Lipid Signaling Pathways Research Articles

Introduction: Druggable Lipid Signaling Pathways.

Lipids are essential for life. They store energy, constitute cellular membranes, serve as signaling molecules, and modify proteins. In the long history of lipid research, many drugs targeting lipid receptors and enzymes that are responsible for lipid metabolism and function have been developed and applied to a variety of diseases. For example, non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed medications for fever, pain, and inflammation. The NSAIDs block prostaglandin production by inhibiting cyclooxygenases. A recent innovative breakthrough in drug discovery for the lipid biology field was the development of the sphingosine 1-phosphate receptor modulators (fingolimod, siponimodand ozanimod) for the treatment of multiple sclerosis, which were approved by the United States Food and Drug Administration in 2010, 2019 and 2020,respectively. This review series of "Druggable Lipid Signaling Pathways" provides 9 outstanding reviews that summarize the currently available drugs that target lipid signaling pathways and also outlines future directions for drug discovery. The review chapters include lipid signaling pathways (prostanoids, leukotrienes, epoxy fatty acids, sphingolipids, lysophospholipids, endocannabinoids, and phosphoinositides) and lipid signaling proteins (lysophospholipid acyltransferases, phosphoinositide 3-kinase,and G protein-coupled receptors (GPCRs)). Drugs targeting lipid signaling pathways promise to be life changing magic for the future of human health and well-being.

A lupine (Lupinus angustifolious L.) peptide prevents non-alcoholic fatty liver disease in high-fat-diet-induced obese mice.

Bioactive peptides are related to the prevention and treatment of many diseases. GPETAFLR is an octapeptide that has been isolated from lupine (Lupinus angustifolius L.) and shows anti-inflammatory properties. The aim of this study was to evaluate the potential activity of GPETAFLR to prevent non-alcoholic fatty liver disease (NAFLD) in high-fat-diet (HFD)-induced obese mice. C57BL/6J mice were fed a standard diet or HFD. Two of the groups fed the HFD diet were treated with GPETAFLR in drinking water at 0.5 mg kg-1 day-1 or 1 mg kg-1 day-1. To determine the ability of GPETAFLR to improve the onset and progression of non-alcoholic fatty liver disease, histological studies, hepatic enzyme profiles, inflammatory cytokine and lipid metabolism-related genes and proteins were analysed. Our results suggested that HFD-induced inflammatory metabolic disorders were alleviated by treatment with GPETAFLR. In conclusion, dietary lupine consumption can repair HFD-induced hepatic damage possibly via modifications of liver's lipid signalling pathways.

Analysis of hepatic and retinal cell microRNAome during AAV infection reveals their diverse impact on viral transduction and cellular physiology

Cellular microRNAs are known to modulate the life-cycle of different viruses. Surprisingly, very little data exists on AAV-induced changes to the cellular microRNAome in general and in hepatic and retinal cells, in particular. We reasoned that inducible microRNA in response to recombinant AAV infection may regulate immediate and long-lived cellular responses necessary for the cell’s own survival as well as its ability to control several aspects of viral life-cycle. To study this, we performed a global small RNA sequencing analysis in Adeno-associated virus (AAV) serotypes 2 and 3 infected hepatic and retinal cell models. This screen identified multiple differentially expressed microRNAs, in AAV infected Huh-7 and ARPE-19 cells. Among these, one microRNA (miR-4488) was found to be significantly down regulated (−2.24 fold for AAV2 and −3.32 fold for ARPE-19) in AAV infected cells. An enrichment and pathway analysis of miR-4488 predicted its possible effects on gene targets involved in multiple biological processes including cell-cycle regulation, endoplasmic reticulum stress response and lipid-signalling pathways. Moreover, validation studies in miR-4488 mimic or sponge transfected cells revealed modulation of these target pathways in a cell-specific manner. Further studies demonstrated that overexpression of miR-4488, modestly increased gene expression (126–128%) from AAV2 and AAV3 vectors in Huh-7 cells whereas miR-4488 inhibition in ARPE-19 cells had a similar increase (142–158%) on AAV2 or AAV3 transduction. Our results highlight that recombinant AAV mediated microRNA expression is cell-type and serotype-specific and can target specific host cellular biological pathways.

