Targeting phospholipid remodeling pathway improves insulin resistance in diabetic mouse models
Tian Y, Lu W, Shi R, McGuffee R, Lee R, Ford DA and Wang B
Targeting phospholipid remodeling pathway improves insulin resistance in diabetic mouse models
Tian Y, Lu W, Shi R, McGuffee R, Lee R, Ford DA and Wang B
Previous studies have revealed that membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) is involved in the development of insulin resistance in type 2 diabetes. In this study, we aimed to investigate the therapeutic potential of targeting Lpcat3 in the treatment of insulin resistance in diabetic mouse models. Lpcat3 expression was suppressed in the whole body by antisense oligonucleotides (ASO) injection or in the liver by adeno-associated virus (AAV)-encoded Cre in high-fat diet (HFD)-induced and genetic ob/ob type 2 diabetic mouse models. Glucose tolerance test (GTT), insulin tolerance test (ITT), fasting blood glucose, and insulin levels were used to assess insulin sensitivity. Lipid levels in the liver and serum were measured. The expression of genes involved in de novo lipogenesis was analyzed by real-time RT-PCR. Metabolic rates were measured by indirect calorimetry using the Comprehensive Lab Animal Monitoring System (CLAMS). Our data demonstrate that acute knockout of hepatic Lpcat3 by AAV-Cre improves both hyperglycemia and hypertriglyceridemia in HFD-fed mice. Similarly, whole-body ablation of Lpcat3 by ASO administration improves obesity and insulin resistance in both HFD-fed and ob/ob mice. These findings demonstrate that targeting LPCAT3 could be a novel therapy for insulin resistance.
Structural architecture of the acidic region of the B domain of coagulation factor V
Mohammed BM, Basore K, Summers B, Pelc LA and Di Cera E
Structural architecture of the acidic region of the B domain of coagulation factor V
Mohammed BM, Basore K, Summers B, Pelc LA and Di Cera E
Coagulation factor V (fV) features an A1-A2-B-A3-C1-C2 domain organization and functions as the inactive precursor of fVa, a component of the prothrombinase complex required for rapid thrombin generation in the penultimate step of the coagulation cascade. An intramolecular interaction within the large B domain (residues 710-1545) involves the basic region (BR, residues 963-1008) and acidic region (AR, residues 1493-1537) and locks fV in its inactive state. However, structural information on this important regulatory interaction, or on the separate architecture of the AR and BR, remain elusive due to conformational disorder of the B domain.
Yeast Rad52 is a homodecamer and possesses BRCA2-like bipartite Rad51 binding modes
Deveryshetty J, Chadda R, Mattice JR, Karunakaran S, Rau MJ, Basore K, Pokhrel N, Englander N, Fitzpatrick JAJ, Bothner B and Antony E
Yeast Rad52 is a homodecamer and possesses BRCA2-like bipartite Rad51 binding modes
Deveryshetty J, Chadda R, Mattice JR, Karunakaran S, Rau MJ, Basore K, Pokhrel N, Englander N, Fitzpatrick JAJ, Bothner B and Antony E
Homologous recombination (HR) is an essential double-stranded DNA break repair pathway. In HR, Rad52 facilitates the formation of Rad51 nucleoprotein filaments on RPA-coated ssDNA. Here, we decipher how Rad52 functions using single-particle cryo-electron microscopy and biophysical approaches. We report that Rad52 is a homodecameric ring and each subunit possesses an ordered N-terminal and disordered C-terminal half. An intrinsic structural asymmetry is observed where a few of the C-terminal halves interact with the ordered ring. We describe two conserved charged patches in the C-terminal half that harbor Rad51 and RPA interacting motifs. Interactions between these patches regulate ssDNA binding. Surprisingly, Rad51 interacts with Rad52 at two different bindings sites: one within the positive patch in the disordered C-terminus and the other in the ordered ring. We propose that these features drive Rad51 nucleation onto a single position on the DNA to promote formation of uniform pre-synaptic Rad51 filaments in HR.
