Sebelipase alfa improves atherogenic biomarkers in adults and children with lysosomal acid lipase deficiency  Don P. Wilson, MD, FNLA, Mark Friedman, MD, Sachin Marulkar, MBBS, MPH, Tyler Hamby, PhD, Eric Bruckert, MD  Journal of Clinical Lipidology  Volume 12, Issue 3, Pages 604-614 (May 2018) DOI: 10.1016/j.jacl.2018.02.020 Copyright © 2018 National Lipid Association Terms and Conditions

Figure 1 Percentage change from baseline in lipid and atherogenic biomarkers in LAL-D patients at 20 weeks of treatment. P values determined using the Wilcoxon rank-sum test. Columns show the mean change with standard deviation bars; median values are denoted by asterisks (*). ApoA1, apolipoprotein A1; apoB, apolipoprotein B; LAL-D, lysosomal acid lipase deficiency; LDL-P, low-density lipoprotein particle; NS, not significant. Journal of Clinical Lipidology 2018 12, 604-614DOI: (10.1016/j.jacl.2018.02.020) Copyright © 2018 National Lipid Association Terms and Conditions

Figure 2 Percentage change from baseline at 20 weeks for HDL-C (A) and LDL-C (B). The letter “L” indicates the patients who also received lipid-lowering medication. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Journal of Clinical Lipidology 2018 12, 604-614DOI: (10.1016/j.jacl.2018.02.020) Copyright © 2018 National Lipid Association Terms and Conditions

Figure 3 Lipid metabolism in normal (A) and LAL-D hepatocytes (B). (A) Low-density lipoprotein (LDL) is taken up into the hepatocyte and delivered to the lysosome via the LDL receptor (LDLR). The secreted protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), causes the degradation of LDLR in the lysosome. Triglycerides (TG) and cholesteryl esters (CE) are de-esterified in the lysosome by lysosomal acid lipase (LAL) to form free cholesterol (FC) and free fatty acids (FFA), respectively. Niemann-Pick C1 protein (NPC1) and C2 (NPC2) translocate FC from lysosome to cytoplasm. FC and FFA interact with sterol regulatory element–binding proteins (SREBP) to provide feedback inhibition, which decreases production and intake of cholesterol. FC causes activation of the nuclear liver X receptor (LXR), which increases the efflux of cholesterol via the adenosine triphosphate–binding cassette transporter A1 (ABCA1)–mediated production of nascent high-density lipoprotein (HDL) particles. (B) In the absence of LAL, cytosolic FC and FFA levels are diminished, resulting in an increase in levels of serum LDL, an increase in receptor-mediated LDL cholesterol uptake, and increased synthesis, packaging, and secretion of very-low-density lipoprotein (VLDL), which contributes to LDL levels and a decrease in FC efflux via HDL. In addition, cholesteryl ester transfer protein (CETP) facilitates the removal of CE from HDL and LDL in exchange for TG, which may further reduce serum HDL cholesterol levels. ACAT, acyl-coenzyme A:cholesterol acyltransferase; apoA1, apolipoprotein A1; apoB100, apolipoprotein B100; FA, fatty acids; HEL, hepatic endothelial lipase; HMGCR, hydroxymethylglutaryl-coenzyme A reductase; IDL, intermediate-density lipoprotein; LAL-D, LAL deficiency; LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; MTTP, microsomal triglyceride transfer protein. Adapted from Reiner et al2 (Atherosclerosis. 2014; 235:21–30) and Maciejko33 (Am J Cardiovasc Drugs. 2017; 17:217–231). Journal of Clinical Lipidology 2018 12, 604-614DOI: (10.1016/j.jacl.2018.02.020) Copyright © 2018 National Lipid Association Terms and Conditions

Figure 4 Lipid-lowering medications intended to improve lipid homeostasis in normal hepatocytes (A) may exacerbate the underlying mechanisms of disease in LAL-D (B). (A) Statins inhibit hydroxymethylglutaryl-coenzyme A reductase (HMGCR), disrupting synthesis of free cholesterol (FC). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors prevent degradation of low-density lipoprotein receptor (LDLR). PCSK9 levels may increase as a feedback response to statins. Upregulation of PCSK9 may attenuate the statin-induced reduction in low-density lipoprotein (LDL) cholesterol. Statins may increase apolipoprotein A1 (apoA1) production. (B) Both statins, which disrupt synthesis of FC, and PCSK9 inhibitors, which prevent degradation of LDLR, can markedly increase LDL uptake. Although not proven, increased uptake of LDL may exacerbate hepatic lipid accumulation in LAL-D. Disrupting synthesis of FC with statins may reduce activity of liver X receptor (LXR) and further decrease high-density lipoprotein (HDL) production. ABCA1, adenosine triphosphate–binding cassette transporter A1; ACAT, acyl-coenzyme A:cholesterol acyltransferase; apoB100, apolipoprotein B100; CE, cholesteryl esters; CETP, cholesteryl ester transfer protein; FA, fatty acids; FFA, free fatty acids; HEL, hepatic endothelial lipase; IDL, intermediate-density lipoprotein; LAL, lysosomal acid lipase; LAL-D, lysosomal acid lipase deficiency; LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; MTTP, microsomal triglyceride transfer protein; Niemann-Pick C1 protein (NPC1) and C2 (NPC2); SREBP, sterol regulatory element–binding proteins; TG, triglycerides; VLDL, very-low-density lipoprotein. Adapted from Reiner et al2 (Atherosclerosis. 2014; 235:21–30) and Maciejko33 (Am J Cardiovasc Drugs. 2017; 17:217–231). Journal of Clinical Lipidology 2018 12, 604-614DOI: (10.1016/j.jacl.2018.02.020) Copyright © 2018 National Lipid Association Terms and Conditions