Role of Class B Scavenger Receptors in Lipid Metabolism and Inflammation

Clinical Center

Investigators

Abstract

Regarding our research in lipid metabolism, we have demonstrated that SR-BI mediates LDL binding as well as cholesterol ester (CE) and triacylglycerol (TAG) sorting followed by their internalization to LDs. While about 60% of LDL- delivered neutral lipid (NL) to be uploaded to LDs requires neutral hydrolysis and de novo neutral lipid synthesis, about 40% is directly sorted and transported to LDs. Most importantly, both in vitro and in vivo data suggest that SR-BI is critical for short term LD formation from LDL in the liver and potentially other organs. Regarding coronary artery disease, collaboration with NHLBI, we have found an association of oxidized apoB and apoA-I with high-risk coronary plaque (PMID: 37698922). Regarding our work in understanding APOBEC-3 regulation, we found that: 1) APOBEC3 induced HBV mutations occurred sequentially on HBV (-)-DNA from the reverse transcription start to termination site in parallel with the reverse transcription process;2) APOBEC3 mutation efficiency varied significantly with an order of A3B>>A3G>A3H-II or A3C with variation observed even with the same APOBEC3, suggesting the presence of other factors affecting APOBEC3 mutation activity; 3) Among APOBEC3s, A3B had a 3-fold higher mutation efficiency with up to 65% of cytidines being mutated, consistent with the kataegis-like A3B mutation signature in cancer. On the other hand, A3C had a unique higher mutation frequency on HBV genome populations with a preference for both 5TC and 5CC; and 4) APOBEC3 induced HBV mutation was detected in HBV rcDNA, not in cccDNA and pgRNA, suggesting that APOBEC3 induced mutation on HBV genomes occurs essentially as a singular event, occurring only within the nucleocapsid and involving rcDNA replication. A recent publication (PMID # 39868801) demonstrated that apobec-1 cofactors regulate APOBEC3 induced mutations in hepatitis B virus. Regarding inflammation, in a collaboration with a U of MD group, we have published that age related accumulation of truncated oxidized phospholipids augments infectious lung injury and endothelial dysfunction (PMID 37566016). In addition with this group, we published this year that the peptide L37pA protects against lung vascular endothelial dysfunction caused by truncated oxidized phospholipids through CD36 antagonism (PMID:37725486). We have begun to evaluate the role of class B scavenger receptors in the pathogenesis of SARS-CoV-2.In a collaboration with NEI, we have published (PMID:37511618) that the low density lipoprotein receptor (LDLR) is involved with SARS-CoV-2 spike protein mediated uptake in ocular cells. We are continuing this collaboration and plan a new manuscript to better understand these published results. We are evaluating the role of class B scavenger receptors in ApoL1 variant associated kidney diseases and have prepared our first manuscript in this area.