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Enhancing the role of women in peacebuilding and politics in Ethiopia

Enhancing the role of women in peacebuilding and politics in Ethiopia 29 June 2022 — 1:00PM TO 2:30PM Anonymous (not verified) 16 June 2022 Online

Panellists discuss the priorities for promoting the agency of women in politics and peacebuilding in Ethiopia and approaches for combatting gender-based discrimination and violence.

The war in northern Ethiopia and conflicts elsewhere have disproportionately affected women and girls – including through the infliction of physical and sexual violence, the heightened impacts of displacement and disruptions to education, and the co-option of women’s experiences in narratives by aggressors of conflict.

Hard-won political gains in women’s rights have been undermined and deep-rooted gender inequalities exacerbated. Despite this, women remain central actors in politics, as well as in conflict resolution and mediation efforts. However, more needs to be done to promote the security and inclusion of women in finding sustainable solutions for Ethiopia’s long-term recovery and to institutionalize reforms for gender equity and development.

At this public event, panellists will discuss the priorities for improving women’s participation and equality in public decision-making in Ethiopia and how to strengthen the implementation of legislation on women’s rights. They will also discuss what societal shifts and approaches are needed to combat gender-based discrimination and violence and to promote the agency of women in peacebuilding.

This webinar is part of a series of events and outputs on Ethiopia’s political transition.

This event will also be broadcast live on the Chatham House Africa Programme’s Facebook page.




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Why Ethiopia must close its political gender gap

Why Ethiopia must close its political gender gap The World Today mhiggins.drupal 29 July 2022

Women urgently need to gain access to high office if the country hopes to survive, say Hilina Berhanu Degefa and Emebet Getachew.

At the end of 2021, Prime Minister Abiy Ahmed’s government announced the formation of a three-year national dialogue to address Ethiopia’s political crisis, looking at the ongoing civil war and conflict, inflation, unemployment, drought and other urgent domestic issues. 

But, while efforts have been made to ensure the participation of women in this dialogue, it must be more than symbolic otherwise gaps in meaningful gender inclusion could have significant implications on the very survival of the country.
 
One of the challenges for meaningful inclusion is that Ethiopia is a highly patriarchal society. Patriarchal norms and practices permeate all aspects of the country’s social, economic and political life. Women constitute over half of the Ethiopian population and represent 41 per cent of the national parliament.

Nevertheless, most political parties, including those with liberal credentials, are exclusively governed by men, with women taking almost no part in key decision-making processes. As a result, women are relegated to the margins of political and economic activities. 

Prime Minister Abiy Ahmed won praise for appointing a gender-balanced cabinet in 2018. By 2021, women accounted for just 36 per cent of positions


Though there has been little systematic study of the structural challenges faced by Ethiopian women in politics, women members of political parties encounter many barriers, including political violence, male-coded norms and sexist discourses across Ethiopian society.
 
The nature and scale of political violence perpetrated against women is particularly disempowering and affects their ability to participate in political spaces.

While attitudes to gender equality, sexual violence and gender discrimination are often trivialized, they remain ever-present threats in women’s lives. As late as 2016, a significant minority of men still believed wife-beating to be justified in certain situations. Even when women overcome social pressure to pursue their political ambitions, patriarchal views and practices within political party structures about the role of women significantly undermine their active participation and engagement. 

The political space is even more inaccessible to women with disabilities and in conflict and climate-related crises such as among internally displaced people and in pastoral communities. Male-coded norms ingrained at both party and community levels remain a significant concern. Specifically, sex in exchange for candidacy, inconsiderate working schedules affecting women with children and denial of access to equal information and financial resources are frequently reported as major internal hurdles among political parties.

Closing the gender gap could offer Ethiopia a new beginning

Many political initiatives designed to tackle these gender imbalances often have been driven by short-term political considerations without proper gender-gap assessment and policy analysis. In most cases, the authorities have viewed gender-targeted reforms as acts of benevolence, dispensed by the government, without adopting the legal and financial measures necessary to ensure sustainability and impact.
 
Take, for example, Abiy’s appointment of a 50:50 gender-balanced cabinet in 2018. At the time, much was made about its transformative potential, with the prime minister attracting widespread global approval. Yet, a cabinet reshuffle in 2021 reduced female representation to 36.3 per cent, with far less scrutiny or accountability.

The proposed national dialogue presents an ideal opportunity for Ethiopian women to begin reshaping attitudes


This indicates that gender equality in Ethiopia is not considered a priority but rather an endeavour for more opportune, ‘stable’ times. Without thorough measures that create the conditions for real change, the aspiration of having a gender-balanced cabinet will always be challenging to translate into lasting equal representation.
 
The proposed national dialogue presents an ideal opportunity for Ethiopian women to begin reshaping attitudes and closing the gender gap through their inclusion and participation in the political process. To do so, three issues must be addressed.
 
First, the varying rights of women need to be consolidated, including on identity, constitutional reform and economic issues .

Second, gender equality considerations must be absorbed into mainstream political discourse at all levels.

Third, the experiences of women in the recent war, other ongoing conflicts and past and lingering legacies of political violence targeting women from specific communities, must be acknowledged and remedied. 

If Ethiopia is indeed serious about addressing its asymmetric gender power dynamics, this national dialogue provides an excellent opportunity to begin the process. Genuine participation of women as independent actors, with their own agency, could offer Ethiopia a new beginning.




