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PubMed2002

Cytokines and their role in lymphoid development, differentiation and homeostasis.

PURPOSE OF REVIEW: The development of lymphoid tissues as well as the ultimate differentiation of naïve and memory T cells are dependent on cytokines. In this review, we will focus on recent advances in the understanding of molecular mechanisms that regulate lymphoid development, homeostasis and tolerance. RECENT FINDINGS: Cytokines play a critical role in the development and differentiation of lymphoid cells. In addition, newer data indicate important roles of interleukin-7 and interleukin-15 in lymphoid homeostasis and memory. Furthermore, a new family of heterodimeric cytokines comprising interleukin-12, interleukin-23 and -27 is important for differentiation of helper T cells and cell-mediated immunity. Finally the importance of tumor necrosis factor superfamily members in the development of lymphoid organs has recently been elucidated and will be discussed in detail. SUMMARY: New cytokines and receptors continue to be identified. The discovery and characterization of cytokines, their receptors and signaling molecules will provide a more complete understanding of normal lymphoid development, differentiation and function. In addition, this knowledge should improve our understanding of the pathogenesis of immunological diseases and hopefully will provide new treatment strategies.

Cytokines↗
PubMedDate not supplied

Polymorphisms associated with thrombophilia and vascular homeostasis and the timing of menarche and menopause in 728 white women.

OBJECTIVE: Genetic factors have been proposed as modulators of the timing of natural menopause. Single nucleotide polymorphisms (SNPs) of genes associated with thrombophilia and vascular homeostasis may interfere with ovarian function and thus are candidate genes for early menopause. We attempted to assess the association of SNPs and the timing of menarche and natural and surgical menopause in an ethnically homogenous cohort of Middle European white women. DESIGN: In the present cross-sectional study, eight SNPs of six genes involved in vascular function and homeostasis were analyzed by sequencing-on-chip using solid-phase polymerase chain reaction on oligonucleotide microarrays in 728 white women: factor V (F5) Leiden G1691A, factor II (F2) prothrombin G20210A, plasminogen activator inhibitor1 (PAI-1) 4G/5G, angiotensinogen (AGT) Met235Thr, endothelial nitric oxide synthase (NOS3) T768C and NOS3 Glu298Asp, apolipoprotein E-1 (APOE-1) Cys112Arg, and APOE-2 Arg158Cys. The women's reproductive and medical histories were correlated to genotypes. RESULTS: In a univariate analysis, current smoking (P = 0.01) and the presence of at least one mutant allele of F5 Leiden (P = 0.03) and APOE-2 (P = 0.03) were significantly associated with a reduced age at natural menopause. The presence of at least one mutant allele of F5 Leiden (P = 0.02) and a body mass index above 25 kg/m (P = 0.009) were significantly associated with an increased risk for surgical menopause by premenopausal hysterectomy (odds ratio = 2.6, 95% CI, 1.2-5.6; odds ratio = 1.9, 95% CI, 1.2-3.0, respectively). Age at menarche was not affected by the carriage of any of the investigated SNPs. Applying stepwise linear regression models considering all two-way interactions, no interactions were found among different SNPs or between SNPs and environmental and lifestyle parameters. CONCLUSION: We identified various genetic and personal history parameters influencing age at natural menopause and the risk of undergoing premenopausal hysterectomy. To the best of our knowledge, we present the largest study to date determining SNPs as contributors to the genetic control of the timing of natural and surgical menopause.

Angiotensinogen↗
PubMed2006

The long and winding road to gut homeostasis.

PURPOSE OF REVIEW: The open ecosystem of the alimentary tract, harboring approximately 1 kg of bacteria, exhibits a rapid, but tightly controlled turnover. Impaired nuclear receptor function can give rise to perturbation in the gut, leading to inflammation and possibly neoplasia. Intriguingly, bacteria-dependent signaling pathways can modulate, and in turn be modulated by, a subset of nuclear receptors. This review attempts to highlight how microbes and nuclear receptors could jointly regulate gut homeostasis. RECENT FINDINGS: Commensal bacteria can utilize peroxisome proliferator activated receptor-gamma-dependent nuclear export of RelA as a novel mechanism to attenuate inflammatory signals triggered by a pathogen. Other nuclear receptors, such as liver X receptor, vitamin D receptor and farnesoid X receptor were also recently shown to interact with bacteria-induced mammalian inflammatory pathways. Although details of this interplay are still being unraveled, a role for these and other nuclear receptors in gastrointestinal inflammation and possibly neoplasia is beyond dispute. SUMMARY: The commensal microflora is being accorded due importance in regulating homeostasis of the gastrointestinal tract. Recent data suggest that the molecular messengers used by these bacteria include nuclear receptors. Exploiting mechanisms of nuclear receptor activity as drug targets, together with a detailed knowledge of the microbiota, could improve our understanding of gut-related ailments, and aid in mitigating their symptoms.

