Expression of lipid transport-associated genes in lipid-deprived cancer cells.

Cancer cells are known to significantly alter their lipid profiles in response to changes in extracellular lipid availability. Recent studies have shown that in response to lipid deprivation, cancer cells display significant changes in their cellular lipid homeostasis. These changes have been linked to the modulation of de novo lipid synthesis pathways that are markedly altered under lipid-deprived growth conditions. However, the effects of such environment on intracellular lipid trafficking-that could also affect cellular lipid homeostasis-have not been widely investigated. The presented work studies the effect of lipid deprivation on expression of genes for lipid transport proteins (LTPs) in cancer cell lines.

Disturbed neurotransmitter homeostasis in ether lipid deficiency.

Plasmalogens, the most prominent ether (phospho)lipids in mammals, are structural components of most cellular membranes. Due to their physicochemical properties and abundance in the central nervous system, a role of plasmalogens in neurotransmission has been proposed, but conclusive data are lacking. Here, we targeted this issue in the glyceronephosphate O-acyltransferase (Gnpat) KO mouse, a model of complete deficiency in ether lipid biosynthesis. Throughout the study, focusing on adult male animals, we found reduced brain levels of various neurotransmitters. In the dopaminergic nigrostriatal tract, synaptic endings but not neuronal cell bodies were affected. Neurotransmitter turnover was altered in ether lipid-deficient murine as well as human post-mortem brain tissue. A generalized loss of synapses did not account for the neurotransmitter deficits, since the levels of several presynaptic proteins appeared unchanged. However, reduced amounts of vesicular monoamine transporter indicate a compromised vesicular uptake of neurotransmitters. As exemplified by norepinephrine, the release of neurotransmitters from Gnpat KO brain slices was diminished in response to strong electrical and chemical stimuli. Finally, addressing potential phenotypic correlates of the disturbed neurotransmitter homeostasis, we show that ether lipid deficiency manifests as hyperactivity and impaired social interaction. We propose that the lack of ether lipids alters the properties of synaptic vesicles leading to reduced amounts and release of neurotransmitters. These features likely contribute to the behavioral phenotype of Gnpat KO mice, potentially modeling some human neurodevelopmental disorders like autism or attention deficit hyperactivity disorder.

Dyslipidaemia pattern and prevalence among type 2 diabetes mellitus patients on lipid-lowering therapy at a tertiary hospital in central South Africa.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is a major cause of death worldwide. A large number of deaths due to ASCVD occurs among people with diabetes mellitus (DM). One of the important modifiable risk factors associated with ASCVD is dyslipidaemia and its prevalence is not known in central South Africa (SA). This study aimed to determine the pattern and prevalence of dyslipidaemia among type 2 diabetes mellitus (T2DM) patients on lipid-lowering therapy. METHODS: This descriptive, retrospective study of patients' records was conducted at Universitas Academic Hospital in Bloemfontein, SA. The study population included 143 consecutive T2DM patients of any age that attended the Diabetes Clinic from 1 January to 31 March 2019. The patients had to be on lipid-lowering therapy for a minimum duration of 3 months. Data were sourced from the clinic files and included the patient's lipid profile, anthropometric and demographic data. Dyslipidaemia was defined using the 2018 SA dyslipidaemia guidelines. RESULTS: The median age of the participants was 63 years (interquartile range [IQR] 52-71 years). The majority of the participants were female (n = 92; 64.3 %). The median duration since the DM diagnosis was 18 years (IQR 13-23 years). The prevalence of dyslipidaemia was 86.7 % (n = 124). Combined dyslipidaemia, namely either triglycerides (TG) + low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL) + TG or HDL + LDL, was the most common pattern (n = 51; 42.5 %) largely due to raised TG + LDL contributing 37.2 % (n = 19) to this pattern. The second and third most common patterns were isolated (either LDL, HDL or TG) and mixed dyslipidaemia (TG + HDL + LDL) at 40.8 % (n = 49) and 16.7 % (n = 20), respectively. The most frequent lipid abnormality (n = 84; 70.0 %) was LDL of ≥ 1.8 mmol/L. Of the 140 participants on statin therapy, only 5 % were on high-intensity therapy. CONCLUSIONS: A high prevalence of dyslipidaemia among DM patients was observed, despite the use of lipid-lowering therapy in this small observational study. Our findings highlight the need to better educate healthcare providers regarding the intensification of lipid-lowering therapy, along with improved strategies to address poor glycaemic control and other modifiable lifestyle factors.

Oleaginous yeasts for sustainable lipid production-from biodiesel to surf boards, a wide range of "green" applications.

A growing world population and a growing number of applications for vegetable oils are generating an increasing demand for these oils, causing serious environmental problems. A sustainable lipid production is then fundamental to address these problems. Oleaginous yeasts are a promising solution for sustainable lipid production, but, with the current knowledge and technology, they are still not a serious alternative in the market. In this review, the potential of these yeasts is highlighted and a discussion is made mainly focused on the economics of the oleaginous yeast oil production and identification of the key points to be improved to achieve lower production costs and higher income. Three main stages of the production process, where costs are higher, were identified. To render economically feasible the production of oils using oleaginous yeasts, a reduction in production costs must occur in all stages, lipid yields and productivities must be improved, and production must be targeted to high-value product applications.

Amplification of mGlu5-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance.

Energy-dense, yet nutritionally poor food is a high-risk factor for mental health disorders. This is of particular concern during adolescence, a period often associated with increased consumption of low nutritional content food and higher prevalence of mental health disorders. Indeed, there is an urgent need to understand the mechanisms linking unhealthy diet and mental disorders. Deficiency in n-3 polyunsaturated fatty acids (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFA deficiency lasting from adolescence into adulthood. Starting nutritional deficits in dietary n-3 PUFAs during adolescence decreased n-3 PUFAs in both medial prefrontal cortex (mPFC) and nucleus accumbens, increased anxiety-like behavior, and decreased cognitive function in adulthood. Importantly, we discovered that endocannabinoid/mGlu5-mediated LTD in the mPFC and accumbens was abolished in adult n-3-deficient mice. Additionally, mPFC NMDAR-dependent LTP was also lacking in the n-3-deficient group. Pharmacological enhancement of the mGlu5/eCB signaling complex, by positive allosteric modulation of mGlu5 or inhibition of endocannabinoid 2-arachidonylglycerol degradation, fully restored synaptic plasticity and normalized emotional and cognitive behaviors in malnourished adult mice. Our data support a model where nutrition is a key environmental factor influencing the working synaptic range into adulthood, long after the end of the perinatal period. These findings have important implications for the identification of nutritional risk factors for disease and design of new treatments for the behavioral deficits associated with nutritional n-3 PUFA deficiency.SIGNIFICANCE STATEMENT In a mouse model mimicking n-3 PUFA dietary deficiency during adolescence and adulthood, we found strong increases in anxiety and anhedonia which lead to decreases in specific cognitive functions in adulthood. We found that endocannabinoid/mGlu5-mediated LTD and NMDAR-dependent LTP were lacking in adult n-3-deficient mice. Acute positive allosteric modulation of mGlu5 or inhibition of endocannabinoid degradation normalized behaviors and synaptic functions in n-3 PUFA-deficient adult mice. These findings have important implications for the identification of nutritional risk for disease and the design of new treatments for the behavioral deficits associated with nutritional n-3 PUFAs' imbalance.

Inflammatory bowel disease as a disorder of an imbalance between pro- and anti-inflammatory molecules and deficiency of resolution bioactive lipids.

The inflammatory process seen in inflammatory bowel disease (IBD) is due to excess production of pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), interferons (IFNs), macrophage migration inhibitory factor (MIF), HMGB1 (high mobility group B1) and possibly, a reduction in anti-inflammatory cytokines IL-10, IL-4, and transforming growth factor-ß (TGF-ß). These pro-inflammatory molecules lead to increased production of reactive oxygen species (ROS) including nitric oxide resulting in target tissue damage. I propose that inadequate production of inflammation resolving molecules lipoxins, resolvins, protectins, maresins and nitrolipids that suppress inflammation, ROS production, enhance wound healing and have cytoprotective properties results in inappropriate inflammation, delay in healing/repair process and so target tissue/organ damage continues in IBD. Hence, suggested therapeutic approach could include administration of stable synthetic analogues of lipoxins, resolvins, protectins, maresins and nitrolipids. This implies that measuring urine, stool and plasma levels of lipoxins, resolvins, protectins, maresins and nitrolipids may be used to detect the onset, progression and response to treatment of IBD.

Mycobacterium tuberculosis strains lacking surface lipid phthiocerol dimycocerosate are susceptible to killing by an early innate host response.

The innate immune response plays an important but unknown role in host defense against Mycobacterium tuberculosis. To define the function of innate immunity during tuberculosis, we evaluated M. tuberculosis replication dynamics during murine infection. Our data show that the early pulmonary innate immune response limits M. tuberculosis replication in a MyD88-dependent manner. Strikingly, we found that little M. tuberculosis cell death occurs during the first 2 weeks of infection. In contrast, M. tuberculosis cells deficient in the surface lipid phthiocerol dimycocerosate (PDIM) exhibited significant death rates, and consequently, total bacterial numbers were reduced. Host restriction of PDIM-deficient M. tuberculosis was not alleviated by the absence of interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), or the phagocyte oxidase subunit p47. Taken together, these data indicate that PDIM protects M. tuberculosis from an early innate host response that is independent of IFN-γ, reactive nitrogen intermediates, and reactive oxygen species. By employing a pathogen replication tracking tool to evaluate M. tuberculosis replication and death during infection, we identify both host and pathogen factors affecting the outcome of infection.

Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticity-associated genes.

Low dietary intake of the n-3 polyunsaturated fatty acids (PUFAs) is a causative factor of neurodevelopmental disorders. However the mechanisms linking n-3 PUFAs low dietary intake and neurodevelopmental disorders are poorly understood. Microglia, known mainly for their immune function in the injured or infected brain, have recently been demonstrated to play a pivotal role in regulating maturation of neuronal circuits during normal brain development. Disruption of this role during the perinatal period therefore could significantly contribute to psychopathologies with a neurodevelopmental neurodevelopmental component. N-3 PUFAs, essential lipids and key structural components of neuronal membrane phospholipids, are highly incorporated in cell membranes during the gestation and lactation phase. We previously showed that in a context of perinatal n-3 PUFAs deficiency, accretion of these latter is decreased and this is correlated to an alteration of endotoxin-induced inflammatory response. We thus postulated that dietary n-3 PUFAs imbalance alters the activity of microglia in the developing brain, leading to abnormal formation of neuronal networks. We first confirmed that mice fed with a n-3 PUFAs deficient diet displayed decreased n-3 PUFAs levels in the brain at post-natal days (PND)0 and PND21. We then demonstrated that n-3 PUFAs deficiency altered microglia phenotype and motility in the post-natal developing brain. This was paralleled by an increase in pro-inflammatory cytokines expression at PND21 and to modification of neuronal plasticity-related genes expression. Overall, our findings show for the first time that a dietary n-3 PUFAs deficiency from the first day of gestation leads to the development of a pro-inflammatory condition in the central nervous system that may contribute to neurodevelopmental alterations.

Tear lipid layer deficiency associated with incomplete blinking: a case report.

BACKGROUND: Meibomian gland obstruction induces hyposecretion of tear film lipids, which results in lipid layer deficiency and evaporative dry eye. Unfortunately, the importance of blinking in meibomian gland dysfunction has been largely overlooked, and it is not known whether incomplete blinking causes tear lipid deficiency, even in the unobstructed meibomian glands. CASE PRESENTATION: A 38-year-old woman suffering from foreign body sensations in her eyes was examined. The cornea was clear and tear secretion was normal. Lid margin abnormalities were not observed and the meibum was clear. However, the lipid layer was very thin, and the patient was given a diagnosis of incomplete blinking. The patient was made aware of her condition and asked to blink consciously and completely. After that, an immediate increase in lipid flow was observed. CONCLUSION: Tear lipid layer deficiency can occur with incomplete blinking, even though meibomian gland structures are intact. This case highlights the importance of complete blinking.

A Mycobacterium marinum TesA mutant defective for major cell wall-associated lipids is highly attenuated in Dictyostelium discoideum and zebrafish embryos.

Infection of the zebrafish with Mycobacterium marinum is regarded as a well-established experimental model to study the pathogenicity of Mycobacterium tuberculosis. Herein, a M. marinum transposon mutant library was screened for attenuated M. marinum phenotypes using a Dictyostelium discoideum assay. In one attenuated mutant, the transposon was located within tesA, encoding a putative type II thioesterase. Thin-layer chromatography analyses indicated that the tesA::Tn mutant failed to produce two major cell wall-associated lipids. Mass spectrometry and nuclear magnetic resonance clearly established the nature of missing lipids as phthioglycol diphthioceranates and phenolic glycolipids, respectively, indicating that TesA is required for the synthesis of both lipids. When injected into the zebrafish embryo bloodstream, the mutant was found to be highly attenuated, thus validating the performance and relevance of the Dictyostelium screen. Consistent with these in vivo findings, tesA::Tn exhibited increased permeability defects in vitro, which may explain its failure to survive in host macrophages. Unexpectedly, virulence was retained when bacteria were injected into the notochord. Histological and ultrastructural studies of the infected notochord revealed the presence of actively proliferating mycobacteria, leading to larval death. This work presents for the first time the notochord as a compartment highly susceptible to mycobacterial infection.

Lipoprotein particles are required for Hedgehog and Wingless signalling.

Wnt and Hedgehog family proteins are secreted signalling molecules (morphogens) that act at both long and short range to control growth and patterning during development. Both proteins are covalently modified by lipid, and the mechanism by which such hydrophobic molecules might spread over long distances is unknown. Here we show that Wingless, Hedgehog and glycophosphatidylinositol-linked proteins copurify with lipoprotein particles, and co-localize with them in the developing wing epithelium of Drosophila. In larvae with reduced lipoprotein levels, Hedgehog accumulates near its site of production, and fails to signal over its normal range. Similarly, the range of Wingless signalling is narrowed. We propose a novel function for lipoprotein particles, in which they act as vehicles for the movement of lipid-linked morphogens and glycophosphatidylinositol-linked proteins.

Dietary wheat germ oil influences gene expression in larvae and eggs of the oriental fruit fly.

Changes in animal nutrition, particularly essential dietary components, alter global gene expression patterns. Our goal is to identify molecular markers that serve as early indicators of the quality of insect culture media. Markers of deficient culture media will increase the efficiency of developing optimal systems for mass rearing beneficial insects and some pest species because decisions on culture media quality can be made without waiting through one or several life cycles. The objective of our current study is to discover molecular markers of essential dietary lipid deficiency in the oriental fruit fly, Bactrocera dorsalis. We reared groups of fruit flies separately on media either devoid of or supplemented with wheat germ oil (WGO) and analyzed gene expression in third instar larvae and F(1) eggs using 2D electrophoresis. Gel densitometry revealed significant changes in expression levels of genes encoding eight proteins in larvae and 22 proteins in eggs. We identified these proteins by using mass spectrometry (MALDI TOF/TOF) and bioinformatic analyses of the protein sequences. Among these, we identified one gene encoding the receptor of activated C Kinase 1 (RACK1) that increased in expression by 6.8-fold in eggs from adults that were reared as larvae on media supplemented with WGO. RACK1 is an essential component of at least three intracellular signal transduction pathways, making it a good molecular marker candidate of lipid deficiency in fruit flies and possibly many other insect species.

No consequences of dietary n-3 polyunsaturated fatty acid deficiency on the severity of scopolamine-induced dry eye.