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Reflections at 100: Empire and decolonization

Reflections at 100: Empire and decolonization Audio MVieira 1 November 2022

How did leading academics and policymakers think about and impact imperialism and decolonization from the 1920s to 1970s?

This episode of Reflections at 100, marking the centenary of International Affairs, looks at how empire and decolonization have been discussed in the journal.

Isabel and Krisztina speak to Meera Sabaratnam about how thinkers and policymakers from the 1920s to 1970s understood both empire and then decolonization. Meera highlights four tensions present within the discussions, and how these may impact the international order today.

Inderjeet Parmar delves deeper into the influence of Chatham House at the time and situates these discussions in the broader think-tank and global context.

Reflections at 100 is a mini-series accompanying the journal’s centenary Archive Collections. The collections bring together articles from our archive which speak to the past, present, and future of current affairs issues. In each podcast episode we speak to editors and contributors to the collection and explore what the research tells us about policymaking today. 

Explore the Archive Collection, free to access until mid-November 2022, including Meera’s introduction: 100 years of empire and decolonization.

International Affairs was started at Chatham House in 1922 to communicate research to members who could not attend in person. Over the past 100 years it has transformed into a journal that publishes academically rigorous and policy relevant research. It is published for Chatham House by Oxford University Press. Read the latest issue here. 




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Fighting over ‘white gold’: Sesame in Ethiopia and Sudan

Fighting over ‘white gold’: Sesame in Ethiopia and Sudan Expert comment LJefferson 3 April 2023

The supply chain of a seemingly innocuous cash crop – sesame – has intersected with transnational conflict dynamics, exacerbating tensions between Ethiopia and Sudan.

Late 2020 saw the beginning of the devastating war in Tigray and the occupation of a disputed region on the Ethiopia–Sudan border – Al Fashaga – by the Sudanese army. These shocks disrupted settled patterns of land ownership and control in both Ethiopia’s volatile north and Sudan’s borderlands, historically the heart of the sesame and oilseed production that is economically vital to both countries.

These seemingly harmless cash crops are now embedded in local, subnational and national political contestations in both countries. Sesame value chains are being reshaped, with power and profits being used to entrench the grip of political and armed actors who are reinforcing new patterns of land control and driving informal and illicit trade – impacting the coping mechanisms of local communities and threatening to fuel further conflict.

Regional rivalries drive contestation over the Ethiopia supply chain

Internal borders between most of Ethiopia’s regions are marked by boundary disputes, which often degenerate into violent conflict. The most important is between the Tigray and Amhara regions. Since the war began in 2020, the Amhara region has annexed vast areas of western and southern Tigray, which the Amhara region claims were taken from them by Tigray 30 years ago, after the Tigray People’s Liberation Front (TPLF) dominated ethnic coalition came to power.

Conflict has exacerbated a steady decline in formal revenues from sesame exports, dropping over $115 million from 2016 to 2021.

Ethiopia’s exports of spices, oilseeds and pulses brought in over half a billion dollars in 2021, roughly a quarter of the country’s total export revenues and second only to coffee. The sector has been rocked by the war in the north, which accounted for much of Ethiopia’s sesame production, with an estimated 500,000 hectares of sesame fields taken out of cultivation during the 2021 growing season. Conflict has exacerbated a steady decline in formal revenues from sesame exports, dropping over $115 million from 2016 to 2021.

Alongside falling production, the previously integrated value chain has been disrupted and decentralized by political fragmentation and land competition between Amharas and Tigrayans. Before the war, the agricultural sector in Western Tigray/Welkait was dominated by Tigrayan business interests, through the TPLF’s regional endowment fund EFFORT, a business conglomerate including subsidiaries such as Guna Trading House, and Hiwot Agricultural Mechanization.

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Two-minute video explainer: Supply chains, land contestation and conflict in the Horn of Africa

The taking of the area by Amhara forces in late 2020 saw the control over agricultural supply chains shift to actors from the Amhara region, amid contestation between regional officials, businessmen and security actors, backed by political elites. Thousands of displaced ethnic Tigrayan inhabitants of the area have been replaced by ethnic Amharas, enticed to settle there by the Amhara regional government’s offer of grants and leases for land which promise better livelihoods. The sesame they farm is now largely exported through informal and illicit channels, with profits used to reinforce de facto regional control.    

But there is also contestation within the Amhara region over the land and sesame supply chain between sub-regional elites from Gojjam, Gondar and indigenous Welkaites. Welkaites, who were marginalized under TPLF rule, believed that by aligning themselves with powerful Amharas they would reclaim land and influence. But this has not been fully realized, with the local administration reliant on Amhara region subsidies, rather than the federal budget. With little support from the federal government, local Welkait officials are strengthening their ties with Eritrea.

The Ethiopian government’s pursuit of peace with Tigray may lead it to turn away from the Amhara region, which could result in a renewed showdown between Amhara and Tigrayan forces.

At the national level, regional contestation over the control over Western Tigray/Welkait feeds into shifting political alliances between the Amhara, Tigrayans and Oromo which threaten the sustainability of the peace agreement struck between the federal government and TPLF in November 2022 – despite efforts by the government to defer the thorny issue.

While the constitutional return of the land to Tigray remains unlikely anytime soon, there is a feeling that Amhara control over Western Tigray/Welkait is no longer certain. The Ethiopian government’s pursuit of peace with Tigray may lead it to turn away from the Amhara region, despite their alliance during and before the war, which could result in a renewed showdown between Amhara and Tigrayan forces.

