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Alterations of Ultra Long-Chain Fatty Acids in Hereditary Skin Diseases-Review Article.

ABSTRACT: The skin is a flexible organ that forms a barrier between the environment and the body's interior; it is involved in the immune response, in protection and regulation, and is a dynamic environment in which skin lipids play an important role in maintaining homeostasis. The different layers of the skin differ in both the composition and amount of lipids. The epidermis displays the best characteristics in this respect. The main lipids in this layer are cholesterol, fatty acids (FAs) and ceramides. FAs can occur in free form and as components of complex molecules. The most poorly characterized FAs are very long-chain fatty acids (VLCFAs) and ultra long-chain fatty acids (ULCFAs). VLCFAs and ULCFAs are among the main components of ceramides and are part of the free fatty acid (FFA) fraction. They are most abundant in the brain, liver, kidneys, and skin. VLCFAs and ULCFAs are responsible for the rigidity and impermeability of membranes, forming the mechanically and chemically strong outer layer of cell membranes. Any changes in the composition and length of the carbon chains of FAs result in a change in their melting point and therefore a change in membrane permeability. One of the factors causing a decrease in the amount of VLCFAs and ULCFAs is an improper diet. Another much more important factor is mutations in the genes which code proteins involved in the metabolism of VLCFAs and ULCFAs-regarding their elongation, their attachment to ceramides and their transformation. These mutations have their clinical consequences in the form of inborn errors in metabolism and neurodegenerative disorders, among others. Some of them are accompanied by skin symptoms such as ichthyosis and ichthyosiform erythroderma. In the following review, the structure of the skin is briefly characterized and the most important lipid components of the skin are presented. The focus is also on providing an overview of selected proteins involved in the metabolism of VLCFAs and ULCFAs in the skin.

SUBMITTER: Zwara A

PROVIDER: S-EPMC8420999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Concerns about global warming, fossil-fuel depletion, food security, and human health have promoted metabolic engineers to develop tools/strategies to overproduce microbial functional oils directly from renewable resources. Medium-chain fatty acids (MCFAs, C8-C12) have been shown to be important sources due to their diverse biotechnological importance, providing benefits ranging from functional lipids to uses in bio-fuel production. However, oleaginous microbes do not carry native pathways for the production of MCFAs, and therefore, diverse approaches have been adapted to compensate for the requirements of industrial demand. Mucor circinelloides is a promising organism for lipid production (15-36% cell dry weight; CDW) and the investigation of mechanisms of lipid accumulation; however, it mostly produces long-chain fatty acids (LCFAs). To address this challenge, we genetically modified strain M. circinelloides MU758, first by integrating heterologous acyl-ACP thioesterase (TE) into fatty acid synthase (FAS) complex and subsequently by modifying the ?-oxidation pathway by disrupting the acyl-CoA oxidase (ACOX) and/or acyl-CoA thioesterase (ACOT) genes with a preference for medium-chain acyl-CoAs, to elevate the yield of MCFAs. The resultant mutant strains (M-1, M-2, and M-3, respectively) showed a significant increase in lipid production in comparison to the wild-type strain (WT). MCFAs in M-1 (47.45%) was sharply increased compared to the wild type strain (2.25%), and it was further increased in M-2 (60.09%) suggesting a negative role of ACOX in MCFAs production. However, MCFAs in M-3 were much decreased compared to M-1,suggesting a positive role of ACOT in MCFAs production. The M-2 strain showed maximum lipid productivity (~1800 milligram per liter per day or mg/L.d) and MCFAs productivity (~1100 mg/L.d). Taken together, this study elaborates on how the combination of two multidimensional approaches, TE gene over-expression and modification of the ?-oxidation pathway via substantial knockout of specific ACOX gene, significantly increased the production of MCFAs. This synergistic approach ultimately offers a novel opportunity for synthetic/industrial biologists to increase the content of MCFAs.

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Alterations of Ultra Long-Chain Fatty Acids in Hereditary Skin Diseases-Review Article.

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