Abstract 17868: Role of Lysosomal Acid Lipase in LDL-C Regulation in Familial Hypercholesterolemia and Metabolic Syndrome

Lysosomal acid lipase (LAL), coded by LIPA gene, is key role player of LDL receptor pathway, and LIPA is a susceptibility gene for CAD in many GWAS studies. LAL hydrolyzes cholesterol-ester in hepatocytes, and is essential for M2 activation of macrophages. Furthermore, LAL-deficiency, with increased LDL-C and premature CAD, has been focused as underdiagnosed disease similar to familial hypercholesterolemia (FH). On the other hand, little is known about the role of physiological LAL activity on atherosclerosis. We investigated LIPA gene as genetic cause of FH, and LAL activity in CAD high-risk group. Methods: This study consisted of two parts. First part was genetic analysis of LIPA gene. From 940 clinically diagnosed hetero-FH patients in Japan, pathogenic mutations were identified in 788 patients through screening in LDLR, PCSK9, and APOB genes. All coding regions of LIPA gene were investigated in 143 hetero-FH patients without pathogenic mutation in those genes. Identified variants were also evaluated in 200 genetically confirmed hetero-FH, 200 non-FH dyslipidemia, and 250 general population samples. Second part was LAL acclivity measurement with very recently developed fluorometric assay method using dried blood spots. A total of 122 CAD high-risk patients (M/F: 67/55, age: 65 ± 15 yrs, established CAD: 34%, DM: 46%, hetero-FH: 25%) were investigated their LAL activity. Results: Analysis in LIPA gene revealed no patients with LAL-deficiency among FH without confirmed mutations. All variants identified were considered as benign. Intriguingly, common LIPA T16P carriers showed lower pre-treatment LDL-C in genetically confirmed hetero-FH (LDL-C 215±61 vs. 242±70 mg/dL, p In activity analysis, LAL activity correlated positively with BMI (R 2 : 10%, p 2 : 11%, p 2 : 5%, p 2 : 4%, p Conclusion: LAL-deficiency was not common genetic cause of FH in Japan. LAL activity increased with obesity, and negatively correlated with LDL-C. Further study will clarify the role of LAL in atherosclerosis.