Fig. 2

Lipoprotein metabolism dysregulation in lysosomal acid lipase deficiency a) The liver secretes VLDL, which is lipolyzed in the periphery by LPL and HL to generate LDL. LDL is taken up via the LDLR and is trafficked to the lysosome for degradation. LAL hydrolyzes the cholesteryl esters and triglycerides in LDL to FFA and FC. FC prevents SREBP pathway activation, thereby decreasing de novo cholesterol biosynthesis. FC also activates the LXR pathway to increase ABCA1 expression. ABCA1 effluxes FC to an APOA1 acceptor. The FC is esterified by LCAT to form the cholesteryl ester in HDL b) In LALD, inability to hydrolyze LDL cholesteryl ester and triglyceride impairs FFA and FC generation. Decreased FC generation results in increased SREBP pathway activation, which increases de novo cholesterol biosynthesis. Decreased FC also decreases LXR pathway activation, which decreases ABCA1 expression and impairs HDL formation. Accumulation of the FC and FFAs in the lysosome causes hepatic, adrenal, and intestinal toxicity. Abbreviations: APOA1: Apolipoprotein A1; ABCA1: ATP-binding cassette transporter-1; FC: Free cholesterol; FFA: Free fatty acid; HL: Hepatic lipase; HDL-C: High-density lipoprotein cholesterol; LCAT: Lecithin-cholesterol acyltransferase; LPL: Lipoprotein lipase; LXR: Liver X receptor; LDL: Low-density lipoprotein cholesterol; LDLR: Low-density lipoprotein receptor; LAL: Lysosomal acid lipase; LALD: Lysosomal acid lipase deficiency; SREBP: Sterol regulatory element-binding protein; VLDL-C: Very-low density lipoprotein cholesterol