Animals↗
PubMed2006

ATP-binding cassette transporter G1 and lipid homeostasis.

PURPOSE OF REVIEW: This review briefly discusses the ATP-binding cassette transporter G (ABCG) family members and emphasizes recent studies that identify ABCG1 as a key regulator of cellular lipid homeostasis. RECENT FINDINGS: The in-vivo importance of ABCG1 has recently been demonstrated with both loss-of-function and gain-of-function studies in mice. Administration of a diet high in both fat and cholesterol to ABCG1 mice results in massive cholesterol accumulation in both the liver and lungs. In contrast, lipid accumulation is greatly attenuated in transgenic mice that express both the murine and human ABCG1 genes. Despite the observed tissue lipid accumulation, plasma lipid levels and lipoprotein cholesterol distribution are not significantly different between wild-type, ABCG1, and hABCG1 transgenic mice. Other studies show that ABCG1 expression is induced following activation of the nuclear receptor LXR and that over expression of ABCG1 results in increased efflux of cellular cholesterol to HDL or phospholipid vesicles. SUMMARY: The ABCG1 transporter plays a key role in regulating cellular cholesterol and lipid homeostasis. Elucidation of the molecular mechanism by which ABCG1 controls sterol flux should provide critical information that may link ABCG1 to the reverse cholesterol transport pathway or diseases such as atherosclerosis.

ATP-Binding Cassette Transporters↗
PubMed2006

Modelling Cl- homeostasis and volume regulation of the cardiac cell.

We aim at introducing a Cl- homeostasis to the cardiac ventricular cell model (Kyoto model), which includes the sarcomere shortening and the mitochondria oxidative phosphorylation. First, we examined mechanisms underlying the cell volume regulation in a simple model consisting of Na+/K+ pump, Na+-K+-2Cl- cotransporter 1 (NKCC1), cystic fibrosis transmembrane conductance regulator, volume-regulated Cl- channel and background Na+, K+ and Cl- currents. The high intracellular Cl- concentration of approximately 30 mM was achieved by the balance between the secondary active transport via NKCC1 and passive currents. Simulating responses to Na+/K+ pump inhibition revealed the essential role of Na+/K+ pump in maintaining the cellular osmolarity through creating the negative membrane potential, which extrudes Cl- from a cell, confirming the previous model study in the skeletal muscle. In addition, this model well reproduced the experimental data such as the responses to hypotonic shock in the presence or absence of beta-adrenergic stimulation. Finally, the volume regulation via Cl- homeostasis was successfully incorporated to the Kyoto model. The steady state was well established in the comprehensive cell model in respect to both the intracellular ion concentrations and the shape of the action potential, which are all in the physiological range. The source code of the model, which can reproduce every result, is available from http://www.sim-bio.org/.

Animals↗
PubMed2006

The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models.

A little more than a decade ago, the molecular basis of the lipostat was largely unknown. At that time, many laboratories were at work attempting to clone the genes encoding the obesity, diabetes, fatty, tubby and agouti loci, with the hope that identification of these obesity genes would help shed light on the process of energy homeostasis, appetite and energy expenditure. Characterization of obesity and diabetes elucidated the nature of the adipostatic hormone leptin and its receptor, respectively, while cloning of the agouti gene eventually led to the identification and characterization of one of the key neural systems upon which leptin acts to regulate intake and expenditure. In this review, we describe the neural circuitry known as the central melanocortin system and discuss the current understanding of its role in feeding and other processes involved in energy homeostasis.

Animals↗
PubMed2026

Azotobacter vinelandii AmrZ is a global regulator linking alginate production and c-di-GMP homeostasis.

