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Effect of the amyloidogenic L75P apolipoprotein A-I variant on HDL subpopulations
Monica Gomaraschi1, Laura Obici, Sara Simonelli
1Center Enrica Grossi Paoletti, Department of Pharmacological Sciences, Università degli Studi di Milano, Milano, Italy.
Background:
Hereditary amyloidosis due to mutations of apolipoprotein A-I (apoA-I) is a rare disease characterized by the deposition of amyloid fibrils constituted by the N-terminal fragment of apoA-I in several organs. L75P is a variant of apoA-I associated with systemic amyloidosis predominantly involving the liver, kidneys, and testis, identified in a large number of unrelated subjects. Objective of the present paper was to evaluate the impact of the L75P apoA-I variant on HDL subpopulations and cholesterol esterification in carriers.
Methods And Results:
Plasma samples were collected from 30 carriers of the amyloidogenic L75P apoA-I (Carriers) and from 15 non affected relatives (Controls). Carriers displayed significantly reduced plasma levels of HDL-cholesterol, apoA-I, and apoA-II compared to Controls. Plasma levels of LpA-I, but not LpA-I:A-II, were significantly reduced in Carriers. HDL subclass distribution was not affected by the presence of the variant. The unesterified to total cholesterol ratio was higher, and cholesterol esterification rate and LCAT activity were lower in Carriers than in Controls.
Conclusions:
The L75P apoA-I variant is associated with hypoalphalipoproteinemia, a selective reduction of LpA-I particles, and a partial defect in cholesterol esterification.
Insights
The L75P apolipoprotein A-I (apoA-I) variant causes hereditary amyloidosis, leading to lower HDL-cholesterol and impaired cholesterol esterification in carriers.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Medicine
Background:
- Hereditary amyloidosis is a rare condition caused by apolipoprotein A-I (apoA-I) mutations.
- The L75P apoA-I variant is linked to systemic amyloidosis affecting the liver, kidneys, and testes.
Purpose of the Study:
- To investigate the impact of the L75P apoA-I variant on high-density lipoprotein (HDL) subpopulations.
- To assess the effect of the L75P apoA-I variant on cholesterol esterification in carriers.
Main Methods:
- Collected plasma samples from 30 carriers of the L75P apoA-I variant and 15 non-affected relatives.
- Measured plasma levels of HDL-cholesterol, apoA-I, apoA-II, LpA-I, and LpA-I:A-II.
- Analyzed HDL subclass distribution, unesterified to total cholesterol ratio, cholesterol esterification rate, and LCAT activity.
Main Results:
- Carriers showed significantly reduced plasma levels of HDL-cholesterol, apoA-I, and apoA-II.
- Plasma levels of LpA-I were significantly reduced in carriers, but LpA-I:A-II levels were not affected.
- Carriers exhibited a higher unesterified to total cholesterol ratio, with lower cholesterol esterification rates and LCAT activity.
Conclusions:
- The L75P apoA-I variant is associated with hypoalphalipoproteinemia.
- A selective reduction of LpA-I particles and a partial defect in cholesterol esterification were observed in carriers.
- These findings highlight the role of the L75P apoA-I variant in lipid metabolism and amyloidosis pathogenesis.
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