NBEAL1 controls SREBP2 processing and cholesterol metabolism and is a susceptibility locus for coronary artery disease

Abstract

Dysregulated cholesterol homeostasis promotes the pathology of atherosclerosis, myocardial infarction and strokes. Cellular cholesterol is mainly regulated at the transcriptional level by SREBP2, but also through uptake of extracellular cholesterol from low density lipoproteins (LDL) via expression of LDL receptors (LDLR) at the cell surface. Identification of the mechanisms involved in regulation of these processes are thus key to understand the pathology of coronary artery disease. Here, we identify the large and poorly characterized BEACH domain protein Neurobeachin-like (NBEAL) 1 as a Golgiassociated protein required for regulation of cholesterol metabolism. NBEAL1 is most abundantly expressed in arteries. Genetic variants in NBEAL1 are associated with decreased expression of NBEAL1 in arteries and increased risk of coronary artery disease in humans. We show that NBEAL1 regulates cholesterol metabolism by modulating LDLR expression in a mechanism involving interaction with SCAP and PAQR3 and subsequent SREBP2-processing. Thus, low expression of NBEAL1 may lead to increased risk of coronary artery disease by downregulation of LDLR levels. NBEAL1 belongs to a family of proteins that shares a highly conserved domain known as the BEACH (Beige and Chediak-Higashi) domain, found in nine human proteins. The cellular functions of most BEACH proteins still remain poorly defined more than a decade after the crystal structure of the BEACH domain was resolved 1,2 , but several family members are linked to membrane trafficking and/or modeling processes, including regulation of lysosome size, autophagy, apoptosis and granule size 3-6. Variants in genes encoding distinct BEACH proteins cause several human diseases, including grey platelet syndrome (NBEAL2) 7-9 , Chédiak-Higashi Syndrome (LYST) 10 and human primary microcephaly (ALFY/WDFY3) 11. NBEAL1 is one of the least understood BEACH proteins and we therefore aimed to elucidate its cellular localization and function, as well as a potential link to disease. Results and Discussion The NBEAL1 locus has previously been associated with coronary artery disease (CAD) (also called coronary heart disease or coronary atherosclerosis) 12,13. However, the culprit at the locus in relation to CAD has remained somewhat unclear. In order to characterize a possible role of NBEAL1 in the disease, we utilized data from the CAD Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) consortium that holds information on genome wide association data for CAD comprising 60,801 cases and 123,504 controls 14,15. NBEAL1 is located on chromosome 2 and using this data we performed a lookup of variants on this chromosome that associated with CAD (Supplemental Table 1). Interestingly, this revealed the strongest association within chromosome 2

Integration of Multiple-Omics Data to Analyze the Population-Specific Differences for Coronary Artery Disease

“…NBEAL1 was known as a susceptibility locus of CAD, which was highly expressed in the heart and artery [ 41 ]. It affected cholesterol metabolism and LDL uptake by regulating the activity of SREBP2 in cells and then affected the pathogenesis of CAD afterwards [ 42 ]. However, FGD6 might be a novel CAD susceptibility locus, which regulated the proangiogenic activity in vitro.…”

Smoking Status and Type 2 Diabetes, and Cardiovascular Disease: A Comprehensive Analysis of Shared Genetic Etiology and Causal Relationship

“…Gene FES, which encodes the human cellular counterpart of a feline sarcoma retrovirus protein with transforming capabilities, is well known to be associated with myeloid leukemia (99), but recent studies observed the function of FES in modulating atherosclerotic plaque vulnerability (100) and the effect of tobacco smoking on DNA methylation of FES (75). Genes ICA1L and NBEAL1 were mapped by the same locus (index SNP: rs114123510), and both are related to cholesterol metabolism, in which dysregulation promotes the pathology of atherosclerosis, MI, and strokes (101). Notably, C2orf69-Brain Caudate basal ganglia gene-trait pair was the only one observed overlapping gene-tissue pair between smoking status and HF.…”

The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking

“…Paradoxically, our results also reveal that cholesterol uptake is highly induced in γ‐secretase‐deficient cells in which C99 levels are increased. The intriguing failure of a negative feedback mechanism to downregulate C99‐mediated cholesterol import suggests that the continuous uptake of cholesterol might occur through one of the SREBP2‐independent cholesterol receptors expressed in the cell (Makar et al , ; Bindesboll et al , ).…”