The role of lecithin:cholesterol acyltransferase in the modulation of cardiometabolic risks - a clinical update and emerging insights from animal models.
Lecithin cholesterol acyltransferase (LCAT) is the key enzyme in mediating the esterification of cholesterol on circulating lipoproteins. It has long been suggested that LCAT plays a crucial role in reverse cholesterol transport, a process depicting the removal of cellular cholesterol through efflux to high density lipoproteins (HDL) and its delivery to the liver for eventual excretion from the body. Although loss-of-function LCAT mutations invariably result in profound HDL deficiency, the role of LCAT in atherogenesis continues to be clouded with controversy. Increasing number of large scale, population-based studies failed to detect an elevated cardiac risk with reduced blood levels of LCAT, suggesting that reduced LCAT activity may not be a risk factor nor a therapeutic target. More recent studies in human LCAT gene mutation carriers tend to suggest that atherogenicity in LCAT deficiency may be dependent on the nature of the mutations, providing plausible explanations for the otherwise contradictory findings. Genetic models of LCAT excess or deficiency yielded mixed findings. Despite its known profound effects on HDL and triglyceride metabolism, the role of LCAT in metabolic disorders, including obesity and diabetes, has not received much attention. Recent studies in LCAT deficient mouse models suggest that absence of LCAT may protect against insulin resistance, diabetes and obesity. Coordinated modulation of a number of anti-obesity and insulin sensitizing pathways has been implicated. Further studies to explore the role of LCAT in the modulation of cardiometabolic disorders and the underlying mechanisms are warranted.
Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Canada. ngd@smh.ca
Dominic S
DS
Ng
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood / Q000235:genetics / Q000378:metabolism*
D008075:Lipoproteins, HDL; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase