Here we demonstrate that the ABC transporter ABCG1 plays a critical role in lipid homeostasis by controlling both tissue lipid levels and the efflux of cellular cholesterol to HDL. Targeted disruption of Abcg1 in mice has no effect on plasma lipids but results in massive accumulation of both neutral lipids and phospholipids in hepatocytes and in macrophages within multiple tissues following administration of a high-fat and -cholesterol diet. In contrast, overexpression of human ABCG1 protects murine tissues from dietary fat-induced lipid accumulation. Finally, we show that cholesterol efflux to HDL specifically requires ABCG1, whereas efflux to apoA1 requires ABCA1. These studies identify Abcg1 as a key gene involved in both cholesterol efflux to HDL and in tissue lipid homeostasis.

The murine Abcg1 gene is reported to consist of 15 exons that encode a single mRNA (herein referred to as Abcg1-a) and protein. We now demonstrate that (i) the murine gene contains two additional coding exons downstream of exon 1, (ii) transcription involves the use of multiple promoters, and (iii) the RNA undergoes alternative splicing reactions. As a result, three mRNAs are expressed that encode three putative protein isoforms that differ at their amino terminus. ABCG1 transcripts are induced in vivo in multiple tissues in response to the liver X receptor ligand T0901317. Identification and characterization of four liver X receptor response elements in the intron downstream of exon 2 provides a mechanism by which this induction occurs. Importantly, cholesterol efflux to high density lipoprotein was stimulated following transfection of Hek293 cells with plasmids encoding individual ABCG1 isoforms. In situ hybridization studies in embryonic day 11.5-15.5 mouse embryos revealed strong expression of ABCG1 transcripts in the olfactory epithelium, hind brain, eye, and dorsal root ganglia. The relatively high levels of expression in neuronal tissues and the eye suggest that ABCG1-dependent cholesterol efflux may be critical for normal neuronal function in addition to its role in macrophages.There are more than 373 members in the ATP-binding cassette (ABC)

Objectives To evaluate the potential impact of the COVID-19 pandemic on out-of-hospital cardiac arrest (OHCA) response and outcomes in two US communities with relatively low infection rates. Background Studies in areas with high COVID-19 infection rates indicate that the pandemic has had direct and indirect effects on community response to OHCA and negative impacts on survival. Data from areas with lower infection rates are lacking. Methods In Multnomah County, OR and Ventura County, CA, we evaluated OHCA with attempted resuscitation by EMS from March 1 – May 31, 2020 and March 1 – May 31, 2019. Results Comparing 231 OHCA in 2019 to 278 in 2020, the proportion receiving bystander CPR was lower in 2020 (61% to 51%, p=0.02) and bystander use of automated external defibrillators (AEDs) declined (5% to 1%, p=0.02). EMS response time increased (6.6 ± 2.0 to 7.6 ± 3.0 minutes, p<0.001), and fewer OHCA survived to hospital discharge (14.7% to 7.9%, p=0.02). Incidences rates did not change significantly (p>0.07), and coronavirus infection rates were low (Multnomah 143/100,000, Ventura 127/100,000 as of May 31), compared to rates of ∼1600-3000/100,000 in the New York City region at that time. Conclusions The community response to OHCA was altered from March to May 2020, with less bystander CPR, delays in EMS response time, and reduced survival from OHCA. These results highlight the pandemic’s indirect negative impact on OHCA even in communities with relatively low incidence of COVID-19 and point to potential opportunities for countering the impact.

Maintaining genomic integrity is critical to avoid life-threatening disorders, such as premature aging, neurodegeneration and cancer. A multiprotein cascade operates at sites of DNA double-strand breaks (DSBs) to recognize, signal and repair damage. RNF168 (ring-finger nuclear factor) contributes to this emerging pathway of several E3 ubiquitin ligases that perform sequential ubiquitylations on damaged chromosomes, chromatin modifications essential for aggregation of repair complexes at the DSB sites. Here, we report the clinical and cellular phenotypes associated with a newly identified homozygous nonsense mutation in the RNF168 gene of a patient with a syndrome mimicking ataxia-telangiectasia. The mutation eliminated both of RNF168's ubiquitin-binding motifs, thus blocking progression of the ubiquitylation cascade and retention of repair proteins including tumor suppressors 53BP1 and BRCA1 at DSB sites, consistent with the observed defective DNA damage checkpoints/repair and pronounced radiosensitivity. Rapid screening for RNF168 pathway deficiency was achieved by scoring patients' lymphoblastoid cells for irradiation-induced nuclear foci containing 53BP1, a robust assay we propose for future diagnostic applications. The formation of radiation-induced DSB repair foci was rescued by ectopic expression of wild-type RNF168 in patient's cells, further causally linking the RNF168 mutation with the pathology. Clinically, this novel syndrome featured ataxia, telangiectasia, elevated alphafetoprotein, immunodeficiency, microcephaly and pulmonary failure and has implications for the differential diagnosis of autosomal recessive ataxias. The human genome is continuously exposed to free radicals, ionizing radiation and other genotoxic agents that cause DNA double-strand breaks (DSBs).1-3 Over one hundred genes are involved in recognition, signaling and repairing DSBs in order to maintain genomic stability and avoid accumulation of disease-predisposing mutations.2 At the cellular level, functions of the DNA damage sensors, signal transducers and effectors ultimately modulate the cell-fate decisions under genotoxic stress conditions, including decisions whether to undergo cell death or survive, or possibly take the route toward oncogenic transformation. [2][3][4] At the level of the whole organism, mutations in a subset of such genes are known to predispose to diverse types of cancer, neurodegenerative disorders, premature aging and/or immunodeficiency syndromes.2-4 On the other hand, the majority of the DNA damage response (DDR) genes are neither completely characterized nor linked to human disease phenotypes. 2-5The RNF168 gene is located on chromosome 3q29 and encodes a 571 amino acid protein that is a member of the 'ring-finger nuclear factor' (RNF) family of ubiquitin ligases.These enzymes modify functional properties of other proteins by covalent attachment of ubiquitin polypeptides, and emerging evidence suggests that this type of modification has a key role in the hierarchically structured genome surveillance pathw...