Direct regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization
Handlin LJ and Dai G
Direct regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization
Handlin LJ and Dai G
Ion channels function within a membrane environment characterized by dynamic lipid compartmentalization. Limited knowledge exists regarding the response of voltage-gated ion channels to transmembrane potential within distinct membrane compartments. By leveraging fluorescence lifetime imaging microscopy (FLIM) and Förster resonance energy transfer (FRET), we visualized the localization of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in membrane domains. HCN4 exhibits a greater propensity for incorporation into ordered lipid domains compared to HCN1. To investigate the conformational changes of the S4 helix voltage sensor of HCN channels, we used dual stop-codon suppression to incorporate different noncanonical amino acids, orthogonal click chemistry for site-specific fluorescence labeling, and transition metal FLIM-FRET. Remarkably, altered FRET levels were observed between VSD sites within HCN channels upon disruption of membrane domains. We propose that the voltage-sensor rearrangements, directly influenced by membrane lipid domains, can explain the heightened activity of pacemaker HCN channels when localized in cholesterol-poor, disordered lipid domains, leading to membrane hyperexcitability and diseases.
The Second Century of Biochemistry and Molecular Biology at Saint Louis University School of Medicine
Eissenberg JC, Jacobs CK and Di Cera E
The Second Century of Biochemistry and Molecular Biology at Saint Louis University School of Medicine
Eissenberg JC, Jacobs CK and Di Cera E
Signaling by Ion Channels: Pathways, Dynamics and Channelopathies
Dai G
Signaling by Ion Channels: Pathways, Dynamics and Channelopathies
Dai G
Charged ions and ion channels play a critical role in regulating the electrical activities of excitable cells. This review discusses the principles of ion channel regulation in the time domain, as well as the diseases that can arise from channel dysfunction and disturbances in ionic balance. Ion channel signaling is a dynamic process that is essential for various physiological functions, including pain sensation, motor control, and the body's response to stress, such as fight-or-flight response.
Metabolic Drivers and Rescuers of Heart Failure
Weiss RC, Menezes TN and McCommis KS
Metabolic Drivers and Rescuers of Heart Failure
Weiss RC, Menezes TN and McCommis KS
Cardiac hypertrophy and heart failure involve a number of metabolic alterations. Human genetic mutations and murine genetic deficiency models of metabolic enzymes or transporters largely suggest that these alterations in metabolism are maladaptive and contribute to the cardiac remodeling and dysfunction. Here, we discuss insights into metabolic alterations identified in cardiac hypertrophy and failure, as well as dietary and pharmacologic therapies that counteract these metabolic alterations and have been shown to significantly improve heart failure.
Forecasting the Future of Antiphospholipid Syndrome: Prospects and Challenges
Taylor A, Kumar S and Pozzi N
Forecasting the Future of Antiphospholipid Syndrome: Prospects and Challenges
Taylor A, Kumar S and Pozzi N
Antiphospholipid syndrome (APS) is an autoimmune condition affecting young patients, primarily women, negatively impacting their quality of life. APS is under-recognized and underdiagnosed and can have devastating results if untreated, mainly due to uncontrolled thrombosis. Research in the past decades has led to several breakthroughs with important implications for clinical practice. Here, we summarize the state of APS diagnosis, treatment, pathophysiology, and research directions that hold promise for advancing diagnosis and treatment.
Uncovering Critical Roles for RNA in Neurodegeneration
Ayala YM
Uncovering Critical Roles for RNA in Neurodegeneration
Ayala YM
RNA-binding proteins, in particular TDP-43, are key players in neurodegenerative disorders, mainly amyotrophic lateral sclerosis and frontotemporal dementia. We aim to elucidate how TDP-43 dysfunction alters cell metabolism and to identify mechanisms linked to aberrant behavior. We find that RNA binding plays a key role in maintaining TDP-43 homeostasis and in controlling cellular organization, two processes of essential importance to TDP-43 pathology. This research will provide insight into pathogenesis and help develop therapeutic interventions.