Angiotensin-converting enzyme (ACE) 2 is a homolog to the carboxypeptidase ACE, which generates angiotensin II, the main active peptide of renin-angiotensin system (RAS). After the cloning of ACE2 in 2000, three major ACE2 functions have been described so far. First ACE2 has emerged as a potent negative regulator of the RAS counterbalancing the multiple functions of ACE. By targeting angiotensin II ACE2 exhibits a protective role in the cardiovascular system and many other organs. Second ACE2 was identified as an essential receptor for the SARS coronavirus that causes severe acute lung failure. Downregulation of ACE2 strongly contributes to the pathogenesis of severe lung failure. Third, both ACE2 and its homologue Collectrin can associate with amino acid transporters and play essential role in the absorption of amino acids in the kidney and gut. In this review, we will discuss the multiple biological functions of ACE2.

Angiotensin-converting enzyme 2 (ACE2), a first homolog of ACE, regulates the renin-angiotensin system by counterbalancing ACE activity. Accumulating evidence in recent years has demonstrated a physiological and pathological role of ACE2 in the cardiovascular, renal and respiratory systems. For instance, in the acute respiratory distress syndrome (ARDS), ACE, AngII, and AT1R promote the disease pathogenesis, whereas ACE2 and the AT2R protect from ARDS. Importantly, ACE2 has been identified as a key SARS-coronavirus receptor and plays a protective role in SARS pathogenesis. Furthermore, the recent explosion of research into the ACE2 homolog, collectrin, has revealed a new physiological function of ACE2 as an amino acid transporter, which explains the pathogenic role of gene mutations in Hartnup disorder. This review summarizes and discusses the recently unveiled roles for ACE2 in disease pathogenesis. (Circ J 2010; 74: 405 - 410)

Current paradigms of cell intrinsic immunity to RNA viruses center on virus-triggered inducible antiviral responses initiated by RIG-I-like receptors (RLRs) or Toll-like receptors (TLRs) that sense pathogen-associated molecular patterns, and signal downstream through interferon regulatory factors (IRFs), transcription factors that induce synthesis of type I and type III interferons (IFNs) 1 . RNA viruses have evolved sophisticated strategies to disrupt these signaling pathways and evade elimination by cells, attesting to their importance 2 . Less attention has been paid how IRFs maintain basal levels of protection against viruses. Here, we depleted antiviral factors linked to RLR and TLR signaling in order to map critical host pathways restricting positive-strand RNA virus replication in immortalized hepatocytes and identified an unexpected role for IRF1. We show constitutively expressed IRF1 acts independently of MAVS, IRF3, and STAT1-dependent signaling to provide intrinsic antiviral protection in actinomycin D-treated cells. IRF1 localizes to the nucleus, where it maintains basal transcription of a suite of antiviral genes that protect against multiple pathogenic RNA viruses, including hepatitis A and C viruses (HAV and HCV), dengue virus (DENV) and Zika virus (ZIKV). Our findings reveal an unappreciated layer of hepatocyte intrinsic immunity to these positive-strand RNA viruses, and identify previously unrecognized antiviral effector genes.

