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Article ; Online: Lipid polarity gradient formed by ω-hydroxy lipids in tear film prevents dry eye disease

Masatoshi Miyamoto / Takayuki Sassa / Megumi Sawai / Akio Kihara

eLife, Vol

2020 Volume 9

Abstract: Meibum lipids form a lipid layer on the outermost side of the tear film and function to prevent water evaporation and reduce surface tension. (O-Acyl)-ω-hydroxy fatty acids (OAHFAs), a subclass of these lipids, are thought to be involved in connecting ... ...

Abstract	Meibum lipids form a lipid layer on the outermost side of the tear film and function to prevent water evaporation and reduce surface tension. (O-Acyl)-ω-hydroxy fatty acids (OAHFAs), a subclass of these lipids, are thought to be involved in connecting the lipid and aqueous layers in tears, although their actual function and synthesis pathway have to date remained unclear. Here, we reveal that the fatty acid ω-hydroxylase Cyp4f39 is involved in OAHFA production. Cyp4f39-deficient mice exhibited damaged corneal epithelium and shortening of tear film break-up time, both indicative of dry eye disease. In addition, tears accumulated on the lower eyelid side, indicating increased tear surface tension. In Cyp4f39-deficient mice, the production of wax diesters (type 1ω and 2ω) and cholesteryl OAHFAs was also impaired. These OAHFA derivatives show intermediate polarity among meibum lipids, suggesting that OAHFAs and their derivatives contribute to lipid polarity gradient formation for tear film stabilization.
Keywords	dry eye disease ; fatty acids ; fatty acid ω-hydroxylase ; lipids ; meibum ; tears ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The role of PNPLA1 in ω-O-acylceramide synthesis and skin barrier function

Hirabayashi, Tetsuya / Akio Kihara / Makoto Murakami

Biochimica et biophysica acta. 2019 June, v. 1864, no. 6

2019

Abstract: The human genome encodes nine enzymes belonging to the patatin-like phospholipase domain-containing lipase (PNPLA)/Ca2+-independent phospholipase A2 (iPLA2) family. Although most PNPLA/iPLA2 enzymes are widely distributed and act on phospholipids or ... ...

Abstract	The human genome encodes nine enzymes belonging to the patatin-like phospholipase domain-containing lipase (PNPLA)/Ca2+-independent phospholipase A2 (iPLA2) family. Although most PNPLA/iPLA2 enzymes are widely distributed and act on phospholipids or neutral lipids as (phospho)lipases to play homeostatic roles in lipid metabolism, the function of PNPLA1 remained a mystery until a few years ago. However, the recent finding that mutations in the human PNPLA1 gene are linked to autosomal recessive congenital ichthyosis (ARCI), as well as evidence obtained from biochemical and gene knockout studies, has shed light on the function of this enzyme in skin-specific sphingolipid metabolism rather than glycerophospholipid metabolism. PNPLA1 is specifically expressed in differentiated keratinocytes and plays a crucial role in the biosynthesis of ω-O-acylceramide, a particular class of sphingolipids that is essential for skin barrier function. PNPLA1 acts as a unique transacylase that specifically transfers linoleic acid from triglyceride to ω-hydroxy fatty acid in ceramide, thus giving rise to ω-O-acylceramide. In this review, we overview the biosynthetic route and biological role of epidermal ω-O-acylceramide, highlight the function of PNPLA1 as a bona fide acylceramide synthase required for proper skin barrier function and keratinocyte differentiation, and summarize the mutations of PNPLA1 currently identified in ARCI patients.This article is part of a Special Issue entitled Novel functions of phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau
Keywords	biochemical pathways ; biosynthesis ; ceramides ; gene targeting ; genes ; ichthyosis ; keratinocytes ; linoleic acid ; lipid metabolism ; mutation ; phospholipase A2 ; phospholipases ; phospholipids ; triacylglycerols
Language	English
Dates of publication	2019-06
Size	p. 869-879.
Publishing place	Elsevier B.V.
Document type	Article
ISSN	1388-1981
DOI	10.1016/j.bbalip.2018.09.010
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1

Masashi Isokawa / Takayuki Sassa / Satoko Hattori / Tsuyoshi Miyakawa / Akio Kihara

FASEB BioAdvances, Vol 1, Iss 12, Pp 747-

2019 Volume 759

Abstract: Abstract Very‐long‐chain fatty acids, with a chain length of >C20, are abundant in myelin sphingolipids. Recently, a de novo mutation in the ELOVL1 gene, which encodes fatty acid elongase, was identified in patients with neurocutaneous disorders ... ...