Azotobacter vinelandii, a member of the Pseudomonadaceae, produces the exopolysaccharide alginate during vegetative growth; however, the circuitry linking alginate biosynthesis to lifestyle transitions remains poorly defined. Here, we show that the Ribbon-Helix-Helix transcription factor AmrZ coordinates alginate production, intracellular c-di-GMP levels and motility. Deletion of amrZ abolished alginate synthesis, whereas chromosomal complementation restored it. A PalgD-gusA fusion and RT-qPCR demonstrated that algD, the first gene in the alginate biosynthetic cluster, depends on AmrZ for expression. Motif analysis identified multiple AmrZ sites upstream of algD, and electrophoretic mobility-shift assays (EMSAs) confirmed specific binding to these regions. AmrZ also positively autoregulates: PamrZ-gusA activity decreased in ΔamrZ, and purified AmrZ bound the amrZ promoter in EMSA. Moreover, PamrZ activity required the sigma factor AlgU, consistent with the presence of an AlgU promoter; this positive, AlgU-dependent feedback may stabilize AmrZ under alginate-inducing conditions. To probe AmrZ control of c-di-GMP, we implemented a riboswitch-based biosensor in A. vinelandii. The ΔamrZ strain showed a markedly reduced signal, similar to a diguanylate cyclase (DGC) mutant, whereas a phosphodiesterase mutant displayed elevated output, validating the assay. RNA-seq and RT-qPCR identified two DGC genes, AVAEIV_RS11610 and AVAEIV_RS18795, as AmrZ-activated targets; EMSA verified direct binding at the RS11610 regulatory region. By contrast, transcription of the principal vegetative DGC AvGReg was not AmrZ-regulated. Lower c-di-GMP in ΔamrZ correlated with larger swimming halos. Collectively, these genetic, biochemical and transcriptomic data support a model in which AmrZ directly activates algD and elevates c-di-GMP via selected DGCs, thereby promoting alginate synthesis while reducing motility. RNA-seq data also indicate that AmrZ influences broader cellular programmes, including metabolism and iron homeostasis, positioning AmrZ as a central regulator that links c-di-GMP homeostasis to coordinated exopolysaccharide production in A. vinelandii. This work contributes to our understanding of the regulatory networks controlled by AmrZ outside the Pseudomonas genus and reveals important differences in its targets and regulatory mechanisms.

Azotobacter vinelandii↗
PubMed2004

In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis.

Integration of diverse signaling pathways is essential in development and homeostasis for cells to interpret context-dependent cues. BMP and MAPK signaling converge on Smads, resulting in differential phosphorylation. To understand the physiological significance of this observation, we have generated Smad1 mutant mice carrying mutations that prevent phosphorylation of either the C-terminal motif required for BMP downstream transcriptional activation (Smad1(C) mutation) or of the MAPK motifs in the linker region (Smad1(L) mutation). Smad1(C/C) mutants recapitulate many Smad1(-/-) phenotypes, including defective allantois formation and the lack of primordial germ cells (PGC), but also show phenotypes that are both more severe (head and branchial arches) and less severe (allantois growth) than the null. Smad1(L/L) mutants survive embryogenesis but exhibit defects in gastric epithelial homeostasis correlated with changes in cell contacts, actin cytoskeleton remodeling, and nuclear beta-catenin accumulation. In addition, formation of PGCs is impaired in Smad1(L/L) mutants, but restored by allelic complementation in Smad1(C/L) compound mutants. These results underscore the need to tightly balance BMP and MAPK signaling pathways through Smad1.

Animals↗
PubMed2005

Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT.

Telomere homeostasis is regulated by telomerase and a collection of associated proteins. Telomerase is, in turn, regulated by post-translational modifications of the rate-limiting catalytic subunit hTERT. Here we show that disruption of Hsp90 by geldanamycin promotes efficient ubiquitination and proteasome-mediated degradation of hTERT. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length. Our data suggest that MKRN1 plays an important role in modulating telomere length homeostasis through a dynamic balance involving hTERT protein stability.

Benzoquinones↗
PubMed2006

Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1alpha/LRP130 complex.

