Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings

Abstract

Lecithin:cholesterol acyltransferase (LCAT) converts free cholesterol to cholesteryl esters in the process of reverse cholesterol transport. Familial LCAT deficiency (FLD) is a genetic disease that was first described by Kaare R. Norum and Egil Gjone in 1967. This report is a summary from a 2017 symposium where Dr. Norum recounted the history of FLD and leading experts on LCAT shared their results. The Tesmer lab shared structural findings on LCAT and the close homolog lysosomal phospholipase A2. Results from studies of FLD patients in Finland, Brazil, Norway, and Italy were presented, as well as the status of a patient registry. Drs. Kuivenhoven and Calabresi presented data from carriers of genetic mutations suggesting that FLD does not necessarily accelerate atherosclerosis. Dr. Ng shared that LCAT null mice were protected from diet-induced obesity, insulin resistance and non-alcoholic fatty liver disease. Dr. Zhou presented multiple innovations for increasing LCAT activity for therapeutic purposes, whereas Dr. Remaley showed results from treatment of an FLD patient with rhLCAT. Dr. Karathanasis showed that rhLCAT infusion in mice stimulates cholesterol efflux and suggested that it could also enhance cholesterol efflux from macrophages. While the role of LCAT in atherosclerosis remains elusive, the consensus is that a continued study of both the enzyme and disease will lead towards better treatments for patients with heart disease and FLD.

Current Understanding of the Relationship of HDL Composition, Structure and Function to Their Cardioprotective Properties in Chronic Kidney Disease

“…Nascent HDL particles transfer lipids to both apoB-containing particles and the plasma resident HDL pool. The unesterified cholesterol content of the nascent HDL pool is transferred to apoB-containing particles, which then redistributes to HDL for its effective esterification by lecithin-cholesterol acyltransferase (LCAT) [39]. HDL-associated cholesteryl-esters are partially transferred back to apoB-containing lipoproteins by cholesterol ester transfer protein (CETP) [40].…”

LCAT Deficiency in Amerindian Populations: A Systematic Review With the Clinical and Genetic Description of Mexican Kindred

“…The cardiovascular risk associated with LCAT de ciency syndromes has been a matter of debate for a number of years. A severe de ciency of HDL-C in LCAT de cient carriers would be expected to increase their risk of developing coronary heart disease (83). Oldoni et al, have compared carotid intima media thickness between 33 heterozygous FLD subjects and 41 heterozygous FED subjects (102).…”

“…The authors proposed that this discrepancy was related to the capacity of LCAT to esterify cholesterol on apolipoprotein B-containing lipoproteins-this capacity is lost in FLD, but is unaffected in FED. In a study of Italian FLD families, the inheritance of a mutated LCAT genotype had a remarkable gene-dose dependent effect in reducing carotid IMT, whereas a subgroup of these carriers also showed normal ow-mediated dilation (65,83,103). A Mendelian randomization study in 54,500 subjects concluded that common genetic variation in LCAT resulting in decreased HDL-C levels, did not associate with an increased risk of ischemic cardiovascular disease (104).…”

“…Earlier identi cation and adequate follow up of patients is urgently needed; the implementation of models of care and national disease registries can aid in this process. Recently, the Norwegian National Advisory Unit on Rare Disorders has been asked to establish a worldwide contact registry on FLD; this will allow the integration of efforts throughout the world to tackle the health burden and improve care for this condition (83).…”

“…Cases are more likely to be found in a uent countries, but also in countries hosting research groups with interest and resources to investigate this disease. In Latin American few cases have been published(82)(83)(84)(85)(86)(87)(88). At present, only six countries have reported probands with LCAT de ciency, and genetic evaluation has only been carried out in three countries.…”