Related Experiment Videos
Evidence against alterations in Lecithin:cholesterol acyltransferase (LCAT) activity in familial combined
J Ribalta1, A E La Ville, J C Vallvé
1Unitat de Recerca de Lipids, Facultat de Medicina, Hospital Universitari de Sant Joan, Universitat Rouirai Virgili, Reus, Spain. jrv@fmcs.urv.es
Insights
Familial combined hyperlipidemia (FCHL) is characterized by altered high-density lipoprotein (HDL) levels, but lecithin:cholesterol acyltransferase (LCAT) activity is normal in FCHL patients. Genetic variations in apolipoprotein A-I influence FCHL expression.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Medicine
Background:
- Familial combined hyperlipidemia (FCHL) is a common genetic dyslipidemia characterized by elevated plasma cholesterol and triglycerides.
- Reduced high-density lipoprotein (HDL) cholesterol concentrations are often observed in FCHL patients.
- Lecithin:cholesterol acyltransferase (LCAT) is crucial for HDL maturation and reverse cholesterol transport, with apolipoprotein A-I (apo A-I) as its activator.
Purpose of the Study:
- To investigate the role of LCAT activity and apo A-I gene sequence in HDL metabolism in FCHL.
- To determine if alterations in LCAT or apo A-I influence HDL subfraction concentrations and composition in FCHL.
Main Methods:
- Studied cholesterol concentrations of HDL subfractions and LCAT activity in 25 FCHL subjects and 48 controls.
- Analyzed LDLc/HDLc and A-I/HDLc ratios.
- Investigated the association between a Ga(-75)-A variation in the apo A-I promoter region and lipid/apolipoprotein concentrations.
Main Results:
- Significantly decreased total HDL and HDL2 cholesterol in FCHL compared to controls, with HDL2 remaining significant after adjustment.
- Elevated LDLc/HDLc and A-I/HDLc ratios in FCHL, suggesting altered HDL particle composition.
- Normal LCAT activity in FCHL patients; a positive correlation between LCAT activity and HDL parameters was observed in FCHL subjects but not controls.
- An association between the apo A-I promoter variation and elevated apo A-I and apo C-III concentrations, influenced by FCHL status.
Conclusions:
- LCAT activity is normal in FCHL and does not explain the observed HDL abnormalities, particularly in the HDL2 subfraction.
- Genetic variations in the apo A-I promoter region play a regulatory role in FCHL expression.
- Altered HDL metabolism in FCHL is likely influenced by factors beyond LCAT activity, including genetic regulation of apo A-I.
Abstract:
Elevated concentrations of plasma cholesterol and triglycerides are characteristic of familial combined hyperlipidemia (FCHL) which may also present with reduced high density lipoprotein (HDL) cholesterol concentrations. Lecithin:cholesterol acyltransferase (LCAT) plays a key role in reverse cholesterol transport by converting unesterified cholesterol to cholesterol ester in the process of maturation of HDL in the presence of its activator, apolipoprotein (apo) A-I. We hypothesised that alterations in LCAT activity or plasma concentrations or gene sequence of apo A-I could influence HDL metabolism in these patients. We studied cholesterol concentrations of high density lipoprotein subfractions and LCAT activity in 25 FCHL subjects and 48 controls. Total HDL (p=0.018) and HDL2 (p=0.008) were significantly decreased in the FCHL group compared with controls. After analyses with adjusted data only HDL2 remained significantly decreased in the FCHL group (p=0.050). The LDLc/HDLc and A-I/HDLc ratios were significantly elevated in the FCHL group (p <0.0001), the latter suggesting the existence of compositional differences in the HDL particles of the FCHL individuals. LCAT activity assessed in the FCHL (19.94+/-3.95 nmol/ml per h) and control (20.13+/-6.86 nmol/ml per h) groups showed no statistically significant differences. A significant positive correlation of LCAT activity with total HDL (r=0.42), HDL3 cholesterol (r=0.46) and apolipoprotein A-I (r=0.47) was observed in affected subjects but not in controls. An association between a Ga(-75)-A variation in the promoter region of the apo A-I gene and elevated concentrations of apo A-I (p=0.009) and apo C-III (p=0.041) was observed. This association was strongly influenced by the status of the subject providing further evidence for a regulatory role of this genetic region in the expression of FCHL. Our data suggests that LCAT activity is normal in FCHL and, therefore, does not account for the abnormalities observed in these patients essentially with regard to the HDL2 subfraction.