Leigh syndrome French Canadian variant (LSFC) is an autosomal recessive neurodegenerative disorder due to mutation in the LRP130 (leucine-rich protein 130 kDa) gene. Unlike classic Leigh syndrome, the French Canadian variant spares the heart, skeletal muscle, and kidneys, but severely affects the liver. The precise role of LRP130 in cytochrome c oxidase deficiency and hepatic lactic acidosis that accompanies this disorder is unknown. We show here that LRP130 is a component of the PGC-1alpha (peroxisome proliferator-activated receptor coactivator 1-alpha) transcriptional coactivator holocomplex and regulates expression of PEPCK (phosphoenolpyruvate carboxykinase), G6P (glucose-6-phosphatase), and certain mitochondrial genes through PGC-1alpha. Reduction of LRP130 in fasted mice via adenoviral RNA interference (RNAi) vector blocks the induction of PEPCK and G6P, and blunts hepatic glucose output. LRP130 is also necessary for PGC-1alpha-dependent transcription of several mitochondrial genes in vivo. These data link LRP130 and PGC-1alpha to defective hepatic energy homeostasis in LSFC, and reveal a novel regulatory mechanism of glucose homeostasis.

Animals↗
PubMed2006

Drosophila lacking microRNA miR-278 are defective in energy homeostasis.

The mechanisms that control energy homeostasis and tissue growth during development are closely linked through the insulin signal transduction pathway. Changes in the level of insulin and other hormones reflect the nutritional status of the animal to control circulating sugar levels and fat metabolism. Systemic defects in insulin responsiveness can lead to elevated circulating glucose levels and fat accumulation. Here we present evidence that the microRNA miR-278 plays a role in the control of energy homeostasis in Drosophila. miR-278 mutants have elevated insulin production and are correspondingly lean. Despite the elevated insulin levels, miR-278 mutants have elevated circulating sugar, mobilized from adipose-tissue glycogen stores. We provide evidence that miR-278 mutants are insulin resistant and that miR-278 acts through regulation of the expanded transcript.

Animals↗
PubMed2002

The voltage-independent cation channel in the plasma membrane of wheat roots is permeable to divalent cations and may be involved in cytosolic Ca2+ homeostasis.

A voltage-independent cation (VIC) channel has been identified in the plasma membrane of wheat (Triticum aestivum) root cells (P.J. White [1999] Trends Plant Sci 4: 245-246). Several physiological functions have been proposed for this channel, including roles in cation nutrition, osmotic adjustment, and charge compensation. Here, we observe that Ca(2+) permeates this VIC channel when assayed in artificial, planar lipid bilayers, and, using an energy barrier model to describe cation fluxes, predict that it catalyzes Ca(2+) influx under physiological ionic conditions. Thus, this channel could participate in Ca(2+) signaling or cytosolic Ca(2+) homeostasis. The pharmacology of (45)Ca(2+) influx to excised wheat roots and inward cation currents through the VIC channel are similar: Both are insensitive to 20 microM verapamil or 1 mM tetraethylammonium, but inhibited by 0.5 mM Ba(2+) or 0.5 mM Gd(3+). The weak voltage dependency of the VIC channel (and its lack of modulation by physiological effectors) suggest that it will provide perpetual Ca(2+) influx to root cells. Thus, it may effect cytosolic Ca(2+) homeostasis by contributing to the basal Ca(2+) influx required to balance Ca(2+) efflux from the cytoplasm through ATP- and proton-coupled Ca(2+) transporters under steady-state conditions.

Barium↗
PubMed2005

At5PTase13 modulates cotyledon vein development through regulating auxin homeostasis.

Phosphatidylinositol signaling pathway and the relevant metabolites are known to be critical to the modulation of different aspects of plant growth, development, and stress responses. Inositol polyphosphate 5-phosphatase is a key enzyme involved in phosphatidylinositol metabolism and is encoded by an At5PTase gene family in Arabidopsis thaliana. A previous study shows that At5PTase11 mediates cotyledon vascular development probably through the regulation of intracellular calcium levels. In this study, we provide evidence that At5PTase13 modulates the development of cotyledon veins through its regulation of auxin homeostasis. A T-DNA insertional knockout mutant, At5pt13-1, showed a defect in development of the cotyledon vein, which was rescued completely by exogenous auxin and in part by brassinolide, a steroid hormone. Furthermore, the mutant had reduced auxin content and altered auxin accumulation in seedlings revealed by the DR5:beta-glucuronidase fusion construct in seedlings. In addition, microarray analysis shows that the transcription of key genes responsible for auxin biosynthesis and transport was altered in At5pt13-1. The At5pt13-1 mutant was also less sensitive to auxin inhibition of root elongation. These results suggest that At5PTase13 regulates the homeostasis of auxin, a key hormone controlling vascular development in plants.

