Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease

Abstract

Lysosomal acid lipase (LAL), encoded by the gene LIPA, is the sole neutral lipid hydrolase in lysosomes, responsible for cleavage of cholesteryl esters and triglycerides into their component parts. Inherited forms of complete (Wolman Disease, WD) or partial LAL deficiency (cholesteryl ester storage disease, CESD) are fortunately rare. Recently, LAL has been identified as a cardiovascular risk gene in genome-wide association studies, though the directionality of risk conferred remains controversial. It has also been proposed that the low expression and activity of LAL in arterial smooth muscle cells (SMCs) that occurs inherently in nature is a likely determinant of the propensity of SMCs to form the majority of foam cells in atherosclerotic plaque. LAL also likely plays a potential role in fatty liver disease. This review highlights the nature of LAL gene mutations in WD and CESD, the association of LAL with prediction of cardiovascular risk from genome-wide association studies, the importance of relative LAL deficiency in SMC foam cells, and the need to further interrogate the pathophysiological impact and cell type-specific role of enhancing LAL activity as a novel treatment strategy to reduce the development and induce the regression of ischemic cardiovascular disease and fatty liver.

Keywords: Cholesteryl Ester Storage Disease; GWAS; LIPA; Wolman Disease; atherosclerosis; lysosomal acid lipase; nonalcoholic fatty liver disease; smooth muscle cells.

FIGURE 1

LAL in deficiency states, GWAS studies of cardiovascular risk variants, and potentially common roles of relative LAL deficiency in the development of atherosclerosis and nonalcoholic fatty liver disease. (A), clinical consequences of complete and partial LAL deficiency; (B), LIPA variants identified in GWAS studies of CVD risk and related effects in cells and tissues. LD, linkage disequilibrium; (C), variable expression of LIPA/LAL in macrophages and smooth muscle cells (SMCs) and consequences for cell cholesterol handling. In macrophages, high levels of LIPA/LAL expression result in efficient hydrolysis of endocytosed lipoprotein cholesteryl esters (CE) to free cholesterol (FC), and trafficking of lysosomally-released FC for re-esterification in the endoplasmic reticulum (ER) or removal from the cell by cholesterol efflux mechanisms. In SMCs, low levels of LIPA/LAL expression result in retention of lipoprotein CE in lysosomes, reducing FC available for re-esterification in the ER or efflux from cells. Adapted from (Dubland et al., 2021); (D), Potential role of LAL in nonalcoholic fatty liver disease (NAFLD). LAL activity in the blood is reduced in NAFLD and lower LAL activity is associated with increased NAFLD severity. Both NAFLD and low LAL are associated with metabolic abnormalities, but no causal relationships between these factors have been determined. No variants in LIPA have been associated with NAFLD, and expression of LAL in NAFLD livers is normal, but activity is low (Gomaraschi et al., 2019), possibly due to accumulation of dysfunctional LAL (Carotti et al., 2021).