PURPOSE: Epidemiological studies suggest that dietary n-3 polyunsaturated fatty acids (PUFAs) may protect against dry eye. This study aimed to evaluate whether a dietary deficiency in n-3 PUFAs may increase the severity of the pathology in a scopolamine-induced model of dry eye in the rat. METHODS: Lewis rats of three consecutive generations were bred under a balanced diet or a diet deprived of n-3 PUFAs. Dry eye was experimentally induced by continuous scopolamine delivery in female animals from the third generation of both groups. After 10 days of treatment, the clinical signs of ocular dryness were evaluated in vivo using fluorescein staining. MHC II and the rat mucin rMuc5AC were immunostained on ocular sphere cryosections. The transcript levels of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were quantified in the exorbital lacrimal glands (LG) and in the conjunctiva using reverse transcription followed by polymerase chain reaction. Lipids were extracted from the exorbital LG for fatty acid analysis of the phospholipids using gas chromatography. RESULTS: When compared to control animals, the scopolamine treatment induced an increase in the cornea fluorescein staining score (from 0.5 ± 0.0 to 2.5 ± 1.0 arbitrary units (AU) for the balanced diet and from 1.2 ± 0.8 to 2.6 ± 0.5 AU for the n-3 PUFA-deficient diet); a decrease in rMuc5AC immunostaining in the conjunctival epithelium (-34% for the balanced diet and -23% for the n-3 PUFA-deficient diet); an increase in the LG transcript levels of TNF-α for the balanced diet and of TNF-α and IFN-γ for the deficient diet; an increase in the conjunctival transcript levels of IL-1ß and IL-6 for the deficient diet; an increase in arachidonic acid (AA) and in the ∆5-desaturase index (ratio of AA to dihomo-gamma-linolenic acid) in the exorbital LG for both diets. When compared to the balanced diet, the n-3 PUFA-deficient diet induced an increase in the LG transcript levels of IL-6 for the control animals and of TNF-α for the control and dry eye animals as well as an increase in the conjunctival transcript levels of IL-6 for the dry eye animals. There was no significant diet difference in fluorescein staining, rMuc5AC, and MHC II immunostaining scores. CONCLUSIONS: Our data suggest that an n-3 PUFA deficiency does not increase the severity of dry eye in a rat model of dry eye.

Real-Life Impact on Lipid Profile of a Switch from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in HIV-Infected Patients.

BACKGROUND: Tenofovir disoproxil fumarate is a prodrug of tenofovir diphosphate that exposes patients to renal toxicity over the long term. Tenofovir alafenamide, a new prodrug, now makes it possible to reduce toxicity, but at the cost of an alteration in lipid profile. There is currently no recommendation for follow-up of lipid profile when switching from tenofovir disoproxil fumarate to tenofovir alafenamide. OBJECTIVE: Our study aimed to evaluate the effects on renal function and lipid profile of a switch from tenofovir disoproxil fumarate to tenofovir alafenamide, and the consequences for patient management. METHODS: Demographic, clinical and biological data was recorded from a retrospective clinical cohort study in real-life, including patients who switched from tenofovir disoproxil fumarate to tenofovir alafenamide. A descriptive analysis of the study population, with a comparison of biological parameters using the paired Student t test for paired data was performed. RESULTS: From January 2016 to January 2019, a total of 103 patients were included. There was no significant difference in renal function before vs after the switch in therapy (p=0.29 for creatinine, p=0.30 for phosphoremia). We observed a change in lipid profile, with a significant increase in total cholesterol (p=0.0006), HDL cholesterol (p=0.0055) and triglycerides (p=0.0242). Four patients received lipid-lowering therapy after switching. CONCLUSION: In patients who switch from tenofovir disoproxil fumarate to tenofovir alafenamide, lipid profile is altered, and may require initiation of lipid-lowering therapy. It seems necessary to monitor lipid parameters after this switch, despite the absence of an official recommendation.

Dietary and plasma blood α-linolenic acid as modulators of fat oxidation and predictors of aerobic performance.

