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 HDL 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 incidence of cardiovascular disease consistent with a beneficial effect of LCAT on atherosclerosis. The role of LCAT in the general population, however, have not revealed a consistent association with cardiovascular disease. Summary Recent research findings from animal and humans 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.

Lecithin cholesterol acyl transferase (LCAT) is a plasma enzyme that esterifies cholesterol and raises high-density lipoprotein cholesterol, but its role in atherosclerosis is not clearly established. Studies of various animal models have yielded conflicting results, but studies done in rabbits and non-human primates, which more closely simulate human lipoprotein metabolism, indicate that LCAT is likely atheroprotective. Although suggestive, there are also no biomarker studies that mechanistically link LCAT with cardiovascular disease. Imaging studies of patients with LCAT deficiency have also not yielded a clear answer to the role of LCAT in atherosclerosis. Recombinant LCAT, however, is currently being developed as a therapeutic product for enzyme replacement therapy of patients with genetic disorders of LCAT for the prevention and/or treatment of renal disease, but it may also have value for the treatment of acute coronary syndrome.

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 Ϯ 0.63 versus 8.29 Ϯ 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 Ϯ 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. Key Words: adipose tissue Ⅲ angiotensin II Ⅲ high-density lipoprotein Ⅲ insulin A dipose tissue has a central role in the energy metabolism adaptation to the nutritional environment because of its ability to store energy as triglycerides. Besides its role in triglyceride storage, adipose tissue is also the body's largest pool of cholesterol store, representing Ϸ25% of whole-body cholesterol in human. 1 A particular interest of adipocytes is that these cells accumulate cholesterol proportionally to triglycerides. Because of an extremely low cholesterol de novo synthesis, 2 adipocytes must acquire cholesterol from exogenous sources. Interestingly, clinical observations have found a correlation between obesity and low levels of high-density lipoprotein (HDL) cholesterol, 3 which is the reflect of an increased incidence of atherosclerosis. 4 There is also growing evidence that altered insulin sensitivity or increased angiotensin II concentrations, which occur along with obesity, play a crucial role in the acceleration of atherosclerosis but mechanisms are not yet fully deciphered. 5,6 The scavenger receptor type-BI (SR-BI) has been identified as a membrane transporter involved in the selective cholesteryl esters (CEs) uptake from HDL. 7 The pivotal role of SR-BI in lipoprotein metabolism and cholesterol transport in steroidogenic tissues and liver has been well-established. 8 SR-BI is also expressed in adipocytes, but little is known about its function and regulation in these cells. 9 Recently, studies from our laboratory have reported that SR-BI provide an important source of cholesterol from HDL in adipose cell lines and that insulin and angiotensin II induce the translocation of this receptor leading to an increase in cholesterol influx and storage. 10,11 However, the nutritional and hormonal regulation of this translocation and its potential consequences on plasma HDL have not been yet explored in vivo. Conclusions-OurBecause cholesterol plays a role in the regulation of signal transduction and gene expression, we further investigated the consequence of the cho...