Cholesterol-mediated regulation of angiogenesis: An emerging paradigm

Angiogenesis, the fundamental process that generates new blood vessels from parental vessels, is essential for embryogenesis and pathogenesis. A variety of underlying molecular and cellular mechanisms control angiogenesis. In this review, we focus on a unique mechanism of action – cholesterol-regulated angiogenesis. We will discuss lipoproteins, including low-density lipoprotein and high-density lipoprotein, cholesterol-rich lipid rafts/caveolae, apoA-I-binding protein (AIBP, also known as NAXE)-regulated cholesterol efflux, the effect of the hydroxycholesterol-activated nuclear receptor liver X receptor α/β on the proangiogenic vascular endothelial growth factor receptor 2 and antiangiogenic Notch signaling, and cholesterol-modified sonic hedgehog signaling. These pathways can be exploited, either alone or in conjunction with the currently available regimen for angiogenesis treatment, to control neovascularization in dyslipidemia. A treatment protocol for angiogenesis that takes into consideration cholesterol management might constitute an important component in precision and personalized medicine

Zebrafish models of dyslipidemia: relevance to atherosclerosis and angiogenesis

Lipid and lipoprotein metabolism in zebrafish and in humans are remarkably similar. Zebrafish express all major nuclear receptors, lipid transporters, apolipoproteins and enzymes involved in lipoprotein metabolism. Unlike mice, zebrafish express cetp and the Cetp activity is detected in zebrafish plasma. Feeding zebrafish a high cholesterol diet, without any genetic intervention, results in significant hypercholesterolemia and robust lipoprotein oxidation, making zebrafish an attractive animal model to study mechanisms relevant to early development of human atherosclerosis. These studies are facilitated by the optical transparency of zebrafish larvae and the availability of transgenic zebrafish expressing fluorescent proteins in endothelial cells and macrophages. Thus, vascular processes can be monitored in live animals. In this review article, we discuss recent advances in using dyslipidemic zebrafish in atherosclerosis-related studies. We also summarize recent work connecting lipid metabolism with regulation of angiogenesis, the work that considerably benefited from using the zebrafish model. These studies uncovered the role of aibp, abca1, abcg1, mtp, apoB, and apoC2 in regulation of angiogenesis in zebrafish and paved the way for future studies in mammals, which may suggest new therapeutic approaches to modulation of excessive or diminished angiogenesis contributing to the pathogenesis of human disease

Systemic metabolite profiling reveals sexual dimorphism of AIBP control of metabolism in mice.

Emerging studies indicate that APOA-I binding protein (AIBP) is a secreted protein and functions extracellularly to promote cellular cholesterol efflux, thereby disrupting lipid rafts on the plasma membrane. AIBP is also present in the mitochondria and acts as an epimerase, facilitating the repair of dysfunctional hydrated NAD(P)H, known as NAD(P)H(X). Importantly, AIBP deficiency contributes to lethal neurometabolic disorder, reminiscent of the Leigh syndrome in humans. Whereas cyclic NADPHX production is proposed to be the underlying cause, we hypothesize that an unbiased metabolic profiling may: 1) reveal new clues for the lethality, e.g., changes of mitochondrial metabolites., and 2) identify metabolites associated with new AIBP functions. To this end, we performed unbiased and profound metabolic studies of plasma obtained from adult AIBP knockout mice and control littermates of both genders. Our systemic metabolite profiling, encompassing 9 super pathways, identified a total of 640 compounds. Our studies demonstrate a surprising sexual dimorphism of metabolites affected by AIBP deletion, with more statistically significant changes in the AIBP knockout female vs male when compared with the corresponding controls. AIBP knockout trends to reduce cholesterol but increase the bile acid precursor 7-HOCA in female but not male. Complex lipids, phospholipids, sphingomyelin and plasmalogens were reduced, while monoacylglycerol, fatty acids and the lipid soluble vitamins E and carotene diol were elevated in AIBP knockout female but not male. NAD metabolites were not significantly different in AIBP knockout vs control mice but differed for male vs female mice. Metabolites associated with glycolysis and the Krebs cycle were unchanged by AIBP knockout. Importantly, polyamine spermidine, critical for many cellular functions including cerebral cortex synapses, was reduced in male but not female AIBP knockout. This is the first report of a systemic metabolite profile of plasma samples from AIBP knockout mice, and provides a metabolic basis for future studies of AIBP regulation of cellular metabolism and the pathophysiological presentation of AIBP deficiency in patients

Proteome identification of binding-partners interacting with cell polarity protein Par3 in Jurkat cells

The evolutionarily conserved cell polarity protein Par3, a scaffold-like PDZ-containing protein, plays a critical role in the establishment and maintenance of epithelial cell polarity. Although the role of Par3 in establishing cell polarity in epithelial cells has been intensively explored, the function of Par3 in hematopoietic cells remains elusive. To address this issue, we generated GST-fusion proteins of Par3 PDZ domains. By combining the GST-pull-down approach with liq-uid chromatography-tandem mass spectrometry, we identi-fied 10 potential novel binding proteins of PDZ domains of Par3 in Jurkat cells (a T-cell line). The interaction of Par3 with three proteins––nuclear transport protein importin-α4 and proteasome activators PA28β and PA28γ––was con-firmed using in vitro binding assay, co-immunoprecipitation assay and immunofluorescence microscopy. Our results hav