BACKGROUND: Among n-3 polyunsaturated fatty acids (PUFAs), the most important is α-linolenic acid (ALA). The biological activity of ALA is not equivalent to that of the long-chain n-3 PUFAs, and it has pleiotropic effects, such as functioning as an energy substrate during long-term training when carbohydrate reserves are depleted. The purpose of this investigation was to study the link between the essential dietary and plasma ALA and aerobic performance, which is estimated via maximal fat oxidation (MFO), among skiers. METHODS: Twenty-four highly trained male athletes from the Russian cross-country skiing team participated in the study. ALA intake was determined by an original program used to assess the actual amount and frequency of fat consumption. The plasma level of ALA was determined using gas-liquid chromatography. The skiers' aerobic performance was estimated via MFO and determined by indirect calorimetry using the system "Oxycon Pro". RESULTS: The consumption of ALA in the diet in half of the skiers was below the recommended level at 0.5 ± 0.2 g/day. The deficiency of plasma ALA levels was on average 0.2 ± 0.1 Mol% for almost all participants. The consumption of ALA in the diet and its level in plasma were associated with MFO (rs = 0.507, p = 0.011; rs = 0.460, p = 0.023). Levels of ALA in plasma (p = 0.0523) and the consumption of ALA in the diet (p = 0.0039) were associated with high aerobic performance. CONCLUSIONS: ALA in the diet of the athletes may be used as nutritional support to increase MFO and aerobic performance.

Metabolomic analysis reveals metabolic alterations of human peripheral blood lymphocytes by perfluorooctanoic acid.

Perfluorooctanoic acid (PFOA) is a dispersive persistent organic pollutant in the environment. Accumulating reports suggest that PFOA is toxic to human lymphocytes; however, the toxicological effects of PFOA on these cells remain largely unclear. In this study, ultra-performance liquid chromatography (UPLC)-based metabolomic analysis was employed to identify metabolites in human peripheral blood lymphocytes and to assess the metabolic alterations caused by PFOA exposure. Our comparative metabolomic analysis results demonstrated that PFOA treatment could increase the level of organic acids and reduce the level of lipid molecules. Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation further highlighted the fact that the PFOA treatment interfered with the metabolism of amino acids, carbohydrates and lipids, which may lead to disruption of the immune system.

Arachidonic and docosahexaenoic acid deficits in preterm neonatal mononuclear cell membranes. Implications for the immune response at birth.

Preterm neonates are more susceptible to infection than term neonates. Arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) are biologically active components of cell membrane phospholipids. Arachidonic acid is a substrate for the synthesis of eicosanoids, potent regulators of immune function. Preterm babies may have a deficiency of arachidonic acid and docosahexaenoic acid, but the impact of this deficit on maturation of the immune system is unknown. To address this we explored links between placental provision of fatty acids to cord blood mononuclear cell (CBMC) membranes using gas chromatography (GC), and maturation of the immune response with gestational age by analysing lymphocyte subsets by flow cytometry. This is the first study to examine the lipid profile of the phosphatidylcholine (PC) and phosphatidylethanolamine (PE) fractions of CBMC membranes from preterm neonates. The long chain polyunsaturated fatty acid (LCPUFA) composition of CBMC membranes was dominated by arachidonic acid in both PE (34%) and PC (15%) fractions in healthy term neonates (> or =37 weeks, n=9), whilst in healthy preterm neonates (<37 weeks, n=10) the level of arachidonic acid was significantly lower at 28.8% and 12.5% respectively (p<0.05). Preterm neonates (<37 weeks, n=23) also had significantly lower absolute numbers of CD4+ (p<0.05) leukocytes and CD4+ (p<0.01) and CD8+ (p<0.05) naïve T-cells than term (> or =37 weeks, n=24) neonates that correlated with gestational age (p<0.01-0.05).

Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet.

