Lecithin:Cholesterol Acyltransferase (LCAT) Deficiency: Molecular Genetics


The lecithin:cholesterol acyltransferase (LCAT) enzyme is responsible for the synthesis of cholesteryl esters in human plasma and plays a critical role in high‐density lipoprotein (HDL) metabolism. Mutations in the LCAT gene leads to the development of two distinct syndromes, classical familial LCAT deficiency (FLD, OMIM 245900) and fish‐eye disease (FED, OMIM 136120). FLD and FED are rare disorders of lipoprotein metabolism, both characterised by low HDL cholesterol levels associated with multiple alterations in HDL structure and particle distribution. Clinical manifestations of the disease include corneal opacity, haemolytic anaemia and renal disease, which represents the major cause of morbidity and mortality in LCAT‐deficient cases. The pathogenesis of renal injury in LCAT deficiency is not understood. No cure presently exists for patients with genetic LCAT deficiency.

Key Concepts:

  • LCAT is the enzyme responsible of cholesterol esterification in plasma.

  • Mutations in the LCAT gene lead to two rare diseases of lipid metabolism: Familial LCAT deficiency (FLD) and fish‐eye disease (FED).

  • FLD and FED cases have very low HDL‐C levels in plasma, not necessarily associated with increased cardiovascular disease.

  • Clinical manifestations of the disease include corneal opacity, hemolytic anemia, and renal disease.

  • Renal disease represents the major cause of morbidity and mortality in homozygous carriers of LCAT deficiency.

Keywords: lecithin:cholesterol acyltransferase (LCAT); familial LCAT deficiency; fish‐eye disease; HDL; atherosclerosis

Figure 1.

The LCAT reaction.



Aranda P, Valdivielso P, Pisciotta L et al. (2008) Therapeutic management of a new case of LCAT deficiency with a multifactorial long‐term approach based on high doses of angiotensin II receptor blockers (ARBs). Clinical Nephrology 69: 213–218.

Asztalos BF, Schaefer EJ, Horvath KV et al. (2007) Role of LCAT in HDL remodeling: investigation of LCAT deficiency states. Journal of Lipid Research 48: 592–599.

Ayyobi AF, McGladdery SH, Chan S et al. (2004) Lecithin: cholesterol acyltransferase (LCAT) deficiency and risk of vascular disease: 25 year follow‐up. Atherosclerosis 177: 361–366.

Baass A, Wassef H, Tremblay M et al. (2009) Characterization of a new LCAT mutation causing familial LCAT deficiency (FLD) and the role of APOE as a modifier gene of the FLD phenotype. Atherosclerosis 207: 452–457.

Blanco‐Vaca F, Qu SJ, Fiol C et al. (1997) Molecular basis of fish‐eye disease in a patient from Spain. Characterization of a novel mutation in the LCAT gene and lipid analysis of the cornea. Arteriosclerosis, Thrombosis, and Vascular Biology 17: 1382–1391.

van den Bogaard B, Holleboom AG, Duivenvoorden R et al. (2012) Patients with low HDL‐cholesterol caused by mutations in LCAT have increased arterial stiffness. Atherosclerosis 225: 481–485.

Borysiewicz LK, Soutar AK, Evans DJ, Thompson GR and Rees AJ (1982) Renal failure in familial lecithin: cholesterol acyltransferase deficiency. Quarterly Journal of Medicine 51: 411–426.

Boscutti G, Calabresi L, Pizzolitto S et al. (2011) LCAT deficiency: a nephrological diagnosis. Giornale Italiano di Nefrologia 28(4): 369–382

Calabresi L, Baldassarre D, Castelnuovo S et al. (2009) Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans. Circulation 120: 628–635.

Calabresi L, Pisciotta L, Costantin A et al. (2005) The molecular basis of lecithin: cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families. Arteriosclerosis, Thrombosis, and Vascular Biology 25: 1972–1978.

Calabresi L, Simonelli S, Gomaraschi M and Franceschini G (2012) Genetic lecithin: cholesterol acyltransferase deficiency and cardiovascular disease. Atherosclerosis 222: 299–306.

Chetiveaux M, Lalanne F, Lambert G et al. (2006) Kinetics of prebeta HDL and alphaHDL in type II diabetic patients. European Journal of Clinical Investigation 36: 29–34.

