Purpose of review We discuss the latest findings on the biochemistry of lecithin: cholesterol acyltransferase (LCAT), the effect of LCAT on atherosclerosis, clinical features of LCAT deficiency, and the impact of LCAT on cardiovascular disease from human studies. Recent findings Although there has been much recent progress in the biochemistry of LCAT and its effect on high-density lipoprotein metabolism, its role in the pathogenesis of atherosclerosis is still not fully understood. Studies from various animal models have revealed a complex interaction between LCAT and atherosclerosis that may be modified by diet and by other proteins that modify lipoproteins. Furthermore, the ability of LCAT to lower apoB appears to be the best way to predict its effect on atherosclerosis in animal models. Recent studies on patients with LCAT deficiency have shown a modest but significant increase in incidence of cardiovascular disease consistent with a beneficial effect of LCAT on atherosclerosis. The role of LCAT in the general population, however, has not revealed a consistent association with cardiovascular disease. Summary Recent research findings from animal and human studies have revealed a potential beneficial role of LCAT in reducing atherosclerosis but additional studies are necessary to better establish the linkage between LCAT and cardiovascular disease.

The chick chorioallantoic membrane (CAM), as an extraembryonic tissue layer generated by the fusion of the chorion with the vascularized allantoic membrane, is easily accessible for manipulation. Indeed, grafting tumor cells on the CAM lets xenografts/ovografts develop in a few days for further investigations. Thus, the CAM model represents an alternative test system that is a simple, fast, and low-cost tool to study tumor growth, drug response, or angiogenesis in vivo. Recently, a new era for the CAM model in immune-oncology-based drug discovery has been opened up. Although there are many advantages offering extraordinary and unique applications in cancer research, it has also disadvantages and limitations. This review will discuss the pros and cons with experts in the field.

Lecithin cholesterol acyl transferase (LCAT) deficiency is associated with low high-density lipoprotein (HDL) and the presence of an abnormal lipoprotein called lipoprotein X (Lp-X) that contributes to end-stage renal disease. We examined the possibility of using LCAT an as enzyme replacement therapy agent by testing the infusion of human recombinant (r)LCAT into several mouse models of LCAT deficiency. Infusion of plasma from human LCAT transgenic mice into LCAT-knockout (KO) mice rapidly increased HDL-cholesterol (C) and lowered cholesterol in fractions containing very-low-density lipoprotein (VLDL) and Lp-X. rLCAT was produced in a stably transfected human embryonic kidney 293f cell line and purified to homogeneity, with a specific activity of 1850 nmol/mg/h. Infusion of rLCAT intravenously, subcutaneously, or intramuscularly into human apoA-I transgenic mice showed a nearly identical effect in increasing HDL-C approximately 2-fold. When rLCAT was intravenously injected into LCAT-KO mice, it showed a similar effect as plasma from human LCAT transgenic mice in correcting the abnormal lipoprotein profile, but it had a considerably shorter half-life of approximately 1.23 ± 0.63 versus 8.29 ± 1.82 h for the plasma infusion. rLCAT intravenously injected in LCAT-KO mice crossed with human apolipoprotein (apo)A-I transgenic mice had a half-life of 7.39 ± 2.1 h and increased HDL-C more than 8-fold. rLCAT treatment of LCAT-KO mice was found to increase cholesterol efflux to HDL isolated from mice when added to cells transfected with either ATP-binding cassette (ABC) transporter A1 or ABCG1. In summary, rLCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-KO mice and increased cholesterol efflux, suggesting the possibility of using rLCAT as an enzyme replacement therapy agent for LCAT deficiency.

Objectives— This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue. Methods and Results— Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms. This occurred along with a decrease in serum HDL and an increase in adipose cholesterol content. Similar results were obtained with transgenic mice overexpressing locally angiotensinogen in adipose tissue. In adipose 3T3-L1 cell line, HDL induced lipogenesis by increasing liver X receptor binding activity. This mechanism was dependent of insulin and angiotensin II. Conclusions— Our results raise the possibility that adipose tissue SR-BI translocation might be a link between adipose tissue lipid storage and HDL clearance.

LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol in atherosclerosis, we examined the effect of LCAT over and under expression in diet-induced atherosclerosis in scavenger receptor class B, member I deficient (SR-BI-KO) mice, which have a secondary defect in cholesterol esterification. SR-BI-KO x LCAT-KO mice display a decrease in HDL-C and a high plasma ratio of free cholesterol/total cholesterol (0.88+/-0.033) and a striking increase in VLDL-C. In comparison, SR-BI-KO x LCAT-Tg mice had lower levels of VLDL-C and LDL-C and a normal plasma free cholesterol/total cholesterol ratio (0.276+/-0.005). Serum from SR-BI-KO x LCAT-Tg mice also showed an increased in the percentage of cholesterol that was esterified during in vitro cholesterol efflux studies (from 3.7+/-0.172% to 13.8+/-0.353% p<0.001), but increased LCAT did not appear to effect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. SR-BI-KO x LCAT-Tg mice also displayed a 51% decrease in aortic atherosclerosis compared to SR-BI-KO mice, whereas SR-BI-KO x LCAT-KO mice had an approximate 3-fold increase (p<0.01). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective most likely through its ability to increase HDL and decrease pro-atherogenic apoB-containing lipoprotein particles.