represents a major protein function diversification mechanism.
Because of the crucial roles PTM plays in biological systems, the
identification of novel PTMs and study of the role of PTMs are gaining
much attention in proteomics research. Of the 300 known PTMs, protein
acylation, including lysine formylation, acetylation, propionylation,
butyrylation, malonylation, succinylation, and crotonylation, regulates
the crucial functions of many eukaryotic proteins involved in cellular
metabolism, cell cycle, aging, growth, angiogenesis, and cancer."
14.
Singh B, Boopathy S, Somasundaram K, Umapathy S.
J Biophotonics. 2012 Mar;5(3):230-9. doi: 10.1002/jbio.201100061. Epub 2012 Jan 19. PMID:22259119
"Histone deacetylase inhibitors (HDIs) have attracted considerable
attention as potential drug molecules in tumour biology. In order to
optimise chemotherapy, it is important to understand the mechanisms of
regulation of histone deacetylase (HDAC) enzymes and modifications
brought by various HDIs."
Proteiinin K-propionylaatio, MYST perhe
https://www.ncbi.nlm.nih.gov/pubmed/29321206
Tapahtuuko propionylaatiota ihmissolussakin? Bakteereissahan ilmiö on yleinen.
Names
K(lysine) acetyltransferase 8 MOZ, YBF2/SAS3, SAS2 and TIP60 protein 1 MYST histone acetyltransferase 1 MYST-1 histone acetyltransferase MYST1 ortholog of Drosophila males absent on the first (MOF) probable histone acetyltransferase MYST1
Summary This gene encodes a member of the MYST histone acetylase
protein family. The encoded protein has a characteristic MYST domain
containing an acetyl-CoA-binding site, a chromodomain typical of
proteins which bind histones, and a C2HC-type zinc finger. Multiple
transcript variants encoding different isoforms have been found for this
gene. [provided by RefSeq, Feb 2012]
Expression Ubiquitous expression in ovary (RPKM 17.1), testis (RPKM 11.9) and 25 other tissues See more Orthologs mouse
all
Related Articles in Pub Med
Structural and Functional Role of Acetyltransferase hMOF K274 Autoacetylation.
McCullough CE, et al. J Biol Chem, 2016 Aug 26. PMID 27382063, Free PMC Article
KAT8 Regulates Androgen Signaling in Prostate Cancer Cells.
Kim JY, et al. Mol Endocrinol, 2016 Aug. PMID 27268279, Free PMC ArticleAndrogen receptor (AR) plays pivotal roles in prostate cancer. Upon
androgen stimulation, AR recruits the Protein kinase N1 (PKN1), which
phosphorylates histone H3 at threonine 11, with subsequent recruitment
of tryptophan, aspartic acid (WD) repeat-containing protein 5 (WDR5) and
the su(var)3-9, enhancer of zeste, trithorax/mixed-lineage leukemia
(SET1/MLL) histone methyltransferase complex to promote AR target gene
activation and prostate cancer cell grow However, the underlying
mechanisms of target gene activation and cell growth subsequent to WDR5
recruitment are not well understood. Here, we demonstrate an epigenetic
cross talk between histone modifications and AR target gene regulation.
We discovered that K(lysine) acetyltransferase 8 (KAT8), a member of the
MOZ, YBF2/SAS2, and TIP 60 protein 1 (MYST) family of histone
acetyltransferases that catalyzes histone H4 lysine 16 acetylation,
colocalized with WDR5 at AR target genes, resulting in hormone-dependent
gene activation in prostate cancer cells. PKN1 or WDR5 knockdown
severely inhibited KAT8 association with AR target genes and histone H4
lysine 16 acetylation upon androgen treatment. Knockdown of KAT8
significantly decreased AR target gene expression and prostate cancer
cell proliferation. Collectively, these data describe a trans-histone
modification pathway involving PKN1/histone H3 threonine 11
phosphorylation followed by WDR5/MLL histone methyltransferase and
KAT8/histone acetyltransferase recruitment to effect androgen-dependent
gene activation and prostate cancer cell proliferation.
A multifaceted role for MOF histone modifying factor in genome maintenance.
Mujoo K, et al. Mech Ageing Dev, 2017 Jan. PMID 27038808, Free PMC Article For example, recent results indicate MOF is an upstream regulator of the
ATM (ataxia-telangiectasia mutated) protein, the loss of which is
responsible for ataxia telangiectasia (AT). ATM is a key regulatory
kinase that interacts with and phosphorylates multiple substrates that
influence critical, cell-cycle control and DNA damage repair pathways in
addition to other pathways. Thus, directly or indirectly, MOF may be
involved in a wide range of cellular functions. This review will focus
on the contribution of MOF to cellular DNA repair and new results that
are beginning to examine the in vivo physiological role of MOF.
The Histone Acetyltransferase MOF Promotes Induces Generation of Pluripotent Stem Cells.
Mu X, et al. Cell Reprogram, 2015 Aug. PMID 2609136In this study, we investigated the function of MOF on the generation of
iPSCs. We show that iPSCs contain high levels of MOF mRNA, and the
expression level of MOF protein is dramatically upregulated following
reprogramming. Most importantly, overexpression of MOF improves
reprogramming efficiency and facilitates the formation of iPSCs, whereas
small hairpin RNA (shRNA)-mediated knockdown of MOF impairs iPSCs
generation during reprogramming. Further investigation reveals that MOF
interacts with the H3K4 methyltransferase Wdr5 to promote endogenous
Oct4 expression during the reprogramming process. Knockdown of MOF
reduces H4K16ac and H3K4me3 modification at the Oct4 promoter. In
conclusion, our data indicate that MOF is an important epigenetic
regulator that is critical for efficient reprogramming.