The prospect of losing territory could also heighten Amhara nationalist claims on Al Fashaga – the loss of which was partly offset by gaining Western Tigray/Welkait – leading to renewed conflagration with Sudan, outside of federal direction. Eritrea’s presence and alliance with Amhara militias remains a concern, given Asmara’s demonstrable ability to inflame tensions.  

Sudan’s securocrats battle over resources to entrench political power

The war in northern Ethiopia was also used opportunistically by the Sudanese Armed Forces (SAF) to take control of the fertile Al Fashaga borderland. This roughly 250 sq km area had been awarded to Sudan when the boundary was initially demarcated by the British in 1903, a ruling that remained contested by Ethiopia. An uneasy truce had seen Ethiopian farmers cultivate the land under nominal Sudanese administration; a settlement that collapsed in 2020 when thousands of predominantly Amhara farmers were evicted.

Local Sudanese farmers have also lost out – with some not compensated for the loss of lands to their own military, with land given to people from other parts of the country, and through lost relationships with Ethiopian farmers, labourers and investors.

The Sudanese military now allegedly controls more than 90 per cent of the disputed areas and security-linked companies and investors have moved into the lucrative sesame sector, re-routing the supply chain, which used to flow largely through Ethiopian markets. These companies are connected to Sudan’s Military Industrial Corporation, a vast conglomerate of business subsidiaries controlled by SAF – which is headed by General Abdel Fattah al-Burhan.

Competition between Sudanese security actors fuels volatile political rivalries, and further entrenches military control of economic resources.

The commander of the paramilitary Rapid Support Forces, General Mohamed Hamdan Dagolo (or Hemedti), also has interests in agriculture, through his family business Al-Junaid. Both sit at the top of Sudan’s Sovereign Council. Hemedti’s competition with Burhan has seen him develop relations with Ethiopia’s prime minister – counter-balanced by recent rapprochement between Abiy and Burhan – as well as senior Amhara leaders, including over business activities.

Moreover, competition between Sudanese security actors fuels volatile political rivalries, and further entrenches military control of economic resources, undermining civilians at a time when pro-democracy forces are seeking to restore a reform-minded government. One of the key challenges for a new civilian government will be to quickly build up a domestic revenue base to compete with the economic heft of the country’s prominent security institutions, which will demand taking on military-controlled holdings in civic sectors such as agriculture, including sesame.

Informal and illicit trade reinforces conflict dynamics

This context has driven the informalization of trade, with cash crops such as sesame increasingly exported outside of formal channels and connected to other illicit cross-border activities between Ethiopia and Sudan. Indications are that sesame production in Western Tigray/Welkait has recovered significantly during the current 2022/23 harvest season. However, rather than contributing much needed currency to soften Ethiopia’s forex crisis, the Amhara elite-controlled supply chain is primarily being used to secure a variety of regional interests.




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Comparison Between Brain and Cerebellar Autoradiography Using [18F]Flortaucipir, [18F]MK6240, and [18F]PI2620 in Postmortem Human Brain Tissue

Visual Abstract




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FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study

Visual Abstract




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[18F]FDG and [68Ga]Ga-FAPI-04-Directed Imaging for Outcome Prediction in Patients with High-Grade Neuroendocrine Neoplasms

Visual Abstract




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Feasibility, Tolerability, and Preliminary Clinical Response of Fractionated Radiopharmaceutical Therapy with 213Bi-FAPI-46: Pilot Experience in Patients with End-Stage, Progressive Metastatic Tumors

Visual Abstract




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Novel Proteomic Profiling of Epididymal Extracellular Vesicles in the Domestic Cat Reveals Proteins Related to Sequential Sperm Maturation with Differences Observed between Normospermic and Teratospermic Individuals

Tricia Rowlison
Dec 1, 2020; 19:2090-2103
Research




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CMMB (Carboxylate Modified Magnetic Bead) -based isopropanol gradient peptide fractionation (CIF) enables rapid and robust off-line peptide mixture fractionation in bottom-up proteomics

Weixian Deng
Dec 22, 2020; 0:RA120.002411v1-mcp.RA120.002411
Research




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Accelerating the field of epigenetic histone modification through mass spectrometry-based approaches

Congcong Lu
Nov 17, 2020; 0:R120.002257v1-mcp.R120.002257
Review




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ProAlanase is an Effective Alternative to Trypsin for Proteomics Applications and Disulfide Bond Mapping

Diana Samodova
Dec 1, 2020; 19:2139-2156
Technological Innovation and Resources




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Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

Stephanie E. Hood
Dec 1, 2020; 61:1720-1732
Research Articles




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Stimulation of ABCB4/MDR3 ATPase activity requires an intact phosphatidylcholine lipid

Martin Prescher
Dec 1, 2020; 61:1605-1616
Research Articles




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PLRP2 selectively localizes synaptic membrane proteins via acyl-chain remodeling of phospholipids

Hideaki Kuge
Dec 1, 2020; 61:1747-1763
Research Articles




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Gene Networks and Pathways for Plasma Lipid Traits via Multi-tissue Multi-omics Systems Analysis

Montgomery Blencowe
Dec 23, 2020; 0:jlr.RA120000713v1-jlr.RA120000713
Research Articles