Arabidopsis↗
PubMed2006

alpha-Tocopherol plays a role in photosynthesis and macronutrient homeostasis of the cyanobacterium Synechocystis sp. PCC 6803 that is independent of its antioxidant function.

alpha-Tocopherol is synthesized exclusively in oxygenic phototrophs and is known to function as a lipid-soluble antioxidant. Here, we report that alpha-tocopherol also has a novel function independent of its antioxidant properties in the cyanobacterium Synechocystis sp. PCC 6803. The photoautotrophic growth rates of wild type and mutants impaired in alpha-tocopherol biosynthesis are identical, but the mutants exhibit elevated photosynthetic activities and glycogen levels. When grown photomixotrophically with glucose (Glc), however, these mutants cease growth within 24 h and exhibit a global macronutrient starvation response associated with nitrogen, sulfur, and carbon, as shown by decreased phycobiliprotein content (35% of the wild-type level) and accumulation of the nblA1-nblA2, sbpA, sigB, sigE, and sigH transcripts. Photosystem II activity and carboxysome synthesis are lost in the tocopherol mutants within 24 h of photomixotrophic growth, and the abundance of carboxysome gene (rbcL, ccmK1, ccmL) and ndhF4 transcripts decreases to undetectable levels. These results suggest that alpha-tocopherol plays an important role in optimizing photosynthetic activity and macronutrient homeostasis in Synechocystis sp. PCC 6803. Several lines of evidence indicate that increased oxidative stress in the tocopherol mutants is unlikely to be the underlying cause of photosystem II inactivation and Glc-induced lethality. Interestingly, insertional inactivation of the pmgA gene, which encodes a putative serine-threonine kinase similar to RsbW and RsbT in Bacillus subtilis, results in a similar increase in glycogen and Glc-induced lethality. Based on these results, we propose that alpha-tocopherol plays a nonantioxidant regulatory role in photosynthesis and macronutrient homeostasis through a signal transduction pathway that also involves PmgA.

Antioxidants↗
PubMed2006

Cell death suppressor Arabidopsis bax inhibitor-1 is associated with calmodulin binding and ion homeostasis.

Cell death suppressor Bax inhibitor-1 (BI-1), an endoplasmic reticulum membrane protein, exists in a wide range of organisms. The split-ubiquitin system, overlay assay, and bimolecular fluorescence complementation analysis demonstrated that Arabidopsis (Arabidopsis thaliana) BI-1 (AtBI-1) interacted with calmodulin in yeast (Saccharomyces cerevisiae) and in plant cells. Furthermore, AtBI-1 failed to rescue yeast mutants lacking Ca2+ ATPase (Pmr1 or Spf1) from Bax-induced cell death. Pmr1 and Spf1, p-type ATPases localized at the inner membrane, are believed to be involved in transmembrane movement of calcium ions in yeast. Thus, the presence of intact Ca2+ ATPases was essential for AtBI-1-mediated cell death suppression in yeast. To investigate the effect of AtBI-1 on calcium homeostasis, we evaluated sensitivity against cyclopiazonic acid (CPA), an inhibitor of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase in AtBI-1-overexpressing or knock-down transgenic Arabidopsis plants. These plants demonstrated altered CPA or ion stress sensitivity. Furthermore, AtBI-1-overexpressing cells demonstrated an attenuated rise in cytosolic calcium following CPA or H2O2 treatment, suggesting that AtBI-1 affects ion homeostasis in plant cell death regulation.

Arabidopsis↗
PubMed2004

P-type ATPase heavy metal transporters with roles in essential zinc homeostasis in Arabidopsis.