Duivenvoorden R, Holleboom AG, van den Bogaard BB et al. (2011) Carriers of lecithin: cholesterol acyltransferase gene mutations have accelerated atherogenesis as assessed by carotid 3.0‐T magnetic resonance imaging. Journal of the American College of Cardiology 58: 2481–2487.

Favari E, Lee M, Calabresi L et al. (2004) Depletion of pre‐beta‐high density lipoprotein by human chymase impairs ATP‐binding cassette transporter A1 – but not scavenger receptor class B type I‐mediated lipid efflux to high density lipoprotein. Journal of Biological Chemistry 279: 9930–9936.

Forte TM, Norum KR, Glomset JA and Nichols AV (1971) Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency. Structure of low and high density lipoproteins as revealed by electron microscopy. Journal of Clinical Investigation 50: 1141–1148.

Franceschini G, Baio M, Calabresi L, Sirtori CR and Cheung MC (1990) Apolipoprotein A‐IMilano. Partial lecithin: cholesterol acyltransferase deficiency due to low levels of a functional enzyme. Biochimica et Biophysica Acta 1043: 1–6.

Franceschini G, Maderna P and Sirtori CR (1991) Reverse cholesterol transport: physiology and pharmacology. Atherosclerosis 88: 99–107.

Frohlich JJ, McLeod R, Pritchard PH, Fesmire J and McConathy WJ (1988) Plasma lipoprotein abnormalities in heterozygotes for familial lecithin: cholesterol acyltransferase deficiency. Metabolism: Clinical and Experimental 37: 3–8.

Funke H, von Eckardstein A, Pritchard PH et al. (1991) A frameshift mutation in the human apolipoprotein A‐I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol acyltransferase deficiency, and corneal opacities. Journal of Clinical Investigation 87: 371–376.

Glomset JA (1968) The plasma lecithin: cholesterol acyltransferase reaction. Journal of Lipid Research 9: 155–162.

Holleboom AG, Kuivenhoven JA, van Olden CC et al. (2011) Proteinuria in early childhood due to familial LCAT deficiency caused by loss of a disulfide bond in lecithin: cholesterol acyl transferase. Atherosclerosis 216: 161–165.

Hovingh GK, Hutten BA, Holleboom AG et al. (2005) Compromised LCAT function is associated with increased atherosclerosis. Circulation 112: 879–884.

Ji Y, Wang N, Ramakrishnan R et al. (1999) Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile. Journal of Biological Chemistry 274: 33398–33402.

Jimi S, Uesugi N, Saku K et al. (1999) Possible induction of renal dysfunction in patients with lecithin: cholesterol acyltransferase deficiency by oxidized phosphatidylcholine in glomeruli. Arteriosclerosis, Thrombosis, and Vascular Biology 19: 794–801.

Jonas A (2000) Lecithin cholesterol acyltransferase. Biochimica et Biophysica Acta 1529: 245–256.

Lambert G, Sakai N, Vaisman BL et al. (2001) Analysis of glomerulosclerosis and atherosclerosis in lecithin: cholesterol acyltransferase‐deficient mice. Journal of Biological Chemistry 276: 15090–15098.

Li L, Hossain MA, Sadat S et al. (2011) Lecithin cholesterol acyltransferase null mice are protected from diet‐induced obesity and insulin resistance in a gender‐specific manner through multiple pathways. Journal of Biological Chemistry 286: 17809–17820.

Miarka P, Idzior‐Walus B, Kuzniewski M et al. (2011) Corticosteroid treatment of kidney disease in a patient with familial lecithin‐cholesterol acyltransferase deficiency. Clinical and Experimental Nephrology 15: 424–429.

Murayama N, Asano Y, Kato K et al. (1984) Effects of plasma infusion on plasma lipids, apoproteins and plasma enzyme activities in familial lecithin: cholesterol acyltransferase deficiency. European Journal of Clinical Investigation 14: 122–129.

Nakamura Y, Kotite L, Gan Y et al. (2004) Molecular mechanism of reverse cholesterol transport: reaction of pre‐beta‐migrating high‐density lipoprotein with plasma lecithin/cholesterol acyltransferase. Biochemistry 43: 14811–14820.

Ng DS, Xie C, Maguire GF et al. (2004) Hypertriglyceridemia in lecithin‐cholesterol acyltransferase‐deficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance. Journal of Biological Chemistry 279: 7636–7642.

O'Leary DH, Polak JF, Kronmal RA et al. (1999) Carotid‐artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. New England Journal of Medicine 340: 14–22.