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LDL apheresis as an alternate method for plasma LPS purification in healthy volunteers and dyslipidemic and septic patients

Auguste Dargent
Dec 1, 2020; 61:1776-1783
Research Articles




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Lipid signature of advanced human carotid atherosclerosis assessed by mass spectrometry imaging

Astrid M. Moerman
Dec 23, 2020; 0:jlr.RA120000974v1-jlr.RA120000974
Research Articles




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Identification of unusual phospholipids from bovine heart mitochondria by HPLC-MS/MS

Junhwan Kim
Dec 1, 2020; 61:1707-1719
Research Articles




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Lipid metabolism dysregulation in diabetic retinopathy

Julia V Busik
Dec 23, 2020; 0:jlr.TR120000981v1-jlr.TR120000981
Thematic Reviews




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Mutation in the distal NPxY motif of LRP1 alleviates dietary cholesterol-induced dyslipidemia and tissue inflammation

Anja Jaeschke
Dec 9, 2020; 0:jlr.RA120001141v1-jlr.RA120001141
Research Articles




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SCD1 promotes lipid mobilization in subcutaneous white adipose tissue

Ying Zou
Dec 1, 2020; 61:1589-1604
Research Articles




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Generation and validation of a conditional knockout mouse model for the study of the Smith-Lemli-Opitz Syndrome

Babunageswararao Kanuri
Nov 17, 2020; 0:jlr.RA120001101v1-jlr.RA120001101
Research Articles




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Perilipin 5 S155 phosphorylation by PKA is required for the control of hepatic lipid metabolism and glycemic control

Stacey N Keenan
Dec 17, 2020; 0:jlr.RA120001126v1-jlr.RA120001126
Research Articles




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Update on LIPID MAPS classification, nomenclature, and shorthand notation for MS-derived lipid structures

Gerhard Liebisch
Dec 1, 2020; 61:1539-1555
Special Report




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Problem Notes for SAS®9 - 61815: SAS Episode Analytics 3.1 - Audit table is required in order to capture user interactions with the user interface

SAS  Episode Analytics 3.1 requires the ability to capture user interactions with the user interface for auditing purposes. To support the required functionality a new table has been add




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Bisretinoid phospholipid and vitamin A aldehyde: Shining a light [Thematic Reviews]

Vitamin A aldehyde covalently bound to opsin protein is embedded in a phospholipid-rich membrane that supports photon absorption and phototransduction in photoreceptor cell outer segments. Following absorption of a photon, the 11-cis-retinal chromophore of visual pigment in photoreceptor cells isomerizes to all-trans-retinal. To maintain photosensitivity 11-cis-retinal must be replaced. At the same time, however, all-trans-retinal has to be handled so as to prevent nonspecific aldehyde activity. Some molecules of retinaldehyde upon release from opsin are efficiently reduced to retinol. Other molecules are released into the lipid phase of the disc membrane where they form a conjugate (N-retinylidene-PE, NRPE) through a Schiff base linkage with phosphatidylethanolamine (PE). The reversible formation of NRPE serves as a transient sink for retinaldehyde that is intended to return retinaldehyde to the visual cycle. However, if instead of hydrolyzing to PE and retinaldehyde, NRPE reacts with a second molecule of retinaldehyde a synthetic pathway is initiated that leads to the formation of multiple species of unwanted bisretinoid fluorophores. We report on recently identified members of the bisretinoid family some of which differ with respect to the acyl chains associated with the glycerol backbone. We discuss processing of the lipid moieties of these fluorophores in lysosomes of retinal pigment epithelial (RPE) cells, their fluorescence characters and new findings related to light and iron-associated oxidation of bisretinoids.




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Lipid Conformational Order and the Etiology of Cataract and Dry Eye [Thematic Reviews]

     Lens and tear film lipids are as unique as the systems they reside in. The major lipid of the human lens is dihydrosphingomylein, found in quantity only in the lens. The lens contains a cholesterol to phospholipid molar ratio as high as 10:1, more than anywhere in the body. Lens lipids contribute to maintaining lens clarity, and alterations in lens lipid composition due to age are likely to contribute to cataract. Lens lipid composition reflects adaptations to the unique characteristics of the lens: no turnover of lens lipids or proteins; the lowest amount of oxygen than any other tissue and contains almost no intracellular organelles. The tear film lipid layer (TFLL) is also unique. The TFLL is a thin, 100 nm layer of lipid on the surface of tears covering the cornea that contributes to tear film stability. The major lipids of the TFLL are wax esters and cholesterol esters that are not found in the lens. The hydrocarbon chains associated with the esters are longer than those found anywhere in the body, as long as 32 carbons, and many are branched. Changes in the composition and structure of the 30,000 different moieties of TFLL contribute to the instability of tears. The focus of the current review is how spectroscopy has been used to elucidate the relationships between lipid composition, conformational order and function and the etiology of cataract and dry eye.




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The emerging roles of the macular pigment carotenoids throughout the lifespan and in prenatal supplementation [Thematic Reviews]

Since the publication of the Age-Related Eye Disease Study (AREDS2) in 2013, the macular pigment carotenoids lutein and zeaxanthin have become well known to both the eye care community and the public. It is a fascinating aspect of evolution that primates have repurposed photoprotective pigments and binding proteins from plants and insects to protect and enhance visual acuity. Moreover, utilization of these plant-derived nutrients has been widely embraced for preventing vision loss from age-related macular degeneration (AMD). More recently, there has been growing awareness that these nutrients can also play a role in improving visual performance in adults. On the other hand, the potential benefits of lutein and zeaxanthin supplementation at very young ages have been underappreciated. In this review, we examine the biochemical mechanisms and supportive data for lutein and zeaxanthin supplementation throughout the lifespan, with particular emphasis on prenatal supplementation. We propose that prenatal nutritional recommendations may aim at improving maternal and infant carotenoid status. Prenatal supplementation with lutein and zeaxanthin might enhance infant visual development and performance and may even prevent retinopathy of prematurity, possibilities that should be examined in future clinical studies.




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Hepatic Deletion of Mboat7 (Lpiat1) Causes Activation of SREBP-1c and Fatty Liver [Research Articles]

Genetic variants that increase the risk of fatty liver disease (FLD) and cirrhosis have recently been identified in the proximity of membrane bound O-acyltransferase domain-containing 7 (MBOAT7).  To elucidate the link between these variants and FLD we characterized Mboat7 liver-specific knock-out mice (Mboat7-LSKO).  Chow-fed Mboat7-LSKO mice developed fatty livers and associated liver injury.  Lipidomic analysis of liver using mass spectrometry revealed a pronounced reduction in 20-carbon polyunsaturated fatty acid content in phosphatidylinositols (PIs), but not in other phospholipids. The change in fatty acid composition of PIs in these mice was associated with a marked increase in de novo lipogenesis due to activation of SREBP-1c, a transcription factor that coordinates the activation of genes encoding enzymes in the fatty acid biosynthesis pathway. Hepatic removal of both SREBP cleavage activating protein (Scap) and Mboat7 normalized hepatic triglycerides relative to Scap only hepatic knock-out showing increased SREBP-1c processing is required for Mboat7 induced steatosis.  This study reveals a clear relationship between PI fatty acid composition and regulation of hepatic fat synthesis and delineates the mechanism by which mutations in MBOAT7 cause hepatic steatosis.




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Lipid and Metabolic Syndrome Traits in Coronary Artery Disease: A Mendelian Randomization Study [Patient-Oriented and Epidemiological Research]

Mendelian randomization (MR) of lipid traits in coronary artery disease (CAD) has provided evidence for causal associations of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted (IVW) and MR-Egger methods in large (n ≥ 300,000) GWAS datasets. We found that 30% of lipid trait genetic variants have effects on metabolic syndrome traits, including body mass index (BMI), type 2 diabetes (T2D), and systolic blood pressure (SBP). Nonetheless, in multivariable MR analysis, LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, BMI, T2D, and SBP are independently associated with CAD, and each of these associations is robust to adjustment for directional pleiotropy. MR at loci linked to direct effects on HDL-C and TG suggests locus- and mechanism-specific causal effects of these factors on CAD.




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Sphingolipids as Critical Players in Retinal Physiology and Pathology [Thematic Reviews]

Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is, therefore, crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) emerges as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide-1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.




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Overview of how N32 and N34 elovanoids sustain sight by protecting retinal pigment epithelial cells and photoreceptors [Thematic Reviews]

The essential fatty acid DHA (22:6, omega-3 or n-3) is enriched in and required for the membrane biogenesis and function of photoreceptor cells (PRC), synapses, mitochondria, etc. of the CNS. PRC DHA becomes an acyl chain at the sn-2 of phosphatidylcholine (PC), amounting to more than 50% of the PRC outer segment phospholipids, where phototransduction takes place. Very long chain PUFAs (VLC-PUFAs,n-3, ≥ 28 carbons) are at the sn-1 of this PC molecular species and interact with rhodopsin. PRC shed their tips (DHA-rich membrane disks) daily, which in turn are phagocytized by the retinal pigment epithelium (RPE), where DHA is recycled back to PRC inner segments to be used for the biogenesis of new photoreceptor membranes. Here, we review the structures and stereochemistry of novel elovanoid (ELV)-N32 and ELV-N34 to be ELV-N32: (14Z,17Z,20R,21E,23E,25Z,27S,29Z)-20,27-dihydroxydo-triaconta-14,17,21,23,25,29-hexaenoic acid; ELV-N34: (16Z,19Z,22R,23E,25E,27Z,29S,31Z)-22,29-dihydroxytetra-triaconta-16,19,23,25,27,31-hexaenoic acid. ELVs are low-abundance, high-potency, protective mediators. Their bioactivity includes enhancing of anti-apoptotic and pro-survival protein expression with concomitant downregulation of pro-apoptotic proteins when RPE is confronted with uncompensated oxidative stress (UOS). ELVs also target PRC/RPE senescence gene programming, the senescence secretory phenotype in the interphotoreceptor matrix (IPM), as well as inflammaging (chronic, sterile, low-grade inflammation). An important lesson on neuroprotection is highlighted by the ELV mediators that target the terminally differentiated PRC and RPE, sustaining a beautifully synchronized renewal process. The role of ELVs in PRC and RPE viability and function uncovers insights on disease mechanisms and the development of therapeutics for age-related macular degeneration (AMD), Alzheimer’s disease (AD), and other pathologies.