Scott Medal to Benjamin Cravatt

Benjamin F. Cravatt, the Gilula Chair in Chemical Biology and professor of chemistry at Scripps Research in California, is the winner of the 2019 A. Ian Scott Medal, presented by the ACS Texas A&M Section and Texas A&M University’s department of chemistry. The award recognizes excellence in biological chemistry research. Cravatt’s work on characterizing biochemical pathways has led to the discovery of key enzymes involved in regulating lipid signaling pathways in the nervous system and cancer. He will receive a gold medal and bronze replica during an awards ceremony at Texas A&M University on Sept. 27.

Coronary Artery Disease Risk-Associated Plpp3 Gene and Its Product Lipid Phosphate Phosphatase 3 Regulate Experimental Atherosclerosis.

Genome-wide association studies identified novel loci in PLPP3(phospholipid phosphatase 3) that associate with coronary artery disease risk independently of traditional risk factors. PLPP3 encodes LPP3 (lipid phosphate phosphatase 3), a cell-surface enzyme that can regulate the availability of bioactive lysophopsholipids including lysophosphatidic acid (LPA). The protective allele of PLPP3 increases LPP3 expression during cell exposure to oxidized lipids, however, the role of LPP3 in atherosclerosis remains unclear. Approach and Results: In this study, we sought to validate LPP3 as a determinate of the development of atherosclerosis. In experimental models of atherosclerosis, LPP3 is upregulated and co-localizes with endothelial, smooth muscle cell, and CD68-positive cell markers. Global post-natal reductions in Plpp3 expression in mice substantially increase atherosclerosis, plaque-associated LPA, and inflammation. Although LPP3 expression increases during ox-LDL (oxidized low-density lipoprotein)-induced phenotypic modulation of bone marrow-derived macrophages, myeloid Plpp3 does not appear to regulate lesion formation. Rather, smooth muscle cell LPP3 expression is a critical regulator of atherosclerosis and LPA content in lesions. Moreover, mice with inherited deficiency in LPA receptor signaling are protected from experimental atherosclerosis. Our results identify a novel lipid signaling pathway that regulates inflammation in the context of atherosclerosis and is not related to traditional risk factors. Pharmacological targeting of bioactive LPP3 substrates, including LPA, may offer an orthogonal approach to lipid-lowering drugs for mitigation of coronary artery disease risk.

Immunotoxic Potential of Bisphenol F Mediated through Lipid Signaling Pathways on Macrophages.

As a bisphenol A (BPA) alternative, bisphenol F (BPF) has been detected in various products, such as paper products, personal care products, and food. More importantly, the toxicity of BPF remains underexplored. We reported an integrated method to study the immunotoxic potentials and the underlying mechanisms of BPF on cell apoptosis, macrophage polarization, reactive oxygen species generation, expression and secretion of immune-related cytokines, and reprogramming of lipid signaling. More serious to BPA, BPF induced apoptosis in macrophages. The apoptosis was induced by activating both sphingomyelin-ceramide signaling pathway and oxidative stress, which included intrinsic (bax and caspase-9) and extrinsic apoptotic pathways (tumor necrosis factor receptor 1, caspase-8, and caspase-3). BPF exposure also induced the proinflammatory phenotype of the macrophage. This alternation was shown to be closely correlated with the modulation of biosynthesis and degradation of glycerophospholipids. This study demonstrated novel evidence that BPF as a substituent of BPA induced immunotoxic effects at environmentally relevant concentrations. We also showed that the reprogramming of lipidome plays a key role in the regulation of macrophage polarization and the induction of immunotoxicity of the BPA analogue.