Expression of hMOF, but not HDAC4, is responsible for the global histone H4K16 acetylation in gastric carcinoma.
Zhu L, et al. Int J Oncol, 2015. PMID 25873202
See all (73) citations in PubMed See citations in PubMed for homologs of this gene provided by HomoloGene
See all GeneRIFs (43)
3.8. 2018
Tapahtuuko propionylaatiota ihmissolussakin? Bakteereissahan ilmiö on yleinen.
LÄHDE: J Biol Chem. 2018 Mar 2;293(9):3410-3420. doi: 10.1074/jbc.RA117.000529. Epub 2018 Jan 10. Revealing the protein propionylation activity of the histone acetyltransferase MOF (males absent on the first). Han Z1, Wu H2, Kim S3, Yang X1, Li Q1, Huang H3, Cai H1, Bartlett MG1, Dong A2, Zeng H2, Brown PJ2, Yang XJ4, Arrowsmith CH2,5, Zhao Y3, Zheng YG6. Abstract (suomenosta)
Lysiinitähteiden (K) asyloituminen lyhyillä rasvahapoilla (SCFA) on havaittu olevan eräs palautuvista posttranslationaalisista modifikaatioista imettäväissoluissa. Asylaatioitten moninaisuus laajentaa käsityksiä proteosomaalisesta maisemasta ja kompleksisuudesta. Näiden ilmiöiden molekyylitason käsittämisessä on olennaisen tärkeää tunnistaa lysiinin (K) asylaatiota säätelevät entsyymit ja effektoriproteiinit. Tässä artikelissaan tutkijat raportoivat lysiiniasyylitransferaasien (KAT) eräästä histoniasetylaasiperheestä MYST, jolla on vahvaa propionyylitransferaasiaktiivisuutta sekä in vitro että in cellulo. .
Erityisesti MYST perheenjäsenilla MOF (KAT8) , MOZ ja HBO1 on propionyylitransferaasiaktiivisuus yhtä vahvaa kuin niiden asetyylitransferaasiaktiivisuus. Kun MOF on yli-ilmentymässä alkion munuaissoluissa 293T se indusoi monissa histoneissa ja ei-histoniproteiineissa merkitsevästi lisääntynyttä propionylaatiota, mikä ulottuu paljon laajemmalle funktioalueelle kuin MOF:in kanoninen histonin H4 lysiinin K16 asetylaatio.
Tutkijat selvittivät myös MOF entsyymiin kiderakenteen kun se on sitoutuneena propionyyliCoA:n kanssa, mistä tarjoutuu suora rakenteellinen perusta MYST perheen KAT entsyymien propionyylitransferaasiaktiivisuudelle. Nämä tiedot yhdessä määrittävät MYST KAT:entsyymien uuden funktion lysiini-propionyylitransferaaseina ja viittaavat paljon laajempaan fysiologiseen vaikutukseen, mitä tämän ryhmän entsyymeillä on tiedetty olevan.
- Short-chain acylation of lysine residues has recently emerged as a group of reversible posttranslational modifications in mammalian cells. The diversity of acylation further broadens the landscape and complexity of the proteome. Identification of regulatory enzymes and effector proteins for lysine acylation is critical to understand functions of these novel modifications at the molecular level. Here, we report that the MYST family of lysine acetyltransferases (KATs) possesses strong propionyltransferase activity both in vitro and in cellulo Particularly, the propionyltransferase activity of MOF, MOZ, and HBO1 is as strong as their acetyltransferase activity. Overexpression of MOF in human embryonic kidney 293T cells induced significantly increased propionylation in multiple histone and non-histone proteins, which shows that the function of MOF goes far beyond its canonical histone H4 lysine 16 acetylation. We also resolved the X-ray co-crystal structure of MOF bound with propionyl-coenzyme A, which provides a direct structural basis for the propionyltransferase activity of the MYST KATs. Our data together define a novel function for the MYST KATs as lysine propionyltransferases and suggest much broader physiological impacts for this family of enzymes.
KEYWORDS:
Males absent on the first (MOF); MOF entsyymi, MYST perheenjäsen , K-asetyylitransferaasi
acetyltransferase; asetyylitransferaasi
crystal structure; kiderakenne
lysine propionylation; lysiinipropionylaatio , K-propionylaatio
post-translational modification (PTM); translaationjälkeinen modifikaatio
protein acylation; proteiinin asylaatio, happotähteen liitto proteiiniin
proteomics
Males absent on the first (MOF); MOF entsyymi, MYST perheenjäsen , K-asetyylitransferaasi
acetyltransferase; asetyylitransferaasi
crystal structure; kiderakenne
lysine propionylation; lysiinipropionylaatio , K-propionylaatio
post-translational modification (PTM); translaationjälkeinen modifikaatio
protein acylation; proteiinin asylaatio, happotähteen liitto proteiiniin
proteomics
- PMCID:
- PMC5836141
- [Available on 2019-03-02]
- DOI:
- 10.1074/jbc.RA117.000529
- Lisätieto KAT8- geeni (16p11.2) antaa katsausta jo tunetusta asetyylitransferaasivaikutuksesta, mutta tässä ei ole vielä erityisiä kliinisiä artikkeleita propionylaatioista.