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Generation and validation of a conditional knockout mouse model for the study of the Smith-Lemli-Opitz Syndrome [Research Articles]

Smith-Lemli-Opitz Syndrome (SLOS) is a developmental disorder (OMIM #270400) caused by autosomal recessive mutations in the Dhcr7 gene, which encodes the enzyme 3β-hydroxysterol-7 reductase. SLOS patients present clinically with dysmorphology and neurological, behavioral and cognitive defects, with characteristically elevated levels of 7-dehydrocholesterol (7-DHC) in all bodily tissues and fluids. Previous mouse models of SLOS have been hampered by postnatal lethality when Dhcr7 is knocked out globally, while a hypomorphic mouse model showed improvement in the biochemical phenotype with ageing, and did not manifest most other characteristic features of SLOS. We report the generation of a conditional knockout of Dhcr7 (Dhcr7flx/flx), validated by generating a mouse with a liver-specific deletion (Dhcr7L-KO). Phenotypic characterization of liver-specific knockout mice revealed no significant changes in viability, fertility, growth curves, liver architecture, hepatic triglyceride secretion, or parameters of systemic glucose homeostasis. Furthermore, qPCR and RNA-Seq analyses of livers revealed no perturbations in pathways responsible for cholesterol synthesis, either in male or female Dhcr7L-KO mice, suggesting hepatic disruption of post-squalene cholesterol synthesis leads to minimal impact on sterol metabolism in the liver. This validated conditional Dhcr7 knockout model may now allow us to systematically explore the pathophysiology of SLOS, by allowing for temporal, cell and tissue-specific loss of DHCR7.




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Multi-modal Functional Imaging of Brown Adipose Tissue [Images in Lipid Research]




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Apolipoprotein C3 and apolipoprotein B colocalize in proximity to macrophages in atherosclerotic lesions in diabetes [Images in Lipid Research]




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Mutation in the distal NPxY motif of LRP1 alleviates dietary cholesterol-induced dyslipidemia and tissue inflammation [Research Articles]

The LDL receptor-related protein-1 (LRP1) is highly expressed in numerous cell types, and its impairment is associated with obesity, diabetes, and fatty liver disease. However, the mechanisms linking LRP1 to metabolic disease are not completely understood. Here, we compared the metabolic phenotype of C57BL/6J wild type and LRP1 knock-in mice carrying an inactivating mutation in the distal NPxY motif after feeding a low fat (LF) diet or high fat diets with (HFHC) or without (HF) cholesterol supplementation. In response to HF feeding, both groups developed hyperglycemia, hyperinsulinemia, and hyperlipidemia, as well as increased adiposity with adipose tissue inflammation and liver steatosis. However, when animals were fed the HF diet supplemented with cholesterol, the LRP1 NPxY mutation prevents hypercholesterolemia, reduces adipose tissue and brain inflammation, and limits liver progression to steatohepatitis. Nevertheless, insulin signaling is impaired in LRP1 NPxY mutant hepatocytes and this mutation does not protect against HFHC-induced insulin resistance. The selective metabolic improvement observed in HFHC-fed LRP1 NPxY mutant mice is due to an apparent increase of hepatic LDL receptor levels, leading to an elevated rate of plasma lipoprotein clearance and lowering of plasma and hepatic cholesterol levels. The unique metabolic phenotypes displayed by LRP1 NPxY mutant mice in response to HF or HFHC diet feeding indicate an LRP1-cholesterol axis in modulating tissue inflammation. The LRP1 NPxY mutant mouse phenotype differs from phenotypes observed in mice with tissue-specific LRP1 inactivation, thus highlighting the importance of an integrative approach to evaluate how global LRP1 dysfunction contributes to metabolic disease development.




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Perilipin 5 S155 phosphorylation by PKA is required for the control of hepatic lipid metabolism and glycemic control [Research Articles]

Perilipin (PLIN) 5 is a lipid droplet-associated protein that coordinates intracellular lipolysis in highly oxidative tissues and is thought to regulate lipid metabolism in response to phosphorylation by protein kinase A (PKA). We sought to identify PKA phosphorylation sites in PLIN5 and assess their functional relevance in cultured cells and the livers of mice. We detected phosphorylation on S155, S161 and S163 of recombinant PLIN5 by PKA in vitro and identified S155 as a functionally important site for lipid metabolism. Expression of phosphorylation-defective PLIN5 S155A in Plin5 null cells resulted in decreased rates of lipolysis and triglyceride-derived fatty acid oxidation compared with cells expressing wildtype PLIN5. These differences in lipid metabolism were not associated with differences in the cellular distribution of PLIN5. Rather, FLIM-FRET analysis of protein-protein interactions showed that PLIN5 S155 phosphorylation regulates PLIN5 interaction with adipose triglyceride lipase (ATGL) at the lipid droplet, but not with the co-activator of ATGL, α-β hydrolase domain-containing 5 (ABHD5). Re-expression of PLIN5 S155A in the liver of Plin5 liver-specific null mice reduced lipolysis when compared to mice with wildtype PLIN5 re-expression, but was not associated with other changes in hepatic lipid metabolism, such as fatty acid oxidation, de novo lipogenesis and triglyceride secretion. Furthermore, glycemic control was impaired in mice with expression of PLIN5 S155A compared with mice expressing PLIN5. Together, these studies demonstrate that PLIN5 S155 is required for PKA-mediated lipolysis and builds on the body of evidence demonstrating a critical role for PLIN5 in coordinating lipid and glucose metabolism