We previously reported that mice deficient in stearoyl-CoA desaturase-1 (Scd1) and maintained on a very low-fat (VLF) diet for 10 days developed severe loss of body weight, hypoglycemia, hypercholesterolemia, and many cholestasis-like phenotypes. To better understand the metabolic changes associated with these phenotypes, we performed microarray analysis of hepatic gene expression in chow- and VLF-fed female Scd1+/+ and Scd1-/- mice. We identified an extraordinary number of differentially expressed genes (>4,000 probe sets) in the VLF Scd1-/- relative to both VLF Scd1+/+ and chow Scd1-/- mice. Transcript levels were reduced for genes involved in detoxification and several facets of fatty acid metabolism including biosynthesis, elongation, desaturation, oxidation, transport, and ketogenesis. This pattern is attributable to the decreased mRNA abundance of several genes encoding key transcription factors, including LXRalpha, RXRalpha, FXR, PPARalpha, PGC-1beta, SREBP1c, ChREBP, CAR, DBP, TEF, and HLF. A robust induction of endoplasmic reticulum (ER) stress is indicated by enhanced splicing of XBP1, increased expression of the stress-induced transcription factors CHOP and ATF3, and elevated expression of several genes involved in the integrated stress and unfolded protein response pathways. The gene expression profile is also consistent with induction of an acute inflammatory response and macrophage recruitment. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining metabolic homeostasis in the absence of sufficient dietary unsaturated fat and point to a novel cellular nutrient-sensing mechanism linking fatty acid availability and/or composition to the ER stress response.

Central lipoprivation-induced suppression of luteinizing hormone pulses is mediated by paraventricular catecholaminergic inputs in female rats.

The present study aims to clarify the role of fatty acids in regulating pulsatile LH secretion in rats. To produce an acute central lipoprivic condition, mercaptoacetate (MA), an inhibitor of fatty acids oxidation, was administered into the fourth cerebroventricle (4V) in ad libitum fed ovariectomized (OVX) rats (0.4, 2, and 10 micromol/rat) with or without an estradiol (E2) implant producing diestrus plasma E2 levels. Pulsatile LH secretion was suppressed by 4V MA administration in a dose-dependent manner in both OVX and OVX plus E2 rats. Mean LH levels and LH pulse frequency and amplitude were significantly reduced by the highest dose of MA in OVX rats, and by the middle and highest dose of MA in E2-treated rats, suggesting that estrogen enhanced LH suppression. Blood glucose levels increased immediately after the highest dose of MA in both groups. Fourth ventricular injection of trimetazidine (2 and 3 micromol/rat), another inhibitor of fatty acids oxidation, also inhibited pulsatile LH release, resulting in significant and dose-dependent suppression of LH pulse frequency and an increase in blood glucose levels in OVX plus E2 rats. In contrast, peripheral injection of the highest 4V dose of MA (10 micromol/rat) did not alter LH release or blood glucose levels. Microdialysis of the hypothalamic paraventricular nucleus (PVN) revealed that norepinephrine release in the region was increased by 4V MA administration. Preinjection of alpha-methyl-p-tyrosine, a catecholamine synthesis inhibitor, into the PVN completely blocked the lipoprivic inhibition of LH and the counter-regulatory increase in blood glucose levels in OVX plus E2 rats. Together, these studies indicate that fatty acid availability may be sensed by a central detector, located in the lower brainstem to maintain reproduction, and that noradrenergic inputs to the PVN mediate this lipoprivic-induced suppression of LH release.

Management of evaporative dry eye in ectrodactyly-ectodermal dysplasia-clefting syndrome.

PURPOSE: The purpose of this study is to report the features of dry eye and ocular surface disease in an unusual case of ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome. CASE REPORT: A single observational case report of a 22-year-old Japanese male with evaporative dry eye and corneal epithelial disease because of lipid layer abnormality resulting from meibomian gland agenesis was treated successfully with low dose lipid base ointment application. DISCUSSION: The clinical features of the dry eye and ocular surface disease and management issues are discussed. CONCLUSION: Low dose lipid base ointment application may be a promising treatment modality for the ocular surface disease in ectrodactyly-ectodermal dysplasia (EEC)-clefting syndrome, which seems to help in alleviating the subjective complaints and in improving the objective clinical findings.