https://www.ncbi.nlm.nih.gov/gene/84148
- Also known as MOF; hMOF; MYST1; ZC2HC8
- Preferred Names
- histone acetyltransferase KAT8
onsdag 1 augusti 2018
LIPA geeni (10q23.31),LAL, Lipase A, lysosomaali happotyyppinen, Kolesteroliesterihydrolaasi (CESD)
https://www.ncbi.nlm.nih.gov/gene/3988
- Also known as
- LAL; CESD
- Summary
- This gene encodes lipase A, the lysosomal acid lipase (also known as cholesterol ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in this gene can result in Wolman disease and cholesteryl ester storage disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2014]
- Expression
- Broad expression in spleen (RPKM 177.6), small intestine (RPKM 113.4) and 21 other tissues See more
Related articles in PubMed
- CRISPR/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages-Brief Report. Zhang H, et al. Arterioscler Thromb Vasc Biol, 2017 Nov. PMID 28882870,
- Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants. Pisciotta L, et al. Atherosclerosis, 2017 Oct. PMID 28881270
-
A Relative Deficiency of Lysosomal Acid Lypase Activity Characterizes Non-Alcoholic Fatty Liver Disease.
Tovoli F, et al. Int J Mol Sci, 2017 May 25. PMID 28587063, Free PMC Articl Abstract Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency
in non-alcoholic fatty liver disease (NAFLD)-however, it is still
unclear whether this mechanism is specific for NAFLD. We aimed to
determine LAL activity in a cohort of NAFLD subjects and in a control
group of hepatitis C virus (HCV)-infected patients, investigating the
role of liver cirrhosis. A total of 81 patients with a diagnosis of
NAFLD, and 78 matched controls with HCV-related liver disease were
enrolled. For each patient, LAL activity was determined on peripheral
dried blood spots (DBS) and correlated with clinical and laboratory
data. A subgroup analysis among cirrhotic patients was also performed.
LAL activity is significantly reduced in NAFLD, compared to that in HCV
patients. This finding is particularly evident in the pre-cirrhotic
stage of disease. LAL activity is also correlated with platelet and
white blood cell count, suggesting an analytic interference of
portal-hypertension-induced pancytopenia on DBS-determined LAL activity.
NAFLD is characterized by a specific deficit in LAL activity,
suggesting a pathogenetic role of LAL. We propose that future studies on
this topic should rely on tissue specific analyses, as peripheral blood
tests are also influenced by confounding factors.KEYWORDS: liver cirrhosis; lysosomal acid lipase; non-alcoholic fatty liver disease; steatohepatitis; steatosis
4. Severe reduction of blood lysosomal acid lipase activity in cryptogenic cirrhosis: A nationwide multicentre cohort study. Angelico F, et al. Atherosclerosis, 2017 Jul. PMID 28396038 Abstract BACKGROUND AND AIMS:
5. Coronary Artery Disease-Associated LIPA Coding Variant rs1051338 Reduces Lysosomal Acid Lipase Levels and Activity in Lysosomes. Morris GE, et al. Arterioscler Thromb Vasc Biol, 2017 Jun. PMID 28279971, Free PMC Article... conclusion, our findings suggest that the CAD-associated variant rs1051338, which causes a missense change in the signal peptide of LAL, disrupts the normal sorting and transport of LAL to the lysosome. LAL containing the risk allele is prone to cytosolic proteasomal degradation, reducing lysosomal LAL protein and activity. Understanding how this affects cholesterol metabolism may provide novel therapeutics for CAD through the modulation of macrophage cholesterol concentrationBlood lysosomal acid lipase (LAL) is reduced in non-alcoholic steatohepatitis, which is the major cause of cryptogenic cirrhosis (CC); few data on LAL activity in CC do exist. We investigated LAL activity in a cohort of patients with liver cirrhosis.METHODS:
This is a multicentre cohort study including 274 patients with liver cirrhosis of different aetiology from 19 centres of Internal Medicine, Gastroenterology and Hepatology distributed throughout Italy. Blood LAL activity (nmol/spot/h) was measured with dried blood spot extracts using Lalistat 2.RESULTS:Overall, 133 patients had CC, and 141 patients had cirrhosis by other causes (61 viral, 53 alcoholic, 20 alcoholic + viral, 7 autoimmune). Mean age was 64.2 ± 13.4 years, and 28.5% were women. Patients with CC were older compared to other aetiology-cirrhosis, with a lower Child-Turcotte-Pugh (CTP, p=0.003) and MELD (p=0.009) score, and a higher prevalence of cardio-metabolic risk factors and previous ischemic events. In the whole cohort, median LAL activity value was 0.58 nmol/spot/h, 0.49 and 0.65 in the groups of CC and known-aetiology cirrhosis, respectively (p=0.002). The difference remained significant after adjustment for white blood cells count (p=0.001). Multivariable linear regression analysis showed that CC (vs. known aetiology, Beta = -0.144, p=0.018), platelet count (Beta = 0.398, p < 0.001) and CTP score (Beta = -0.133, p=0.022) were associated with log-LAL activity. Similar results were found using MELD as covariate.CONCLUSIONS:
We found a marked reduction of LAL activity in patients with cryptogenic cirrhosis compared to the other known aetiologies. A prospective study will clarify the role of LAL in chronic liver diseases.Copyright © 2017 Elsevier B.V. All rights reserved.