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Lipid signature of advanced human carotid atherosclerosis assessed by mass spectrometry imaging [Research Articles]

Carotid atherosclerosis is a risk factor for ischemic stroke, one of the main causes of mortality and disability worldwide. The disease is characterized by plaques, heterogeneous deposits of lipids and necrotic debris in the vascular wall, which grow gradually and may remain asymptomatic for decades. However, at some point a plaque can evolve to a high-risk plaque phenotype, which may trigger a cerebrovascular event. Lipids play a key role in the development and progression of atherosclerosis, but the nature of their involvement is not fully understood. Using matrix-assisted laser desorption/ionization mass spectrometry imaging, we visualized the distribution of approximately 200 different lipid signals, originating of > 90 uniquely assigned species, in 106 tissue sections of 12 human carotid atherosclerotic plaques. We performed unsupervised classification of the mass spectrometry dataset, as well as a histology-directed multivariate analysis. These data allowed us to extract the spatial lipid patterns associated with morphological plaque features in advanced plaques from a symptomatic population, revealing spatial lipid patterns in atherosclerosis and their relation to histological tissue type. The abundances of sphingomyelin and oxidized cholesteryl ester species were elevated specifically in necrotic intima areas, while diacylglycerols and triacylglycerols were spatially correlated to areas containing the coagulation protein fibrin. These results demonstrate a clear co-localization between plaque features and specific lipid classes, as well as individual lipid species in high-risk atherosclerotic plaques.




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Gene Networks and Pathways for Plasma Lipid Traits via Multi-tissue Multi-omics Systems Analysis [Research Articles]

Genome-wide association studies (GWAS) have implicated ~380 genetic loci for plasma lipid regulation. However, these loci only explain 17-27% of the trait variance and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely total cholesterol (TC), high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides (TG), from GWAS were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in ‘interferon signaling’, ‘autoimmune/immune activation’, ‘visual transduction’, and ‘protein catabolism’ were significantly associated with all lipid traits. Additionally, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL, glutathione metabolism for HDL, valine, leucine and isoleucine biosynthesis for TC, and insulin signaling and complement pathways for TG. Finally, utilizing gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g. APOH, APOA4, and ABCA1) and novel (e.g. F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (Coagulation Factor II, Thrombin) in 3T3-L1 and C3H10T1/2 adipocytes reduced gene expression of Abcb11, Apoa5, Apof, Fabp1, Lipc, and Cd36, reduced intracellular adipocyte lipid content, and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.




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Lipid metabolism dysregulation in diabetic retinopathy [Thematic Reviews]

Lipid metabolic abnormalities have emerged as potential risk factors for the development and progression of diabetic complications, including diabetic retinopathy (DR).  This review article provides an overview of the results of clinical trials evaluating the potential benefits of lipid lowering drugs, such as fibrates, omega 3 fatty acids, and statins, for the prevention and treatment of DR. Although several clinical trials demonstrated that treatment with fibrates leads to improvement of DR, there is a dissociation between the protective effects of fibrates in the retina, and the intended blood lipid classes, including plasma triglycerides, total cholesterol or HDL/LDL cholesterol ratio. Guided by these findings, plasma lipid and lipoprotein-independent mechanisms are addressed based on clinical, cell culture and animal model studies. Potential retinal-specific effects of fatty acids oxidation products, cholesterol, and ceramide, as well as lipid independent effects of PPAR alpha activation are summarized based on current literature. Overall, this review highlights promising potential of lipid-based treatment strategies further enhanced by the new knowledge of intra-retinal lipids and lipoproteins in DR.




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Developing a vaccine against Zika




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Esterification of 4{beta}-hydroxycholesterol and other oxysterols in human plasma occurs independently of LCAT [Patient-Oriented and Epidemiological Research]

The acyltransferase LCAT mediates FA esterification of plasma cholesterol. In vitro studies have shown that LCAT also FA-esterifies several oxysterols, but in vivo evidence is lacking. Here, we measured both free and FA-esterified forms of sterols in 206 healthy volunteers and 8 individuals with genetic LCAT deficiency, including familial LCAT deficiency (FLD) and fish-eye disease (FED). In the healthy volunteers, the mean values of the ester-to-total molar ratios of the following sterols varied: 4β-hydroxycholesterol (4βHC), 0.38; 5,6α-epoxycholesterol (5,6αEC), 0.46; 5,6β-epoxycholesterol (5,6βEC), 0.51; cholesterol, 0.70; cholestane-3β,5α,6β-triol (CT), 0.70; 7-ketocholesterol (7KC), 0.75; 24S-hydroxycholesterol (24SHC), 0.80; 25-hydroxycholesterol (25HC), 0.81; 27-hydroxycholesterol (27HC), 0.86; and 7α-hydroxycholesterol (7αHC), 0.89. In the individuals with LCAT deficiency, the plasma levels of the FA-esterified forms of cholesterol, 5,6αEC, 5,6βEC, CT, 7αHC, 7KC, 24SHC, 25HC, and 27HC, were significantly lower than those in the healthy volunteers. The individuals with FLD had significantly lower FA-esterified forms of 7αHC, 24SHC, and 27HC than those with FED. It is of note that, even in the three FLD individuals with negligible plasma cholesteryl ester, substantial amounts of the FA-esterified forms of 4βHC, 5,6αEC, 7αHC, 7KC, and 27HC were present. We conclude that LCAT has a major role in the FA esterification of many plasma oxysterols but contributes little to the FA esterification of 4βHC. Substantial FA esterification of 4βHC, 5,6αEC, 7αHC, 7KC, and 27HC is independent of LCAT.