Parthenolide inhibits lipid accumulation via activation of Nrf2/Keap1 signaling during adipocyte differentiation

The effects of parthenolide (PL), a sesquiterpene lactone obtained from feverfew plant, on lipid accumulation and signaling pathway in adipocytes were investigated. PL significantly inhibited lipid accumulation and adipogenic factors during adipogenesis. In particular, PL exerted its inhibitory effects in early adipogenic stage by regulating the early adipogenic factors. In addition, PL regulated the expression of adipokines; leptin, retinol binding protein, and resistin mRNAs were downregulated, whereas adiponectin gene expression was increased. Furthermore, PL significantly reduced intracellular reactive oxygen species (ROS) production during adipogenesis. This PL-mediated regulation of ROS production was associated with the regulation of nuclear factor erythroid 2-related factor (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) pathway. PL effectively increased the abundance of Nrf2 and its target proteins, heme oxygenase-1 (HO-1) and NADPH dehydrogenase 1 (NQO1), by promoting the nuclear translocation of Nrf2, indicating that PL-mediated anti-adipogenic effects are associated with the Nrf2/Keap1 pathway.

3173 – AP2A2 KO MICE LINK FETAL LIVER HAEMATOPOIESIS EXHAUSTION TO LOSS OF HSC QUIESCENCE, PERTURBED ASYMMETRICAL FATE AND ALTERED LIPID METABOLISM

We identified Ap2a2 as an enhancer of mouse long-term (LT-) HSC function via a bone marrow (BM) transplantation screen, and a HSC cell fate determinant during live cell HSC videomicroscopy. We hypothesised Ap2a2-transduced HSCs acquired in-vitro quiescence. Using the Tet-On H2B-GFP mouse line - We transduced vector versus AP2A2 into H2B-GFP HSCs for an in-vivo pulse-chase transplantation assay. This showed a 3-fold increase in the dormant GFP-high (CD150+48-LSK) LT-HSC subpopulation of Ap2a2-transduced-HSC recipients. We present two new mouse transgenic lines: an Ap2a2-LacZ reporter where X-Gal/FDG staining of BM cells confirmed higher endogenous Ap2a2 expression in LT- versus short-term (ST- CD150-48-LSKs) HSCs and a constitutive Ap2a2 knock-out (KO) line. Analyses of heterozygote Ap2a2 KO matings showed less than expected 25% Ap2a2-/- Mendelian inheritance at weaning consistent with fetal and peri-natal lethality. E14. 5 Ap2a2-/- embryos had smaller livers but twice as many LT-HSCs, confirmed by limit dilution assay. Ki67/DAPI cell cycle analyses showed loss of G0 in E14.5 LT- versus ST-HSCs. At E16.5-E18.5, there were two embryonic phenotypes: Ap2a2-/- survivors defined by restoration of FL LT-HSC G0 and differentiation as opposed to Ap2a2-/- non-survivors with continued loss of G0 and failed differentiation. Numb staining of Ap2a2-/- E14.5 LT-HSCs showed perturbed asymmetrical to symmetrical divisions. RNAseq analyses of Ap2a2-/- compared to Ap2a2+/+ E14.5 LT-HSCs showed differential upregulation of PPAR and lipid signaling pathways. Functionally, E14.5 Ap2a2-/- FL cells have maintained splenic colony formation but significantly impaired competitive transplant reconstitution. We conclude constitutive Ap2a2 deletion results in FL HSC exhaustion via loss of LT-HSC G0 quiescence and differentiation, which mechanistically involves the PPAR-lipid metabolism pathways.

Exercise alters the molecular pathways of insulin signaling and lipid handling in maternal tissues of obese pregnant mice.

Obesity during gestation adversely affects maternal and infant health both during pregnancy and for long afterwards. However, recent work suggests that a period of maternal exercise during pregnancy can improve metabolic health of the obese mother and her offspring. This study aimed to identify the physiological and molecular impact of exercise on the obese mother during pregnancy that may lead to improved metabolic outcomes. To achieve this, a 20‐min treadmill exercise intervention was performed 5 days a week in diet‐induced obese female mice from 1 week before and up to day 17 of pregnancy. Biometric, biochemical and molecular analyses of maternal tissues and/or plasma were performed on day 19 of pregnancy. We found exercise prevented some of the adverse changes in insulin signaling and lipid metabolic pathways seen in the liver, skeletal muscle and white adipose tissue of sedentary‐obese pregnant dams (p110β, p110α, AKT, SREBP). Exercise also induced changes in the insulin and lipid signaling pathways in obese dams that were different from those observed in control and sedentary‐obese dams. The changes induced by obesity and exercise were tissue‐specific and related to alterations in tissue lipid, protein and glycogen content and plasma insulin, leptin and triglyceride concentrations. We conclude that the beneficial effects of exercise on metabolic outcomes in obese mothers may be related to specific molecular signatures in metabolically active maternal tissues during pregnancy. These findings highlight potential metabolic targets for therapeutic intervention and the importance of lifestyle in reducing the burden of the current obesity epidemic on healthcare systems.