Kylmäaltistus ja rasvahappojen vapautuminen rasvapisaroista betaoksidaatiotiehen energiaksi
https://ars.els-cdn.com/content/image/1-s2.0-S1550413115005240-fx1.jpg
Volume 23, Issue 1, 12 January 2016, Pages 113-127
Article
Autophagy in the CNS and Periphery Coordinate Lipophagy and Lipolysis in the Brown Adipose Tissue and Liver
haku: Lysosomal Acidic Lipase deficiencey. LAL-geenifunktion puute tai heikkous
Best matches for Lysosomal Acidic lipase deficiency:
Infant case of lysosomal acid lipase deficiency: Wolman's disease.
Sadhukhan M et al. BMJ Case Rep.
(2014)
Lysosomal lipase deficiency: molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease.
Fasano T et al. Mol Genet Metab.
(2012)
1.
Duta-Mare
M, Sachdev V, Leopold C, Kolb D, Vujic N, Korbelius M, Hofer DC, Xia W,
Huber K, Auer M, Gottschalk B, Magnes C, Graier WF, Prokesch A, Radovic
B, Bogner-Strauss JG, Kratky D.
Biochim Biophys Acta. 2018 Apr;1863(4):467-478. doi: 10.1016/j.bbalip.2018.01.011. Epub 2018 Jan 31.
Biochim Biophys Acta. 2018 Apr;1863(4):467-478. doi: 10.1016/j.bbalip.2018.01.011. Epub 2018 Jan 31.
Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis.
Duta-Mare M1, Sachdev V1, Leopold C1, Kolb D2, Vujic N1, Korbelius M1, Hofer DC3, Xia W3, Huber K3, Auer M1, Gottschalk B1, Magnes C4, Graier WF5, Prokesch A1, Radovic B5, Bogner-Strauss JG6, Kratky D7.
Abstract
Abstract
Lysosomal acid lipase
(LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and
triacylglycerols in lysosomes of multiple cells and tissues. Here, we
explored the role of LAL in brown adipose tissue (BAT). LAL-deficient
(Lal-/-) mice exhibit markedly reduced UCP1 expression in BAT, modified
BAT morphology with accumulation of lysosomes, and mitochondrial
dysfunction, consequently leading to regular hypothermic events in mice
kept at room temperature. Cold exposure resulted in reduced lipid uptake
into BAT, thereby aggravating dyslipidemia and causing life threatening
hypothermia in Lal-/- mice. Linking LAL as a potential regulator of
lipoprotein lipase activity, we found Angptl4 mRNA expression upregulated in BAT. Our data demonstrate that LAL is critical for shuttling fatty acids derived from circulating lipoproteins to BAT during cold exposure. We conclude that inhibited lysosomal lipid hydrolysis in BAT leads to impaired thermogenesis in Lal-/- mice.KEYWORDS:
Brown adipose tissue; Dyslipidemia; LAL deficiency; Lysosome; Thermogenesis; UCP1
Free PMC Article
2.
Tuohetahuntila M, Molenaar MR, Spee B, Brouwers JF, Wubbolts R, Houweling M, Yan C, Du H, VanderVen BC, Vaandrager AB, Helms JB.
J Biol Chem. 2017 Jul 28;292(30):12436-12448. doi: 10.1074/jbc.M117.778472. Epub 2017 Jun 14.
Activation of hepatic stellate cells (HSCs) is a critical step in the
development of liver fibrosis. During activation, HSCs lose their lipid
droplets (LDs) containing triacylglycerols (TAGs), cholesteryl esters,
and retinyl esters (REs). We previously provided evidence for the
presence of two distinct LD pools, a preexisting and a dynamic LD pool.
Here we investigate the mechanisms of neutral lipid metabolism in the
preexisting LD pool. To investigate the involvement of lysosomal degradation of neutral lipids, we studied the effect of lalistat, a specific lysosomal acid lipase (LAL/Lipa) inhibitor on LD degradation in HSCs during activation in vitro
The LAL inhibitor increased the levels of TAG, cholesteryl ester, and
RE in both rat and mouse HSCs. Lalistat was less potent in inhibiting
the degradation of newly synthesized TAG species as compared with a more
general lipase inhibitor orlistat. Lalistat also induced the presence of RE-containing LDs in an acidic
compartment. However, targeted deletion of the Lipa gene in mice
decreased the liver levels of RE, most likely as the result of a gradual
disappearance of HSCs in livers of Lipa-/- mice. Lalistat
partially inhibited the induction of activation marker α-smooth muscle
actin (α-SMA) in rat and mouse HSCs. Our data suggest that LAL/Lipa is
involved in the degradation of a specific preexisting pool of LDs and
that inhibition of this pathway attenuates HSC activation.Free PMC Article
3.
Chuang JC, Lopez AM, Turley SD.
Biochem Pharmacol. 2017 Jul 1;135:116-125. doi: 10.1016/j.bcp.2017.03.010. Epub 2017 Mar 18.
- PMID:
- 28322747
4.
Xu X, Yuan X, Li N, Dewey WL, Li PL, Zhang F.