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ANGPTL4 inactivates lipoprotein lipase by catalyzing the irreversible unfolding of LPLs hydrolase domain [Images In Lipid Research]




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Different rates of flux through the biosynthetic pathway for long-chain versus very-long-chain sphingolipids [Research Articles]

The backbone of all sphingolipids (SLs) is a sphingoid long-chain base (LCB) to which a fatty acid is N-acylated. Considerable variability exists in the chain length and degree of saturation of both of these hydrophobic chains, and recent work has implicated ceramides with different LCBs and N-acyl chains in distinct biological processes; moreover, they may play different roles in disease states and possibly even act as prognostic markers. We now demonstrate that the half-life, or turnover rate, of ceramides containing diverse N-acyl chains is different. By means of a pulse-labeling protocol using stable-isotope, deuterated free fatty acids, and following their incorporation into ceramide and downstream SLs, we show that very-long-chain (VLC) ceramides containing C24:0 or C24:1 fatty acids turn over much more rapidly than long-chain (LC) ceramides containing C16:0 or C18:0 fatty acids due to the more rapid metabolism of the former into VLC sphingomyelin and VLC hexosylceramide. In contrast, d16:1 and d18:1 ceramides show similar rates of turnover, indicating that the length of the sphingoid LCB does not influence the flux of ceramides through the biosynthetic pathway. Together, these data demonstrate that the N-acyl chain length of SLs may not only affect membrane biophysical properties but also influence the rate of metabolism of SLs so as to regulate their levels and perhaps their biological functions.




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Accessibility of cholesterol at cell surfaces [Images In Lipid Research]




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A sensitive S-Trap-based approach to the analysis of T cell lipid raft proteome [Methods]

The analysis of T cell lipid raft proteome is challenging due to the highly dynamic nature of rafts and the hydrophobic character of raft-resident proteins. We explored an innovative strategy for bottom-up lipid raftomics based on suspension-trapping (S-Trap) sample preparation. Mouse T cells were prepared from splenocytes by negative immunoselection, and rafts were isolated by a detergent-free method and OptiPrep gradient ultracentrifugation. Microdomains enriched in flotillin-1, LAT, and cholesterol were subjected to proteomic analysis through an optimized protocol based on S-Trap and high pH fractionation, followed by nano-LC-MS/MS. Using this method, we identified 2,680 proteins in the raft-rich fraction and established a database of 894 T cell raft proteins. We then performed a differential analysis on the raft-rich fraction from nonstimulated versus anti-CD3/CD28 T cell receptor (TCR)-stimulated T cells. Our results revealed 42 proteins present in one condition and absent in the other. For the first time, we performed a proteomic analysis on rafts from ex vivo T cells obtained from individual mice, before and after TCR activation. This work demonstrates that the proposed method utilizing an S-Trap-based approach for sample preparation increases the specificity and sensitivity of lipid raftomics.




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Genetic susceptibility, dietary cholesterol intake, and plasma cholesterol levels in a Chinese population [Patient-Oriented and Epidemiological Research]

Accompanied with nutrition transition, non-HDL-C levels of individuals in Asian countries has increased rapidly, which has caused the global epicenter of nonoptimal cholesterol to shift from Western countries to Asian countries. Thus, it is critical to underline major genetic and dietary determinants. In the current study of 2,330 Chinese individuals, genetic risk scores (GRSs) were calculated for total cholesterol (TC; GRSTC, 57 SNPs), LDL-C (GRSLDL-C, 45 SNPs), and HDL-C (GRSHDL-C, 65 SNPs) based on SNPs from the Global Lipid Genetics Consortium study. Cholesterol intake was estimated by a 74-item food-frequency questionnaire. Associations of dietary cholesterol intake with plasma TC and LDL-C strengthened across quartiles of the GRSTC (effect sizes: –0.29, 0.34, 2.45, and 6.47; Pinteraction = 0.002) and GRSLDL-C (effect sizes: –1.35, 0.17, 5.45, and 6.07; Pinteraction = 0.001), respectively. Similar interactions with non-HDL-C were observed between dietary cholesterol and GRSTC (Pinteraction = 0.001) and GRSLDL-C (Pinteraction = 0.004). The adverse effects of GRSTC on TC (effect sizes across dietary cholesterol quartiles: 0.51, 0.82, 1.21, and 1.31; Pinteraction = 0.023) and GRSLDL-C on LDL-C (effect sizes across dietary cholesterol quartiles: 0.66, 0.52, 1.12, and 1.56; Pinteraction = 0.020) were more profound in those having higher cholesterol intake compared with those with lower intake. Our findings suggest significant interactions between genetic susceptibility and dietary cholesterol intake on plasma cholesterol profiles in a Chinese population.




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{beta}-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice [Research Articles]

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of CVDs, and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affects atherosclerosis progression in the atheroprone LDLR-deficient mice. Compared with control-fed Ldlr–/– mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr–/–/Bco1–/– mice despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.




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Distinctive sphingolipid patterns in chronic multiple sclerosis lesions [Research Articles]

Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. MS-related CNS damage and its clinical course have two main phases: active and inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course. The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology. We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases. Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions. Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques. In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS. These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.