A synthetic biological approach to reconstitution of inositide signaling pathways in bacteria.

Inositide lipid (PIP) and soluble (IP) signaling pathways produce essential cellular codes conserved in eukaryotes. In many cases, deconvoluting metabolic and functional aspects of individual pathways are confounded by promiscuity and multiplicity of PIP and IP kinases and phosphatases. We report a molecular genetic approach that reconstitutes eukaryotic inositide lipid and soluble pathways in a prokaryotic cell which inherently lack inositide kinases and phosphatases in their genome. By expressing synthetic cassettes of eukaryotic genes, we have reconstructed the heterologous formation of a range of inositide lipids, including PI(3)P, PI(4,5)P2 and PIP3. In addition, we report the reconstruction of lipid-dependent production of inositol hexakisphosphate (IP6). Our synthetic system is scalable, reduces confounding metabolic issues, for example it is devoid of inositide phosphatases and orthologous kinases, and enables accurate characterization gene product enzymatic activity and substrate selectivity. This genetically engineered tool is designed to help interpret metabolic pathways and may facilitate in vivo testing of regulators and small molecule inhibitors. In summary, heterologous expression of inositide pathways in bacteria provide a malleable experimental platform for aiding signaling biologists and offers new insights into metabolism of these essential pathways.

Metformin improved oxidized low-density lipoprotein-impaired mitochondrial function and increased glucose uptake involving Akt-AS160 pathway in raw264.7 macrophages.

Macrophage accumulation in the vascular wall is a hallmark of atherosclerosis. Studies showed that shifting of oxidized lipids-induced inflammatory macrophages towards an anti-inflammatory phenotype by promoting oxidative metabolism attenuated atherosclerosis progression. Therefore, this study aimed to investigate whether metformin, which has ameliorated atherosclerosis in animal models and clinical trials, modulated oxidized low-density lipoprotein (Ox-LDL) induced inflammatory status in macrophages by regulating cellular oxidative metabolism. Murine raw264.7 macrophages were incubated with Ox-LDL (50 μg/mL) in the presence or absence of metformin (15 μmol/L) for 24 h. Real-time polymerase chain reaction was used to quantify the transcription of classically activated (M1) pro-inflammatory and alternatively activated (M2) anti-inflammatory markers and mitochondrial DNA copy numbers. Cellular reactive oxygen species (ROS) production and mitochondrial membrane potential were detected by immunofluorescence. Cellular adenosine triphosphate (ATP) synthesis, glucose uptake, and lactic acid production were measured by commercial kit and normalized to cellular lysates. Western blotting analysis was performed to detect the expression of mitochondrial fusion/fission related proteins, enzymes mediating lipid metabolism and signaling pathway of glucose transport. Differences between groups were analyzed using one-way analysis of variance. Metformin improved Ox-LDL-impaired anti-inflammatory phenotype in raw264.7 macrophages as shown by up-regulated transcription of anti-inflammatory markers including interleukin 10 (0.76 ± 0.04 vs. 0.94 ± 0.01, P = 0.003) and Resistin-like molecule alpha (0.67 ± 0.08 vs. 1.78 ± 0.34, P = 0.030). Conversely, Ox-LDL-diminished phosphorylation of Akt was up-regulated by metformin treatment (0.47 ± 0.05 vs. 1.02 ± 0.08, P = 0.040), associated with an improvement of mitochondrial function, characterized by decreased ROS generation (2.50 ± 0.07 vs. 2.15 ± 0.04, P = 0.040), increased lipid oxidation, and elevated cellular ATP production (0.026 ± 0.001 vs. 0.035 ± 0.003, P = 0.020). Moreover, metformin-mediated Akt activation increased Akt substrate of 160 kDa (AS160) phosphorylation (0.51 ± 0.04 vs. 1.03 ± 0.03, P = 0.0041), promoted membrane translocation of glucose transporter 1, and increased glucose influx into the cells (4.78 ± 0.04 vs. 5.47 ± 0.01, P < 0.001). This study suggested that targeting macrophage metabolism with new or existing drugs had therapeutic potential for the prevention and treatment of diabetes-accelerated atherosclerosis.

In vitro 6-hydroxydopamine-induced neurotoxicity: New insights on NFκB modulation

Neuronal exposure to 6-hydroxydopamine (6-OHDA), a hydroxylated analog of dopamine, constitutes a very useful strategy for studying the molecular events associated with neuronal death in Parkinson's disease. 6-OHDA increases oxidant levels and impairs mitochondrial respiratory chain, thus promoting neuronal injury and death. Despite the extensive use of 6-OHDA in animal models, the exact molecular events triggered by this neurotoxicant at the neuronal level have not been yet fully understood.Human IMR-32 neuroblastoma cells exposed to increasing concentrations of 6-OHDA displayed high levels of reactive oxygen species and increased plasma membrane permeability with concomitant cell viability diminution. As part of the neuronal response to 6-OHDA exposure, the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) p65 subunit was observed. NFκB nuclear localization was also accompanied by an increase of IκB phosphorylation as well as a rise in cyclooxygenase-2 (COX-2) and the prostaglandin receptor, EP4, mRNA levels.Even though the canonical pathways participating in the modulation of NFκB have been extensively described, here we tested the hypothesis that 6-OHDA-induced injury can activate lipid signaling and, in turn, modulate the transcriptional response. 6-OHDA challenge triggered the activation of lipid signaling pathways and increased phosphatidic acid (PA), diacylglycerol and free fatty acid levels in human neuroblastoma cells. The inhibition of PA production was able to prevent the decrease in cell viability triggered by 6-OHDA, the nuclear translocation of NFκB p65 subunit and the rise in COX-2 mRNA expression. Our results indicate that the onset of the inflammatory process triggered by 6-OHDA involves the activation of PA signaling that, in turn, governs NFκB subcellular localization and COX-2 expression.

PB1959 THE ROLE OF FLOW CYTOMETRY IN DIFFERENTIAL DIAGNOSIS OF CMML AND REACTIVE MONOCYTOSIS. THE LIPID SIGNAL PATHWAY CHARACTERISTICS IN CLONAL MONOCYTOSIS

Background:Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases characterized by ineffective erythropoiesis and dysplasia. MDS and its subtype CMML is highly associated with chronic inflammatory and autoimmune diseases; however the combination of MDS with other bone marrow neoplasms is not a common entity. Only few cases of MDS combined with other blood malignancies have been described. The pathogenesis and mechanisms of two different clones evolution in MDS is an unclear multistep process involving molecular genetic instability, epigenetic factors and innate immune response deregulation. The role of plasma lipid signaling pathway have been also defined in recent years.Aims:Is to investigate the role of immunophenotyping in differential diagnosis of CMML and reactive monocytosis and clarify the possible significance of phosphoinositides in diagnosis of CMML.Methods:Blood samples of patient with CMML combined with plasma cell disorder, patient with CMML and blood samples of 2 patients with monocytosis were examined in our laboratory. Peripheral blood CBC, bone marrow smear cytological examination, pathohistology, flow cytometry and PCR were performed for the diagnostic purposes. In parallel with classic diagnostic work‐up the chromatograph method was used to investigate the cytoplasmatic mono and di‐phosphoinositides in patients with CMML.Results:CBC reveal monocytosis &gt;1000 less than 1 month duration, PCR analysis were negative for BCR ABL in all 4 cases. Case N = 1 histology examination Results: &gt;30% of plasma cells express CD56 and CD138, atypical cells express MPO and CD14 and epithelioid granulomas. In case N = 1 Immuntophenotype results were the following: (CD64+)‐52%, (CD16+)‐44%, (CD14‐). In case N = 2 the dysplasia, megakaryocytes and monocytes were observed by histology examination. Immunophenotype Results: (CD14+/CD16)‐31.1%, (CD14+/‐CD16+)‐49.3%, (CD14‐/CD16‐)‐4.3%. There were monocytosis and secondary changes of hematopoietic tissue in histology examination of cases N = 3 and N = 4. Immunophenotype showed: (CD14‐/16‐)‐13%, (CD64+)15%, (CD56‐)‐3%. High level of mono and di‐phosphoinositides were registered in first 2 cases in compare with cases N3 and N4. The flow cytometry revealed monocyte specific markers in all 4 cases with certain variations.Summary/Conclusion:The exact immunophenotype markers for clonal monocytosis must be defined. Lipid signaling pathway components, such as cytoplasmatic mono and di‐phosphoinositides must be investigated in the context of clonal monocytosis and diagnostic purposes.