Abstract	Abstract Very‐long‐chain fatty acids, with a chain length of >C20, are abundant in myelin sphingolipids. Recently, a de novo mutation in the ELOVL1 gene, which encodes fatty acid elongase, was identified in patients with neurocutaneous disorders involving skin ichthyosis and multiple neurological abnormalities, including hypomyelination, spastic paraplegia, and high‐frequency deafness. However, the consequences of ELOVL1 deficiency for lipid composition and detailed pathological changes in the brain remain unclear. Here, we analyzed Elovl1 mutant mice as a model of human ELOVL1 deficiency. The mice exhibited a decreased postnatal survival rate, and some died of startle epilepsy. The acyl chain length of sphingolipids such as galactosylceramides, sulfatides, sphingomyelins, and ceramides in the brains of these mice was markedly shortened. Moreover, the mice exhibited reduced levels of galactosylceramides, which are important for myelin formation and stability. Electron microscope analysis of the corpus callosum in Elovl1 mutant mice revealed modest hypomyelination, especially in large‐diameter axons. Furthermore, behavioral testing of the mice revealed deficits such as poorer motor coordination and reduced acoustic startle response to high‐intensity stimulus. These findings provide clues to the molecular mechanism of the neurological symptoms of patients with the ELOVL1 mutation.
Keywords	galactosylceramide ; lipid ; spastic paraplegia ; very‐long‐chain fatty acids ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide

Yusuke Ohno / Nozomi Kamiyama / Shota Nakamichi / Akio Kihara

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 8

Abstract: Loss-of-function mutations in an enzyme of unknown function, PNPLA1, cause dry and scaling skin in humans. Here Ohnoet al. show that PNPLA1 is a transacylase that acts in the final step of acylceramide production- esterification between ω-hydroxyceramide ...

Abstract	Loss-of-function mutations in an enzyme of unknown function, PNPLA1, cause dry and scaling skin in humans. Here Ohnoet al. show that PNPLA1 is a transacylase that acts in the final step of acylceramide production- esterification between ω-hydroxyceramide and linoleic acid acylceramide, yielding a lipid essential for skin barrier function.
Keywords	Science ; Q
Language	English
Publishing date	2017-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Two modes of regulation of the fatty acid elongase ELOVL6 by the 3-ketoacyl-CoA reductase KAR in the fatty acid elongation cycle.

Tatsuro Naganuma / Akio Kihara

PLoS ONE, Vol 9, Iss 7, p e

2014 Volume 101823

Abstract: Fatty acids (FAs) are diverse molecules, and such diversity is important for lipids to exert their functions under several environmental conditions. FA elongation occurs at the endoplasmic reticulum and produces a variety of FA species; the FA elongation ...

Abstract	Fatty acids (FAs) are diverse molecules, and such diversity is important for lipids to exert their functions under several environmental conditions. FA elongation occurs at the endoplasmic reticulum and produces a variety of FA species; the FA elongation cycle consists of four distinct enzyme reactions. For this cycle to be driven efficiently, there must exist coordinated regulation of protein components of the FA elongation machinery. However, such regulation is poorly understood. In the present study, we performed biochemical analyses using the FA elongase ELOVL6 and the 3-ketoacyl-CoA reductase KAR, which catalyze the first and second steps of the FA elongation cycle, respectively. In vitro FA elongation assays using membrane fractions demonstrated that ELOVL6 activity was enhanced ∼10-fold in the presence of NADPH, although ELOVL6 itself did not require NADPH for its catalysis. On the other hand, KAR does use NADPH as a reductant in its enzyme reaction. Activity of purified ELOVL6 was enhanced by ∼3-fold in the presence of KAR. This effect was KAR enzyme activity-independent, since it was observed in the absence of NADPH and in the KAR mutant. However, ELOVL6 enzyme activity was further enhanced in a KAR enzyme activity-dependent manner. Therefore, KAR regulates ELOVL6 via two modes. In the first mode, KAR may induce conformational changes in ELOVL6 to become structure that can undergo catalysis. In the second mode, conversion of 3-ketoacyl-CoA to 3-hydroxyacyl-CoA by KAR may facilitate release of the product from the presumed ELOVL6-KAR complex.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Widespread tissue distribution and synthetic pathway of polyunsaturated C24:2 sphingolipids in mammals