Arabidopsis thaliana has eight genes encoding members of the type 1(B) heavy metal-transporting subfamily of the P-type ATPases. Three of these transporters, HMA2, HMA3, and HMA4, are closely related to each other and are most similar in sequence to the divalent heavy metal cation transporters of prokaryotes. To determine the function of these transporters in metal homeostasis, we have identified and characterized mutants affected in each. Whereas the individual mutants exhibited no apparent phenotype, hma2 hma4 double mutants had a nutritional deficiency phenotype that could be compensated for by increasing the level of Zn, but not Cu or Co, in the growth medium. Levels of Zn, but not other essential elements, in the shoot tissues of a hma2 hma4 double mutant and, to a lesser extent, of a hma4 single mutant were decreased compared with the wild type. Together, these observations indicate a primary role for HMA2 and HMA4 in essential Zn homeostasis. HMA2promoter- and HMA4promoter-reporter gene constructs provide evidence that HMA2 and HMA4 expression is predominantly in the vascular tissues of roots, stems, and leaves. In addition, expression of the genes in developing anthers was confirmed by RT-PCR and was consistent with a male-sterile phenotype in the double mutant. HMA2 appears to be localized to the plasma membrane, as indicated by protein gel blot analysis of membrane fractions using isoform-specific antibodies and by the visualization of an HMA2-green fluorescent protein fusion by confocal microscopy. These observations are consistent with a role for HMA2 and HMA4 in Zn translocation. hma2 and hma4 mutations both conferred increased sensitivity to Cd in a phytochelatin-deficient mutant background, suggesting that they may also influence Cd detoxification.

Adenosine Triphosphatases↗
PubMed2005

Regulation of phosphate homeostasis by MicroRNA in Arabidopsis.

In this study, we reveal a mechanism by which plants regulate inorganic phosphate (Pi) homeostasis to adapt to environmental changes in Pi availability. This mechanism involves the suppression of a ubiquitin-conjugating E2 enzyme by a specific microRNA, miR399. Upon Pi starvation, the miR399 is upregulated and its target gene, a ubiquitin-conjugating E2 enzyme, is downregulated in Arabidopsis thaliana. Accumulation of the E2 transcript is suppressed in transgenic Arabidopsis overexpressing miR399. Transgenic plants accumulated five to six times the normal Pi level in shoots and displayed Pi toxicity symptoms that were phenocopied by a loss-of-function E2 mutant. Pi toxicity was caused by increased Pi uptake and by translocation of Pi from roots to shoots and retention of Pi in the shoots. Moreover, unlike wild-type plants, in which Pi in old leaves was readily retranslocated to other developing young tissues, remobilization of Pi in miR399-overexpressing plants was impaired. These results provide evidence that miRNA controls Pi homeostasis by regulating the expression of a component of the proteolysis machinery in plants.

Arabidopsis↗
PubMed1993

Inhibition of cholesterol and sphingolipid synthesis causes paradoxical effects on permeability barrier homeostasis.

Cholesterol, fatty acid, and sphingolipid synthesis are required for barrier homeostasis, as demonstrated by studies where synthesis of these species is stimulated in parallel with barrier repair. Moreover, blockade of synthesis of these lipids with inhibitors of two of the rate-limiting enzymes, HMGCoA reductase (lovastatin, fluvastatin) and serine palmitoyl transferase (beta-chloroalanine), alters the kinetics of barrier repair. Whereas these studies demonstrated a requirement for these lipids individually, we asked here whether these lipids are required in either an additive or cooperative fashion. We applied each class of inhibitor alone or the two classes of inhibitors together to acetone-treated skin, or each class separately to essential fatty acid deficient murine skin. When fluvastatin or beta-chloroalanine was applied individually to acetone-treated skin, each caused a delay in the early or late stages of barrier recovery, respectively (assessed as transepidermal water loss). However, when applied together they caused no further worsening at the early time point and a paradoxical improvement at the later time points. This improvement correlated with an accelerated return of sphingolipids, which was perhaps due to a global stimulation of lipid synthesis induced by HMGCoA reductase inhibitors. In essential fatty acid deficient animals, inhibition of HMGCoA reductase caused drastic worsening of both clinical appearance and barrier function, but beta-chloroalanine caused a paradoxical improvement, which correlated with a significant reduction in epidermal sphingolipids. These results are consistent with a requirement for both cholesterol and sphingolipids for barrier homeostasis, and also with the suggestion that both of these lipids must be present (with free fatty acids) for optimal barrier function.

Acetone↗