Using Literature Based Discovery to Gain Insights Into the Metabolomic Processes of Cardiac Arrest

In this paper, we describe how we applied LBD techniques to discover lecithin cholesterol acyltransferase (LCAT) as a druggable target for cardiac arrest. We fully describe our process which includes the use of high-throughput metabolomic analysis to identify metabolites significantly related to cardiac arrest, and how we used LBD to gain insights into how these metabolites relate to cardiac arrest. These insights lead to our proposal (for the first time) of LCAT as a druggable target; the effects of which are supported by in vivo studies which were brought forth by this work. Metabolites are the end product of many biochemical pathways within the human body. Observed changes in metabolite levels are indicative of changes in these pathways, and provide valuable insights toward the cause, progression, and treatment of diseases. Following cardiac arrest, we observed changes in metabolite levels pre- and post-resuscitation. We used LBD to help discover diseases implicitly linked via these metabolites of interest. Results of LBD indicated a strong link between Fish Eye disease and cardiac arrest. Since fish eye disease is characterized by an LCAT deficiency, it began an investigation into the effects of LCAT and cardiac arrest survival. In the investigation, we found that decreased LCAT activity may increase cardiac arrest survival rates by increasing ω-3 polyunsaturated fatty acid availability in circulation. We verified the effects of ω-3 polyunsaturated fatty acids on increasing survival rate following cardiac arrest via in vivo with rat models.

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Evidence for Deficiency of High Density Lipoprotein Lecithin: Cholesterol Acyltransferase Activity (α-LCAT) in Fish Eye Disease

Acta Medica Scandinavica ◽

10.1111/j.0954-6820.1985.tb08846.x ◽

2009 ◽

Vol 218 (2) ◽

pp. 189-196 ◽

Cited By ~ 55

Author(s):

LARS A. CARLSON ◽

LEIF HOLMQUIST

Keyword(s):

High Density Lipoprotein ◽

Cholesterol Acyltransferase ◽

Density Lipoprotein ◽

High Density ◽

Eye Disease ◽

Acyltransferase Activity ◽

Lecithin Cholesterol Acyltransferase ◽

Fish Eye

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Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease.

Journal of Clinical Investigation ◽

10.1172/jci116962 ◽

1994 ◽

Vol 93 (1) ◽

pp. 321-330 ◽

Cited By ~ 90

Author(s):

D J Rader ◽

K Ikewaki ◽

N Duverger ◽

H Schmidt ◽

H Pritchard ◽

...

Keyword(s):

Cholesterol Acyltransferase ◽

High Density ◽

High Density Lipoproteins ◽

Eye Disease ◽

Lecithin Cholesterol Acyltransferase ◽

Apolipoprotein A ◽

Fish Eye

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T13M mutation of lecithin–cholesterol acyltransferase gene causes fish-eye disease

Clinica Chimica Acta ◽

10.1016/j.cccn.2004.01.014 ◽

2004 ◽

Vol 343 (1-2) ◽

pp. 201-208 ◽

Cited By ~ 8

Author(s):

Takashi Miida ◽

Bo Zhang ◽

Konen Obayashi ◽

Utako Seino ◽

Ying Zhu ◽

...

Keyword(s):

Cholesterol Acyltransferase ◽

Eye Disease ◽

Lecithin Cholesterol Acyltransferase ◽

Fish Eye

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LCAT deficiency: a systematic review with the clinical and genetic description of Mexican kindred

Lipids in Health and Disease ◽

10.1186/s12944-021-01498-6 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Roopa Mehta ◽

Daniel Elías-López ◽

Alexandro J. Martagón ◽

Oscar A Pérez-Méndez ◽

Maria Luisa Ordóñez Sánchez ◽

...

Keyword(s):

Systematic Review ◽

Latin America ◽

Meta Analysis ◽

Cholesterol Acyltransferase ◽

Eye Disease ◽

Premature Coronary Artery Disease ◽

Racial Groups ◽

Premature Coronary Heart Disease ◽

Lcat Deficiency ◽

Fish Eye

Abstract Background LCAT (lecithin-cholesterol acyltransferase) deficiency is characterized by two distinct phenotypes, familial LCAT deficiency (FLD) and Fish Eye disease (FED). This is the first systematic review evaluating the ethnic distribution of LCAT deficiency, with particular emphasis on Latin America and the discussion of three Mexican-Mestizo probands. Methods A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) Statement in Pubmed and SciELO. Articles which described subjects with LCAT deficiency syndromes and an assessment of the ethnic group to which the subject pertained, were included. Results The systematic review revealed 215 cases (154 FLD, 41 FED and 20 unclassified) pertaining to 33 ethnic/racial groups. There was no association between genetic alteration and ethnicity. The mean age of diagnosis was 42 ± 16.5 years, with fish eye disease identified later than familial LCAT deficiency (55 ± 13.8 vs. 41 ± 14.7 years respectively). The prevalence of premature coronary heart disease was significantly greater in FED vs. FLD. In Latin America, 48 cases of LCAT deficiency have been published from six countries (Argentina (1 unclassified), Brazil (38 FLD), Chile (1 FLD), Columbia (1 FLD), Ecuador (1 FLD) and Mexico (4 FLD, 1 FED and 1 unclassified). Of the Mexican probands, one showed a novel LCAT mutation. Conclusions The systematic review shows that LCAT deficiency syndromes are clinically and genetically heterogeneous. No association was confirmed between ethnicity and LCAT mutation. There was a significantly greater risk of premature coronary artery disease in fish eye disease compared to familial LCAT deficiency. In FLD, the emphasis should be in preventing both cardiovascular disease and the progression of renal disease, while in FED, cardiovascular risk management should be the priority. The LCAT mutations discussed in this article are the only ones reported in the Mexican- Amerindian population.

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