Edagawa, Mai / Megumi Sawai / Yusuke Ohno / Akio Kihara

Biochimica et biophysica acta. 2018 Dec., v. 1863, no. 12

2018

Abstract: Sphingolipids are multifunctional lipids and a major constituent of the cell membranes of eukaryotes. Although the fatty acid (FA) moiety of sphingolipids is usually a saturated or monounsaturated FA, polyunsaturated FA (PUFA)-containing species also ... ...

Abstract	Sphingolipids are multifunctional lipids and a major constituent of the cell membranes of eukaryotes. Although the fatty acid (FA) moiety of sphingolipids is usually a saturated or monounsaturated FA, polyunsaturated FA (PUFA)-containing species also exist in mammalian tissues. In the present study, we showed that C24:2 PUFA-containing ceramide is one of the seven major ceramide species in a wide range of tissues. C24:2 ceramide levels were especially high in spleen and small intestine; in the former, it was the fourth most abundant ceramide species. However, both the synthetic pathway and the physiological function of C24:2 ceramide had yet to be identified. Tracer analysis using deuterium-labeled linoleic acid (C18:2) revealed that C24:2 ceramide is produced via elongation of linoleic acid. We also found that the FA elongase ELOVL1 and the ceramide synthase CERS2 were involved in C24:2 ceramide production. Sphingolipids are known to form lipid microdomains in membranes; however, in a detergent-resistant membrane (DRM) assay, we observed a lower proportion of C24:2 sphingomyelin in the DRM fraction than of saturated sphingomyelins, suggesting that C24:2 sphingolipids may act to negatively regulate lipid microdomain formation. Our findings expand our knowledge of sphingolipid diversity, and provide insight into how different sphingolipid molecular species play different functions in biological membranes.
Keywords	cell membranes ; ceramides ; eukaryotic cells ; linoleic acid ; mammals ; moieties ; monounsaturated fatty acids ; polyunsaturated fatty acids ; small intestine ; sphingomyelins ; sphingosine N-acyltransferase ; spleen ; tissue distribution ; tissues
Language	English
Dates of publication	2018-12
Size	p. 1441-1448.
Publishing place	Elsevier B.V.
Document type	Article
ISSN	1388-1981
DOI	10.1016/j.bbalip.2018.09.002
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Diverse meibum lipids produced by Awat1 and Awat2 are important for stabilizing tear film and protecting the ocular surface

Megumi Sawai / Keisuke Watanabe / Kana Tanaka / Wataru Kinoshita / Kento Otsuka / Masatoshi Miyamoto / Takayuki Sassa / Akio Kihara

iScience, Vol 24, Iss 10, Pp 103160- (2021)

2021

Keywords	Science ; Q
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Diverse meibum lipids produced by Awat1 and Awat2 are important for stabilizing tear film and protecting the ocular surface

Megumi Sawai / Keisuke Watanabe / Kana Tanaka / Wataru Kinoshita / Kento Otsuka / Masatoshi Miyamoto / Takayuki Sassa / Akio Kihara

iScience, Vol 24, Iss 5, Pp 102478- (2021)

2021

Abstract: Summary: A lipid layer consisting of meibum lipids exists in the tear film and functions in preventing dry eye disease. Although the meibum lipids include diverse lipid classes, the synthesis pathway and role of each class remain largely unknown. Here, ... ...

