T329S Mutation in the FMO3 Gene Alleviates Lipid Metabolic Diseases in Chickens in the Late Laying Period

The T329S mutation in flavin-containing monooxygenase 3 (FMO3) impairs the trimethylamine (TMA) metabolism in laying hens. The TMA metabolic pathway is closely linked to lipid metabolic diseases, such as atherosclerosis and fatty liver disease. We aimed to evaluate the effects of the T329S mutation in FMO3 on lipid metabolism in chickens during the late laying period. We selected 18 FMO3 genotyped individuals (consisting of six AA, six AT, and six TT hens) with similar body weight and production performance. The lipid metabolism and deposition characteristics of the laying hens with different genotypes were compared. The T329S mutation moderated the serum-lipid parameters in TT hens compared to those in AA and AT hens from 49 to 62 weeks. Furthermore, it reduced the serum trimethylamine N-oxide concentrations and increased the serum total bile acid (p < 0.05) and related lipid transporter levels in TT hens. Moreover, it significantly (p < 0.01) decreased atherosclerotic lesions and hepatic steatosis in TT hens compared to those in the AA and AT hens. Our findings may help improve the health status in laying hens during the late laying period.

HI (HARLEQUIN ICHTHYOSIS) BABY

HI is a very rare type of genetical abnormality but can be seen and scared by seeing various social media footages. It is associated with deletion and truncation mutations of a keratinocyte lipid transporter. Harlequin disorder is categorized by diffuse epidermal hyperkeratinization along with defective desquamation. During birth, the HI phenotype is conspicuous with thick hyperkeratotic plate-like scales with deep dermal ssures, severe ectropion and eclabium, among other ndings. In this ichthyosis marked eclabium and ectropion are present secondary to the taut as well as in the unyielding skin. The ears may be inattentive, absent or poorly developed. Even the arms, feet, and digits have exion contractures and may be hypoplastic. The skin wall is harshly compromised, leading to undue water loss, causes electrolyte abnormalities, temperature alteration and an increased risk of deadly infection. Some of the primary treatments are smearing retinoids application for shedding the hard and scaly skin, topical antibiotics application can prevent infection, insertion an ET tube in the airway to assistance with breathing, applying lubricating eye drops or protective devices on the eyes. Following ongoing treatment like humidied incubator (for premature infants), continuous monitoring of TPR and SpO2, early intubation(optional), frequent cultures of the skin should be taken for lab testing, monitoring serum electrolyte levels, maintaining a germ-free environment to evade infection etc.

Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter

Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters participate in lipid translocation, but their mechanisms remain largely unknown. Major facilitator superfamily (MFS) lipid transporters play central roles in cell wall synthesis, brain development and function, lipids recycling, and cell signaling. Recent structures of MFS lipid transporters revealed overlapping architectural features pointing towards a common mechanism. Here we used cysteine disulfide trapping, molecular dynamics simulations, mutagenesis analysis, and transport assays in vitro and in vivo, to investigate the mechanism of LtaA, a proton-dependent MFS lipid transporter essential for lipoteichoic acids synthesis in the pathogen Staphylococcus aureus. We reveal that LtaA displays asymmetric lateral openings with distinct functional relevance and that cycling through outward- and inward-facing conformations is essential for transport activity. We demonstrate that while the entire amphipathic central cavity of LtaA contributes to lipid binding, its hydrophilic pocket dictates substrate specificity. We propose that LtaA catalyzes lipid translocation by a trap-and-flip mechanism that might be shared among MFS lipid transporters.

The common ABCA3E292V variant disrupts AT2 cell quality control and increases susceptibility to lung injury and aberrant remodeling

ATP binding cassette class A3 (ABCA3) is a lipid transporter that plays a critical role in pulmonary surfactant function. The substitution of valine for glutamic acid at codon 292 (E292V) produces a hypomorphic variant that accounts for a significant portion of ABCA3 mutations associated with lung disorders spanning from neonatal respiratory distress syndrome and childhood interstitial lung disease to diffuse parenchymal lung disease (DPLD) in adults including pulmonary fibrosis. The mechanisms by which this and similar ABCA3 mutations disrupt alveolar type 2 (AT2) cell homeostasis and cause DPLD are largely unclear. The present study, informed by a patient homozygous for the E292V variant, used an in vitro and a preclinical murine model to evaluate the mechanisms by which E292V expression promotes aberrant lung injury and parenchymal remodeling. Cell lines stably expressing EGFP-tagged ABCA3 isoforms show a functional deficiency of the ABCA3E292V variant as a lipid transporter. AT2 cells isolated from mice constitutively homozygous for ABCA3E292V demonstrate the presence of small electron-dense lamellar bodies, time dependent alterations in macroautophagy, and induction of apoptosis. These changes in AT2 cell homeostasis are accompanied by a spontaneous lung phenotype consisting of both age dependent inflammation and fibrillary collagen deposition in alveolar septae. Older ABCA3E292V mice exhibit increased vulnerability to exogenous lung injury by bleomycin. Collectively, these findings support the hypothesis that the ABCA3E292V variant is a susceptibility factor for lung injury through effects on surfactant deficiency and impaired AT2 autophagy.