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Genetic variation of human mononuclear leukocyte lysosomal acid lipase activity. Relationship to atherosclerosis
Insights
Reduced lysosomal acid lipase activity in leukocytes is linked to premature cardiovascular disease. This enzyme deficiency may be an independent risk factor for atherosclerosis, even without high cholesterol or triglycerides.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Medicine
Background:
- Premature cardiovascular disease (CVD) is a significant health concern.
- The role of specific enzyme activities in CVD pathogenesis requires further investigation.
- Lysosomal acid lipase (LAL) plays a crucial role in lipid metabolism.
Purpose of the Study:
- To investigate lysosomal acid lipase activity in leukocytes of patients with premature cardiovascular disease.
- To determine if reduced LAL activity is associated with CVD, independent of lipid levels.
- To explore the potential genetic basis for reduced LAL activity in affected individuals.
Main Methods:
- Measurement of lysosomal acid lipase activity in mononuclear leukocytes.
- Comparison of enzyme activity between patients with premature CVD and age-matched controls.
- Analysis of LAL activity in relation to plasma lipid profiles (cholesterol, triglycerides).
- Family studies to investigate the inheritance pattern of reduced LAL activity.
Main Results:
- Significantly lower LAL activity was observed in male patients with premature CVD compared to controls.
- Reduced LAL activity was found even in patients with normal plasma lipid levels.
- A notable percentage of patients with normal lipids exhibited LAL activity in the range seen in heterozygotes for inherited LAL deficiency.
- Family studies suggested an autosomal mutation associated with reduced LAL activity.
Conclusions:
- Reduced lysosomal acid lipase activity in leukocytes is associated with premature cardiovascular disease.
- This enzymatic deficiency may represent an independent risk factor for atherosclerosis.
- An autosomal mutation might underlie the reduced LAL activity and contribute to CVD risk.
Abstract:
Lysosomal acid lipase activity was measured in mononuclear leukocytes of patients selected on the basis of premature cardiovascular disease, with or without hyperlipidemia. Enzyme activity was significantly lower in the patient population (4.8 +/- 1.3 nmol/min/mg protein, n = 190 males) than in an age-matched control population (5.4 +/- 1.3 nmol/min/mg protein, n = 124 males). There was no effect of hypercholesterolemia or hypertriglyceridemia on the enzyme activity. In the group of patients with normal plasma lipids (n = 77), 18% had mononuclear leukocyte acid lipase activity which fell below the control population 5th percentile, and in the range of enzyme activity observed in cells from obligate heterozygotes for inherited acid lipase deficiency (Wolman disease and cholesteryl ester storage disease). Studies of acid lipase activity in families of our patients provided evidence that an autosomal mutation is associated with (or responsible for) this reduced enzymatic activity and may represent an independent risk factor for the premature development of atherosclerosis.