Abstract	Summary: A lipid layer consisting of meibum lipids exists in the tear film and functions in preventing dry eye disease. Although the meibum lipids include diverse lipid classes, the synthesis pathway and role of each class remain largely unknown. Here, we created single and double knockout (KO and DKO, respectively) mice for the two acyl-CoA wax alcohol acyltransferases (Awat1 and Awat2) and investigated their dry eye phenotypes and meibum lipid composition. Awat2 KO and DKO mice exhibited severe dry eye with meibomian gland dysfunction, whereas Awat1 KO mice had mild dry eye. In these mice, specific meibum lipid classes were reduced: (O-acyl)-ω-hydroxy fatty acids and type 1ω wax diesters in Awat1 KO mice, wax monoesters and types 1ω and 2ω wax diesters in Awat2 KO mice, and most of these in DKO mice. Our findings reveal that Awat1 and Awat2 show characteristic substrate specificity and together produce diverse meibum lipids.
Keywords	Science ; Q
Subject code	572
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Phs1 and the synthesis of very long chain Fatty acids are required for ballistospore formation.

Giuseppe Ianiri / Ritika Abhyankar / Akio Kihara / Alexander Idnurm

PLoS ONE, Vol 9, Iss 8, p e

2014 Volume 105147

Abstract: The production and dissemination of spores by members of the fungal kingdom is a major reason for the success of this eukaryotic lineage in colonizing most terrestrial ecosystems. Ballistospores are a type of spore produced by basidiomycete fungi, such ... ...

Abstract	The production and dissemination of spores by members of the fungal kingdom is a major reason for the success of this eukaryotic lineage in colonizing most terrestrial ecosystems. Ballistospores are a type of spore produced by basidiomycete fungi, such as the mushrooms and plant pathogenic rusts. These spores are forcefully discharged through a unique liquid-drop fusion mechanism, enabling the aerosolization of these particles that can contribute to plant disease and human allergies. The genes responsible for this process are unknown due to technical challenges in studying many of the fungi that produce ballistospores. Here, we applied newly-developed techniques in a forward genetic screen to identify genes required for ballistospore formation or function in a tractable red yeast, a species of Sporobolomyces. One strain bearing a mutation in the PHS1 gene was identified as a mirror mutant. PHS1 encodes 3-hydroxyacyl-CoA dehydratase required for the third step in very long chain fatty acid biosynthesis. The Sporobolomyces PHS1 gene complements the essential functions of a S. cerevisiae phs1 mutant. The Sporobolomyces phs1 mutant strain has less dehydratase activity and a reduction in very long chain fatty acids compared to wild type. The mutant strain also exhibits sensitivity to cell wall stress agents and loss of shooting due to a delay in ballistospore formation, indicating that the role of Phs1 in spore dissemination may be primarily in cellular integrity.
Keywords	Medicine ; R ; Science ; Q
Subject code	580
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: AM251 Suppresses Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells.

Tomoyo Yoshinaga / Kenichiro Uwabe / Shoichi Naito / Kenichi Higashino / Toru Nakano / Yoshito Numata / Akio Kihara

PLoS ONE, Vol 11, Iss 12, p e

2016 Volume 0167848

Abstract: Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is one of the causative mechanisms of kidney fibrosis. In our study, we screened lipophilic compounds using a lipid library including approximately 200 lipids to identify those ... ...

Abstract	Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is one of the causative mechanisms of kidney fibrosis. In our study, we screened lipophilic compounds using a lipid library including approximately 200 lipids to identify those that suppressed EMT induced by a transforming growth factor (TGF)-β1 stimulus. Initial screening was performed with the immortalized HK-2 renal tubule epithelial cell line. The most promising compounds were further tested in RPTEC primary renal tubule epithelial cells. We found that the synthetic lipid AM251 suppressed two hallmark events associated with EMT, the upregulation of collagen 1A1 (COL1A1) and downregulation of E-cadherin. Though AM251 is known to act as an antagonist for the cannabinoid receptor type 1 (CB1) and an agonist for the G protein-coupled receptor 55 (GRP55), the suppression of EMT by AM251 was not mediated through either receptor. Microarray analyses revealed that AM251 inhibited induction of several EMT transcription factors such as SNAIL1, which is the key inducer of EMT, and the AP-1 transcription factors FOSB and JUNB. Activation of SMAD2/3 and p38 mitogen-activated protein kinase (MAPK) was inhibited by AM251, with greater inhibition of the latter, indicating that AM251 acted upstream of SMAD/p38 MAPK in the TGF-β signaling pathway. Our findings regarding the effects of AM251 on the TGF-β signaling pathway may inform development of a novel therapeutic agent suppressing EMT, thus preventing kidney fibrosis.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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