Pisciotta L, Calabresi L, Lupattelli G et al. (2005) Combined monogenic hypercholesterolemia and hypoalphalipoproteinemia caused by mutations in LDL‐R and LCAT genes. Atherosclerosis 182: 153–159.

Rousset X, Vaisman B, Auerbach B et al. (2010) Effect of recombinant human lecithin cholesterol acyltransferase infusion on lipoprotein metabolism in mice. Journal of Pharmacology and Experimental Therapeutics 335: 140–148.

Rye KA and Barter PJ (2004) Formation and metabolism of prebeta‐migrating, lipid‐poor apolipoprotein A‐I. Arteriosclerosis, Thrombosis, and Vascular Biology 24: 421–428.

Santamarina‐Fojo S, Hoeg JM, Assmann G and BrewerHB Jr (2001) Lecithin cholesterol acyltransferase deficiency and fish eye disease. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Diseases, pp. 2817–2833. New York, NY: McGraw‐Hill.

Schwartz CC, VandenBroek JM and Cooper PS (2004) Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. Journal of Lipid Research 45: 1594–1607.

Schwartz CC, Vlahcevic ZR, Berman M et al. (1982) Central role of high density lipoprotein in plasma free cholesterol metabolism. Journal of Clinical Investigation 70: 105–116.

Sensi C, Simonelli S, Zanotti I et al. (2014) Distant homology modeling of LCAT and its validation through in silico targeting and In Vitro and In Vivo assays. PLoS One 9: e95044.

Sessa A, Battini G, Meroni M et al. (2001) Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin‐cholesterol acyltransferase deficiency due to two different allelic mutations. Nephron 88: 268–272.

Song H, Zhu L, Picardo CM et al. (2006) Coordinated alteration of hepatic gene expression in fatty acid and triglyceride synthesis in LCAT‐null mice is associated with altered PUFA metabolism. American Journal of Physiology: Endocrinology and Metabolism 290: E17–E25.

Stoekenbroek RM, van den Bergh Weerman MA, Hovingh GK et al. (2013) Familial LCAT deficiency: from renal replacement to enzyme replacement. Netherlands Journal of Medicine 71: 29–31.

Subbaiah PV and Monshizadegan H (1988) Substrate specificity of human plasma lecithin‐cholesterol acyltransferase towards molecular species of phosphatidylcholine in native plasma. Biochimica et Biophysica Acta 963: 445–455.

Suda T, Akamatsu A, Nakaya Y, Masuda Y and Desaki J (2002) Alterations in erythrocyte membrane lipid and its fragility in a patient with familial lecithin: cholesterol acyltrasferase (LCAT) deficiency. Journal of Medical Investigation 49(3–4): 147–155.

Tanigawa H, Billheimer JT, Tohyama JI et al. (2009) Lecithin: cholesterol acyltransferase expression has minimal effects on macrophage reverse cholesterol transport in vivo. Circulation 120:160–169.

Tsuchiya Y, Ubara Y, Hiramatsu R et al. (2011) A case of familial lecithin‐cholesterol acyltransferase deficiency on hemodialysis for over 20 years. Clinical Nephrology 76: 492–498.

Yee MS, Pavitt DV, Richmond W et al. (2009) Changes in lipoprotein profile and urinary albumin excretion in familial LCAT deficiency with lipid lowering therapy. Atherosclerosis 205: 528–532.

Zhao Y, Thorngate FE, Weisgraber KH, Williams DL and Parks JS (2005) Apolipoprotein E is the major physiological activator of lecithin‐cholesterol acyltransferase (LCAT) on apolipoprotein B lipoproteins. Biochemistry 44: 1013–1025.

Further Reading

Ahsan L, Ossoli A, Freeman L et al. (2014) Role of lecithin: cholesterol acyltransferase in HDL metabolism and atherosclerosis. In: Komoda T (ed.) The HDL Handbook: Biological Functions and Clinical Implications, pp. 159–194. Elsevier: Academic Press.

Kontush A and Chapman MJ (eds) (2012) Metabolism. In: High‐Density Lipoproteins: Structure, Metabolism, Function and Therapeutics, pp. 74–112. Hoboken, NJ: John Wiley and Sons.

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Calabresi, Laura, Ossoli, Alice, and Franceschini, Guido(Oct 2014) Lecithin:Cholesterol Acyltransferase (LCAT) Deficiency: Molecular Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024984]