Diacylglycerol Lipase-β Is Required for TNF-α Response but Not CD8+ T Cell Priming Capacity of Dendritic Cells

Diacylglycerol lipase-β (DAGLβ) hydrolyzes arachidonic acid (AA)-esterified diacylglycerols to produce 2-arachidonoylglycerol (2-AG) and downstream prostanoids that mediate inflammatory responses of macrophages. Here, we utilized DAGL-tailored activity-based protein profiling and genetic disruption models to discover that DAGLβ regulates inflammatory lipid and protein signaling pathways in primary dendritic cells (DCs). DCs serve as an important link between innate and adaptive immune pathways by relaying innate signals and antigen to drive Tcell clonal expansion and prime antigen-specific immunity. We discovered that disruption of DAGLβ in DCs lowers cellular 2-AG and AA that is accompanied by reductions in lipopolysaccharide (LPS) stimulated tumor necrosis factor α secretion. Cell-based vaccination studies revealed that DC maturation exvivo and immunogenicity invivo was surprisingly unaffected by DAGLβ inactivation. Collectively, we identify DAGLβ pathways as a means for attenuatingDC inflammatory signaling while sparing criticaladaptive immune functions and further expand theutility of targeting lipid pathways for immunomodulation.

Expression analysis and genotyping of DGKZ: a GWAS-derived risk gene for schizophrenia.

Schizophrenia (SCZ) is a disabling and severe mental illness characterized by abnormal social behavior and disrupted emotions. Similar to other neuropsychological disorders, both genetics and environmental factors interplay so as to develop SCZ. It is acknowledged that genes such as DGKZ are involved in lipid signaling pathways that are the basis of neural activities, memory, and learning and are considered as candidate loci for SCZ. The aim of the present study was to evaluate the expression level and genotypes of DGKZ in patients with SCZ and controls. We used q-PCR to measure the relative expression of DGKZ in blood. To determine DGKZ-rs7951870 genotypes, tetra-ARMS PCR was used. Our results showed a significant difference in DGKZ mRNA ratio between SCZ patients and healthy controls (P = 2 × 10-4). Also, we showed that rs7951870-TT genotype was strongly associated with increased DGKZ expression level (P = 0.038). In conclusion, our findings revealed dysregulation of DGKZ in SCZ patients and a significant correction between the gene expression and DGKZ variant rs7951870.

Scaffold and organism hopping with chemical probes.

Chemical probes that irreversibly inhibit protein function may be used across species to discover proteins. Combining phenotypic screening and activity-based protein profiling, a new study uncovers a discrete lipid signaling pathway regulating lifespan in the worm Caenorhabditis elegans.

A Slow-Digesting Carbohydrate Diet during Rat Pregnancy Protects Offspring from Non-Alcoholic Fatty Liver Disease Risk through the Modulation of the Carbohydrate-Response Element and Sterol Regulatory Element Binding Proteins.

High-fat (HF) and rapid digestive (RD) carbohydrate diets during pregnancy promote excessive adipogenesis in offspring. This effect can be corrected by diets with similar glycemic loads, but low rates of carbohydrate digestion. However, the effects of these diets on metabolic programming in the livers of offspring, and the liver metabolism contributions to adipogenesis, remain to be addressed. In this study, pregnant insulin-resistant rats were fed high-fat diets with similar glycemic loads but different rates of carbohydrate digestion, High Fat-Rapid Digestive (HF–RD) diet or High Fat-Slow Digestive (HF–SD) diet. Offspring were fed a standard diet for 10 weeks, and the impact of these diets on the metabolic and signaling pathways involved in liver fat synthesis and storage of offspring were analyzed, including liver lipidomics, glycogen and carbohydrate and lipid metabolism key enzymes and signaling pathways. Livers from animals whose mothers were fed an HF–RD diet showed higher saturated triacylglycerol deposits with lower carbon numbers and double bond contents compared with the HF–SD group. Moreover, the HF–RD group exhibited enhanced glucose transporter 2, pyruvate kinase (PK), acetyl coenzyme A carboxylase (ACC) and fatty acid (FA) synthase expression, and a decrease in pyruvate carboxylase (PyC) expression leading to an altered liver lipid profile. These parameters were normalized in the HF–SD group. The changes in lipogenic enzyme expression were parallel to changes in AktPKB phosphorylation status and nuclear expression in carbohydrate-response element and sterol regulatory element binding proteins. In conclusion, an HF–RD diet during pregnancy translates to changes in liver signaling and metabolic pathways in offspring, enhancing liver lipid storage and synthesis, and therefore non-alcoholic fatty liver disease (NAFLD) risk. These changes can be corrected by feeding an HF–SD diet during pregnancy.

Lysosomal Metabolic Cues in Orchestrating Cellular and Organism Homeostasis

Lysosomes are highly specialized cellular organelles with crucial functions in metabolic digestion and recycling. They carry a variety of hydrolases that function at low pH and generate specific metabolic products. Work in my laboratory is interested in understanding how these metabolic activities of lysosomes are linked to their signaling communication with other cellular organelles, such as mitochondria, endoplasmic reticulum (ER) and the nucleus. We discovered a lysosome‐to‐nucleus retrograde lipid signaling pathway in promoting healthy aging and metabolic fitness, and revealed its critical roles in the metabolic and signaling interaction between lysosomes and mitochondria. Most recently, we discovered a lysosome‐specific nucleotide hydrolase and its key functions in the control of ER stress responses through interacting with mTOR signaling. These studies highlight the signaling role of lysosomes in the active coordination of cellular homeostasis and in the improvement of the healthy survival of an organism.Support or Funding InformationThis work was supported by HHMI and National Institutes of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Fatty Acid-Binding Protein 4 in Cardiovascular and Metabolic Diseases.

Fatty acid-binding proteins (FABPs), a family of lipid chaperones, contribute to systemic metabolic regulation via several lipid signaling pathways. Fatty acid-binding protein 4 (FABP4), known as adipocyte FABP (A-FABP) or aP2, is mainly expressed in adipocytes and macrophages and plays important roles in the development of insulin resistance and atherosclerosis in relation to metabolically driven low-grade and chronic inflammation, referred to as ‘metaflammation’. FABP4 is secreted from adipocytes in a non-classical pathway associated with lipolysis and acts as an adipokine for the development of insulin resistance and atherosclerosis. Circulating FABP4 levels are associated with several aspects of metabolic syndrome and cardiovascular disease. Ectopic expression and function of FABP4 in cells and tissues are also related to the pathogenesis of several diseases. Pharmacological modification of FABP4 function by specific inhibitors, neutralizing antibodies or antagonists of unidentified receptors would be novel therapeutic strategies for several diseases, including obesity, diabetes mellitus, atherosclerosis and cardiovascular disease. Significant roles of FABP4 as a lipid chaperone in physiological and pathophysiological conditions and the possibility of FABP4 being a therapeutic target for metabolic and cardiovascular diseases are discussed in this review.

The circadian clock components BMAL1 and REV-ERB\u03b1 regulate flavivirus replication

The circadian clock regulates immune responses to microbes and affects pathogen replication, but the underlying molecular mechanisms are not well understood. Here we demonstrate that the circadian components BMAL1 and REV-ERBα influence several steps in the hepatitis C virus (HCV) life cycle, including particle entry into hepatocytes and RNA genome replication. Genetic knock out of Bmal1 and over-expression or activation of REV-ERB with synthetic agonists inhibits the replication of HCV and the related flaviruses dengue and Zika via perturbation of lipid signaling pathways. This study highlights a role for the circadian clock component REV-ERBα in regulating flavivirus replication.