J Cell Mol Med. 2016 Jun;20(6):1001-13. doi: 10.1111/jcmm.12788. Epub 2016 Jan 28.
The disruption in transportation of oxLDL-derived cholesterol and the
subsequent lipid accumulation in macrophages are the hallmark events in
atherogenesis. Our recent studies demonstrated that lysosomal
Ca(2+) messenger of nicotinic acid adenine dinucleotide phosphate
(NAADP), an enzymatic product of CD38 ADP-ribosylcyclase (CD38),
promoted lipid endocytic trafficking in human fibroblast cells. The
current studies are designed to examine the functional role of
CD38/NAADP pathway in the regulation of lysosomal
cholesterol efflux in atherosclerosis. Oil red O staining showed that
oxLDL concentration-dependently increased lipid buildup in bone
marrow-derived macrophages from both wild type and CD38(-/-) , but to a
significant higher extent with CD38 gene deletion. Bodipy 493/503
fluorescence staining found that the deposited lipid in macrophages was
mainly enclosed in lysosomal
organelles and largely enhanced with the blockade of CD38/NAADP
pathway. Filipin staining and direct measurement of lysosome fraction
further revealed that the free cholesterol constituted a major portion
of the total cholesterol segregated in lysosomes. Moreover, in situ
assay disclosed that both lysosomal lumen acidity and the acid lipase
activity were reduced upon cholesterol buildup in lysosomes. In
CD38(-/-) mice, treatment with Western diet (12 weeks) produced
atherosclerotic damage in coronary artery with striking lysosomal
cholesterol sequestration in macrophages. These data provide the first
experimental evidence that the proper function of CD38/NAADP pathway
plays an essential role in promoting free cholesterol efflux from
lysosomes and that a defection of this signalling leads to lysosomal cholesterol accumulation in macrophages and results in coronary atherosclerosis in CD38(-/-) mice.Free PMC Article
5.
Zhao T, Du H, Blum JS, Yan C.
Oncotarget. 2016 Jan 12;7(2):1529-43. doi: 10.18632/oncotarget.6414.
Lysosomal acid lipase
(LAL) is a key enzyme controlling neutral lipid metabolic signaling in
myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient
(lal-/-) mice directly stimulate cancer cell proliferation. PPARγ ligand
treatment inhibited lal-/- MDSCs stimulation of tumor cell growth and
metastasis in vivo, and tumor cell proliferation and migration in vitro.
In addition, PPARγ ligand treatment impaired lal-/- MDSCs
transendothelial migration, and differentiation from lineage-negative
cells. The corrective effects of PPARγ ligand on lal-/- MDSCs functions
were mediated by regulating the mammalian target of rapamycin (mTOR)
pathway, and subsequently blocking MDSCs ROS overproduction.
Furthermore, in the myeloid-specific dominant-negative PPARγ (dnPPARγ)
overexpression bitransgenic mouse model, tumor growth and metastasis
were enhanced, and MDSCs from these mice stimulated tumor cell
proliferation and migration. MDSCs with dnPPARγ overexpression showed
increased transendothelial migration, overactivation of the mTOR
pathway, and ROS overproduction. These results indicate that PPARγ plays
a critical role in neutral lipid metabolic signaling controlled by LAL,
which provides a mechanistic basis for clinically targeting MDSCs to
reduce the risk of cancer proliferation, growth and metastasis.KEYWORDS:
lipid metabolic signaling; lysosomal acid lipase; myeloid-derived suppressor cells; peroxisome proliferator-activated receptor-γ; tumor growth and metastasis
Free PMC Article
6.
Rajamohan F, Reyes AR, Ruangsiriluk W, Hoth LR, Han S, Caspers N, Tu M, Ward J, Kurumbail RG.Protein Expr Purif. 2015 Jun;110:22-9. doi: 10.1016/j.pep.2014.12.009. Epub 2015 Jan 22.
Lysosomal acid lipase
(LAL) is a serine hydrolase which hydrolyzes cholesteryl ester and
triglycerides delivered to the lysosomes into free cholesterol and free
fatty acids.
Mutations in the LAL gene (LIPA) result in accumulation of triglycerides
and cholesterol esters in various tissues of the body, leading to
pathological conditions such as Wolman's disease (WD) and cholesteryl
ester storage disease (CESD). CESD patients homozygous for His295Tyr
(H295Y) mutation have less than 5% of normal LAL activity. To shed light
on the molecular basis for this loss-of-function phenotype, we have
generated the recombinant H295Y enzyme and studied its biophysical and
biochemical properties. No significant differences were observed in the
expression levels or glycosylation patterns between the mutant and the
wild type LAL. However, the H295Y mutant displayed only residual
enzymatic activity (<5 20="" 5.0="" a="" aggregate.="" amino="" as="" at="" besides="" class="highlight" compared="" exists="" expression="" fibroblasts="" h295y="" has="" high="" his295="" in="" is="" lal="" lower="" majority="" melting="" molecular="" monomer="" mostly="" mutant="" mutation="" of="" other="" ph="" showed="" soluble="" span="" studies="" temperature="" that="" the="" to="" transient="" type.="" type="" vast="" wd="" while="" wild="">acids
Cholesteryl ester storage disease (CESD); LAL-deficiency; Lipid metabolism; Lysosomal acid lipase (LAL); Protein aggregation; Wolman’s disease (WD)
7.