al cooperation between LPA4 and LPA6 is essential for embryonic development. Since Lpa4;Lpa5-DKO and Lpa5;Lpa6-DKO mice were born at the expected Mendelian ratios and had no obvious abnormalities (Supplemental Tables 4 and 5), LPA5 is unlikely to be involved in embryonic development. To examine the roles of LPA4 and LPA6 in embryonic development, yolk sac and embryo proper were observed at various stages of gestation. At E8.5, both Lpa4;Lpa6-DKO yolk sac and embryo proper appeared normal (Supplemental Figure 1, A and B). However, at E9.5-10.5, almost all of Lpa4;Lpa6-DKO embryos proper had various morphological abnormalities, such as severe pericardial effusion (Figure 1A and Supplemental Figure 1, B-D), axial turning abnormality (Supplemental Figure 1, B, E, and F), and developmental delay (Figure 1, A and B, and Supplemental Figure 1, B, G, and H). DKO yolk sacs lacked large blood vessels at E9.5-10.5, whereas WT yolk sacs had well-developed blood vessels (Figure 1B and Supplemental Figure 1, A, I, and J). We observed that all DKO embryos died by E11.5 (Supplemental Figure 1, B, K, and L, and Supplemental Table 6). Histological analysis showed that the endoderm and mesoderm of the yolk sacs were more widely separated in the DKO tissue (Figure 1C). Despite this vascular defect, erythrocytes were present in Lpa4;Lpa6-DKO yolk sacs (Figure 1C). Blood vessel-stained whole-mount embryos at E10.5 revealed that DKO embryos had enlarged dorsal aortae and poor vascular networks in the head and intersomitic regions, compared with WT embryos (Figure 1D). Furthermore, blood vessel-stained cross sections of embryos at E9.5 also revealed that DKO embryos had enlarged dorsal aortae and thinned neural tubes, compared with WT embryos (Figure 1E). These results strongly suggest that both LPA4 and LPA6 are indispensable for embryonic angiogenesis. Endothelial LPA4 and LPA6 are involved in retinal angiogenesis. Previously, we detected mRNA expression of Lpa4 and LPA6 in vascular ECs (8, 16). To investigate the functional roles of endothelial LPA4 and LPA6, we generated a tamoxifen-inducible and EC-specific Lpa4/Lpa6 deletion mouse line by crossing Lpa4;Lpa6 double-floxed mutants with transgenic mice carrying Cdh5-CreER T2 (ref. 37, Figure 2A, and Supplemental Figure 2A). The resulting Lpa4 fl/fl(Y) Lpa6 fl/fl Cdh5-CreER T2 mice (termed hereafter Lpa4; Lpa6 iΔEC) were treated with tamoxifen from P1 to P3. Allele-specific PCR confirmed recombination of both floxed alleles in the tails of Lpa4;Lpa6 iΔEC mice at P5 (Supplemental Figure 2B). At P5, we found that the radial expansion, EC area, and retinal blood vessel branching were significantly reduced in Lpa4;Lpa6 iΔEC mice compared with those in control CreER T2-negative Lpa4 fl/fl(Y) ;Lpa6 fl/fl littermates (Figure 2, C and F-H). At the angiogenic front, sprouts of retinal vessels were significantly reduced in Lpa4;Lpa6 iΔEC retina (Figure 2, D and I). Additionally, both the number and length of sprouting filopodia were significantly reduced in Lpa4;Lpa6 iΔEC retina (Figure 2, E, J...

Summary The role of lipid metabolism in human pluripotent stem cells (hPSCs) is poorly understood. We have used large-scale targeted proteomics to demonstrate that undifferentiated hPSCs express different fatty acid (FA) biosynthesis-related enzymes, including ATP citrate lyase and FA synthase (FASN), than those expressed in hPSC-derived cardiomyocytes (hPSC-CMs). Detailed lipid profiling revealed that inhibition of FASN resulted in significant reduction of sphingolipids and phosphatidylcholine (PC); moreover, we found that PC was the key metabolite for cell survival in hPSCs. Inhibition of FASN induced cell death in undifferentiated hPSCs via mitochondria-mediated apoptosis; however, it did not affect cell survival in hPSC-CMs, neurons, or hepatocytes as there was no significant reduction of PC. Furthermore, we did not observe tumor formation following transplantation of FASN inhibitor-treated cells. Our findings demonstrate the importance of de novo FA synthesis in the survival of undifferentiated hPSCs and suggest applications for FASN inhibition in regenerative medicine.

No abstract

No abstract

DDHD2/KIAA0725p is a mammalian intracellular phospholipase A1 that exhibits phospholipase and lipase activities. Mutation of the DDHD2 gene causes hereditary spastic paraplegia (SPG54), an inherited neurological disorder characterized by lower limb spasticity and weakness. Although previous studies demonstrated lipid droplet accumulation in the brains of SPG54 patients and DDHD2 knockout mice, the cause of SPG54 remains elusive. Here, we show that ablation of DDHD2 in mice induces age-dependent apoptosis of motor neurons in the spinal cord. In vitro, motor neurons and embryonic fibroblasts from DDHD2 knockout mice fail to survive and are susceptible to apoptotic stimuli. Chemical and probe-based analysis revealed a substantial decrease in cardiolipin content and an increase in reactive oxygen species generation in DDHD2 knockout cells. Reactive oxygen species production in DDHD2 knockout cells was reversed by the expression of wild-type DDHD2, but not by an active-site DDHD2 mutant, DDHD2 mutants related to hereditary spastic paraplegia, or DDHD1, another member of the intracellular phospholipase A1 family whose mutation also causes spastic paraplegia (SPG28). Our results demonstrate the protective role of DDHD2 for mitochondrial integrity and provide a clue to the pathogenic mechanism of SPG54.