Sadhukhan M, Saha A, Vara R, Bhaduri B.
BMJ Case Rep. 2014 May 15;2014. pii: bcr2013202652. doi: 10.1136/bcr-2013-202652.
Lysosomal acid lipase (LAL) deficiency
is a rare autosomal recessive disorder which causes two distinct
clinical phenotypes: Wolman's disease and cholesterol ester storage
disease. LAL hydrolyses LDL-derived triglycerides and cholesterol esters
to glycerol or cholesterol and free fatty acids. Its deficiency leads to accumulation of intracellular triglycerides and/or cholesterol esters. In early onset LAL deficiency,
clinical manifestations start in the first few weeks of life with
persistent vomiting, failure to thrive, hepatosplenomegaly, liver
dysfunction and hepatic failure. Adrenal calcification is a striking
feature but is present in only about 50% of cases. We report a case of
an infant presenting with vomiting, diarrhoea, hepatosplenomegaly and
poor weight gain that was subsequently diagnosed as Wolman's disease. He
was entered into a clinical trial for LAL replacement therapy. This
case reinforces that early onset LAL deficiency should be considered in a baby presenting with failure to thrive, gastrointestinal symptoms and hepatosplenomegaly.
- PMID:
- 24832708
- PMCID:
- PMC4024536
- DOI:
- 10.1136/bcr-2013-202652
8.
Ding X, Du H, Yoder MC, Yan C.
Am J Pathol. 2014 Feb;184(2):397-408. doi: 10.1016/j.ajpath.2013.10.015. Epub 2013 Nov 26.
Lysosomal acid lipase (LAL) is essential for the hydrolysis of cholesteryl esters and triglycerides to generate cholesterol and free fatty acids
in cellular lysosomes. Ablation of the lal gene (lal(-/-)) systemically
increased expansion of cluster of differentiation molecule 11b (CD11b),
lymphocyte antigen 6G (Ly6G) myeloid-derived suppressor cells (MDSCs)
that caused myeloproliferative neoplasms in mice. Study of lal(-/-) bone
marrow Ly6G(+) MDSCs via transcriptional profiling showed increases in
mammalian target of rapamycin (mTOR) signaling pathway transcripts.
Injection of mTOR pharmacologic inhibitors into lal(-/-) mice
significantly reduced bone marrow myelopoiesis and systemic
CD11b(+)Ly6G(+) cell expansion. Rapamycin treatment of lal(-/-) mice
stimulated a shift from immature CD11b(+)Ly6G(+) cells to CD11b(+)
single-positive cells in marrow and tissues and partially reversed the
increased cell proliferation, decreased apoptosis, increased ATP
synthesis, and increased cell cycling of bone marrow CD11b(+)Ly6G(+)
cells obtained from lal(-/-) mice. Pharmacologic and siRNA suppression
of mTOR, regulatory-associated protein of mTOR, rapamycin-insensitive
companion of mTOR, and Akt1 function corrected CD11b(+)Ly6G(+) cell in
lal(-/-) mice development from Lin(-) progenitor cells and reversed the
immune suppression on T-cell proliferation and function in association
with decreased reactive oxygen species production, and recovery from
impairment of mitochondrial membrane potential compared with control
mutant cells. These results indicate a crucial role of LAL-regulated
mTOR signaling in the production and function of CD11b(+)Ly6G(+) cells.
The mTOR pathway may serve as a novel target to modulate the emergence
of MDSCs in those pathophysiologic states in which these cells play an
immunosuppressive role.Free PMC Article
9.
Thelwall
PE, Smith FE, Leavitt MC, Canty D, Hu W, Hollingsworth KG, Thoma C,
Trenell MI, Taylor R, Rutkowski JV, Blamire AM, Quinn AG.
J Hepatol. 2013 Sep;59(3):543-9. doi: 10.1016/j.jhep.2013.04.016. Epub 2013 Apr 25.Abstract BACKGROUND & AIMS:Lysosomal Acid Lipase (LAL) deficiency
is a rare metabolic storage disease, caused by a marked reduction in
activity of LAL, which leads to accumulation of cholesteryl esters (CE)
and triglycerides (TG) in lysosomes in many tissues. We used (1)H
magnetic resonance (MR) spectroscopy to characterize the abnormalities
in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency
rat model. Secondly, we used MR spectroscopy to monitor the effects of
an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant
human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model. METHODS:Human
studies employed cohorts of LAL-deficient patients and NAFLD subjects.
Rat experimental groups comprised ex vivo liver samples of wild type,
NAFLD, LAL-deficient, and LAL-deficient rats receiving 4weeks of
sebelipase alfa treatment. Hepatic (1)H MR spectroscopy was performed
using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic
cholesterol and triglyceride content. RESULTS: CE accumulation was identified in LAL deficiency
in both human and preclinical studies. A significant decrease in
hepatic CE was observed in LAL-deficient rats following treatment with
sebelipase alfa. CONCLUSIONS: We demonstrate an entirely
non-invasive method to identify and quantify the hepatic lipid signature
associated with a rare genetic cause of fatty liver. The approach
provides a more favorable alternative to repeated biopsy sampling for
diagnosis and disease progression / treatment monitoring of patients
with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters.
Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. KEYWORDS: (1)H
MR spectroscopy; (13)C MR spectroscopy; CE; CESD; Cholesteryl ester
storage disease; ERT; Enzyme replacement therapy; LAL; LAL deficiency; LIPA; Liver fat; Lysosomal acid lipase; NAFLD; Sebelipase alfa; TG; Wolman disease; cholesteryl ester; cholesteryl ester storage disease; enzyme replacement therapy; lysosomal acid lipase; non-alcoholic fatty liver disease; triglyceride
10.
Fasano T, Pisciotta L, Bocchi L, Guardamagna O, Assandro P, Rabacchi C, Zanoni P, Filocamo M, Bertolini S, Calandra S.
Mol Genet Metab. 2012 Mar;105(3):450-6. doi: 10.1016/j.ymgme.2011.12.008. Epub 2011 Dec 17.
Wolman Disease (WD) and cholesteryl ester storage disease (CESD)
represent two distinct phenotypes of the same recessive disorder caused
by the complete or partial deficiency of lysosomal acidic lipase
(LAL), respectively. LAL, encoded by the LIPA gene, hydrolyzes
cholesteryl esters derived from cell internalization of plasma
lipoproteins. WD is a rapidly progressive and lethal disease
characterized by intestinal malabsorption, hepatic and adrenal failure.
CESD is characterized by hepatic fibrosis, hyperlipidemia and
accelerated atherosclerosis. Aim of the study was the identification of
LIPA mutations in three WD and eight CESD patients. The WD patients, all
deceased before the first year of age, were homozygous for two novel
mutations (c.299+1G>A and c.419G>A) or a mutation (c.796G>T)
previously reported as compound heterozygosity in a CESD patient. The
two mutations (c.419G>A and c.796G>T) resulting in truncated
proteins (p.W140* and p.G266*) and the splicing mutation (c.229+1G>A)
were associated with undetectable levels of LIPA mRNA in fibroblasts.
All eight CESD patients carried the common mutation c.894G>A known to
result not only in a major non-functional transcript with the skipping
of exon 8 (p.S275_Q298del), but also in a minor normally spliced
transcript producing 5-10% residual LAL activity. The c.894G>A
mutation was found in homozygosity in four patients and, as compound
heterozygosity, in association with a known (p.H295Y and p.G342R) or a
novel (p.W140*) mutation in four other CESD patients. Segregation
analysis performed in all patients harboring c.895G>A showed its
occurrence on the same haplotype suggesting a common founder ancestor.
The other WD and CESD mutations were associated with different
haplotypes.
11.
Qu P, Yan C, Blum JS, Kapur R, Du H.
J Immunol. 2011 Oct 1;187(7):3854-66. doi: 10.4049/jimmunol.1003358. Epub 2011 Sep 7.
- PMID:
- 21900179
12.
Xie X, Brown MS, Shelton JM, Richardson JA, Goldstein JL, Liang G.
Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15330-5. doi: 10.1073/pnas.1112751108. Epub 2011 Sep 6.
- PMID:
- 21896731
13.
Kaphalia BS, Bhopale KK, Kondraganti S, Wu H, Boor PJ, Ansari GA.
Toxicol Appl Pharmacol. 2010 Aug 1;246(3):154-62. doi: 10.1016/j.taap.2010.05.002. Epub 2010 May 15.
- PMID:
- 20478324
14.
Qu P, Du H, Wilkes DS, Yan C.
Am J Pathol. 2009 Mar;174(3):944-56. doi: 10.2353/ajpath.2009.080562. Epub 2009 Jan 29.
Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids
and cholesterol in lysosomes. In LAL gene-knockout (lal(-/-)) mice,
blockage of cholesteryl ester and triglyceride metabolism led to
abnormal organization of the thymus and spleen, as well as neutral lipid
accumulation in these organs. LAL deficiency
impaired T cell development in the thymus. Peripheral T cells were
reduced dramatically in lal(-/-) mice, due largely to increased
apoptosis and decreased proliferation of lal(-/-) T cells in the thymus
and peripheral compartments. These lal(-/-) T cells lost the ability to
respond to T cell receptor stimulation, including reduced expression of
cell surface receptor CD69, abolishment of T cell proliferation, and
decreased expression of T lymphokines after stimulation by either
anti-CD3 plus anti-CD28 or phorbol-12-myristate-13-acetate and
ionomycin. Differentiation of Th1 and Th2 CD4(+) effector lymphocytes by
T cell receptor stimulation was blocked in lal(-/-) mice. The ratio of
CD4(+)CD25(+)FoxP3(+) Tregs to CD4(+) T cells was increased in lal(-/-)
spleens. Bone marrow chimeras demonstrated retardation of T cell
development and maturation in lal(-/-) mice due to defects in T cell
precursors. Therefore, LAL, its downstream genes, and lipid mediators
all play essential roles in development, homeostasis, and function of T
cells. The altered development and function of lal(-/-) T cells
contributes to disease formation in various organs during LAL deficiency.Free PMC Article
15.
Lu JY, Hofmann SL.
J Lipid Res. 2006 Jul;47(7):1352-7. Epub 2006 Apr 20. Review.
- PMID:
- 16627894
16.
Lian X, Yan C, Qin Y, Knox L, Li T, Du H.
Am J Pathol. 2005 Sep;167(3):813-21.
The functional roles of neutral lipids in the lung are poorly
understood. However, blocking cholesteryl ester and triglyceride
metabolism in lysosomal acid lipase
gene knockout mice (lal-/-) results in severe pathogenic phenotypes in
the lung, including massive neutrophil infiltration, foamy macrophage
accumulation, unwanted cell growth, and emphysema. To elucidate the
mechanism underlining these pathologies, we performed Affymetrix
GeneChip microarray analysis of 1-, 3-, and 6-month-old mice and
identified aberrant gene expression that progressed with age. Among
changed genes, matrix metalloproteinase (MMP)-12, apoptosis inhibitor 6
(Api-6), erythroblast transformation-specific domain (Ets) transcription
factor family member Spi-C, and oncogene MafB were increased 100-, 70-,
40-, and 10-fold, respectively, in lal-/- lungs versus the wild-type
lungs. The pathogenic increases of these molecules occurred primarily in
alveolar type II epithelial cells. Transcriptional activities of the
MMP-12 and Api-6 promoters were stimulated by Spi-C or MafB in
respiratory epithelial cells. Treatment with 9-hydroxyoctadecanoic acids
and ciglitazone significantly rescued lal-/- pulmonary inflammation and
aberrant gene expression. In addition, both compounds as well as
peroxisome proliferator-activated receptor gamma inhibited MMP-12 and
Api-6 promoter activities. These data suggest that
inflammation-triggered cell growth and emphysema during lysosomal acid lipase deficiency are partially caused by peroxisome proliferator-activated receptor-gamma inactivation.Free PMC Article
17.
Lee J, Jiao X, Hejtmancik JF, Kaiser-Kupfer M, Gahl WA, Markello TC, Guo J, Chader GJ.
Invest Ophthalmol Vis Sci. 2001 Jul;42(8):1707-14.
- PMID:
- 11431432
18.
Das AK, Bellizzi JJ 3rd, Tandel S, Biehl E, Clardy J, Hofmann SL.
J Biol Chem. 2000 Aug 4;275(31):23847-51.
Palmitoyl-protein thioesterase-1 (PPT1) is a newly described lysosomal enzyme that hydrolyzes long chain fatty acids from lipid-modified cysteine residues in proteins. Deficiency
in this enzyme results in a severe neurodegenerative storage disorder,
infantile neuronal ceroid lipofuscinosis. Although the primary structure
of PPT1 contains a serine lipase
consensus sequence, the enzyme is insensitive to commonly used
serine-modifying reagents phenylmethylsulfonyl fluoride (PMSF) and
diisopropylfluorophosphate. In the current paper, we show that the
active site serine in PPT1 is modified by a substrate analog of PMSF,
hexadecylsulfonylfluoride (HDSF) in a specific and site-directed manner.
The apparent K(i) of the inhibition was 125 micrometer (in the presence
of 1.5 mm Triton X-100), and the catalytic rate constant for
sulfonylation (k(2)) was 3.3/min, a value similar to previously
described sulfonylation reactions. PPT1 was crystallized after
inactivation with HDSF, and the structure of the inactive form was
determined to 2.4 A resolution. The hexadecylsulfonyl was found to
modify serine 115 and to snake through a narrow hydrophobic channel that
would not accommodate an aromatic sulfonyl fluoride. Therefore, the
geometry of the active site accounts for the reactivity of PPT1 with
HDSF but not PMSF. These observations suggest a structural explanation
as to why certain serine lipases are resistant to modification by
commonly used serine-modifying reagents.Free Article
19.
Redonnet-Vernhet I, Chatelut M, Salvayre R, Levade T.
Hum Mutat. 1998;11(4):335-6.
- PMID:
- 9554751
20.
Ameis D, Brockmann G, Knoblich R, Merkel M, Ostlund RE Jr, Yang JW, Coates PM, Cortner JA, Feinman SV, Greten H.
J Lipid Res. 1995 Feb;36(2):241-50.
Cholesteryl ester storage disease (CESD) results from inherited deficiencies of the lysosomal hydrolase, acid lipase (LAL; E.C. 3.1.1.13). To establish the molecular defects in LAL deficiency,
two unrelated probands with severely reduced LAL activity were
examined. DNA amplification by reverse-transcription polymerase chain
reaction and subsequent sequence analysis of LAL cDNA identified two
mutant alleles. Patient 1, presenting with hepatosplenomegaly, mildly
elevated liver function tests, and hyperlipidemia, was homozygous for a
deletion of nucleotides 823 to 894 of the LAL cDNA. This 72-bp deletion
maintained the reading frame and resulted in a loss of 24 amino acids
from the LAL protein. Analysis of genomic DNA revealed that the 72 bp
corresponded to an exon of the LAL gene. A single G to A point mutation
at the last exon position was observed in the genomic DNA of patient 1,
indicating a splicing defect with consecutive exon skipping underlying
the 72-bp deletion. Patient 2 was a compound heterozygote for the 72-bp
deletion and a dinucleotide deletion at positions 967 and 968. This
deletion resulted in a shifted reading frame carboxyterminal of codon
296, and 43 random amino acids followed the frame shift. A premature stop at codon 339 truncated the mutant LAL protein by 34 amino acids.
Allele-specific hybridization confirmed that patient 1 was homozygous
for the 72-bp deletion mutation, and that patient 2 was a compound
heterozygote for the 72-bp deletion and the 2-bp deletion.Free Article
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