Albert Einstein is credited with saying “We cannot solve problems with the same thinking we used to create them.” It is this spirit of taking risks, asking difficult questions, and breaking away from outdated paradigms that have been instrumental in moving medicine forward. In fact, the process of “question-asking” is enshrined in the scientific method: would-be seekers must propose a hypothesis in answer to an exploratory question before a study can formally take place.
This spirit of returning to the basics and asking bold, probing questions — then conducting the studies needed to answer those questions — remains vital in rare diseases we know so little about, such as lysosomal acid lipase deficiency (LAL-D). Researchers conducted a review of existing scientific literature regarding LAL-D and published their findings in Current Opinion in Lipidology. Our existing collective understanding of LAL-D is pointedly summarized in the conclusion of this study: “despite years of research, our understanding of LAL-D is incomplete.”
In this article, we will review the current evidence surrounding LAL-D and frame a few questions that might shape our therapeutic management of this disease in the future.
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Read more about LAL-D etiology
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl ester and triglyceride in the lysosome and can do so in an acidic environment. It is encoded by the lipase A (LIPA) gene.
In both animal and human studies, loss of function mutations of the LIPA gene have resulted in 2 genetic diseases that are inherited in an autosomal recessive manner: Wolman disease and cholesteryl ester storage disease (CESD). Wolman disease tends to occur in infancy and is a lethal diagnosis, due to the complete absence of LAL activity. CESD tends to occur in children or adults and is characterized by the accumulation of cholesteryl ester and triglycerides in human organs, such as the spleen and liver, as well as in macrophages across the body. The lethality of CESD lies in its ability to cause liver failure and atherosclerosis (probably secondary to chronic hyperlipidemia).
Decades of research have not improved our understanding of the role of LAL in atherosclerosis and chronic heart disease. The purpose of this study was to highlight key recent discoveries that might shed further light on this matter.
What Is the Regulatory Role of LAL-Derived Cholesterol and Fatty Acids?
We know that LAL-mediated lipid catabolism causes the release of cholesterol and fatty acids. “Recent work has revealed that fatty acids derived from LAL-mediated lipolysis have an important functional impact on macrophage alternative activation, metabolic reprogramming of CD8+ memory T cells, lipid mediator synthesis, and hepatocyte very-low-density lipoprotein (VLDL) assembly,” the authors of this study wrote.
Our understanding of this newly expanded role of LAL has significant implications: LAL plays a role in mediating the body’s immune response through the activation of macrophages, which in turn is involved with healing wounds, maintaining metabolic homeostasis, and mediating immunity for parasites.
What Role Does LAL Play in Lipid Catabolism?
Intracellularly, lysosomal hydrolysis of mildly oxidized low-density lipoprotein (LDL) causes the release of free cholesterol into the lysosome. The progressive accumulation of free cholesterol inhibits the acidification of lysosomes and the subsequent hydrolysis of cholesteryl esters, causing both to accumulate in the body.
Researchers also discovered that hydrolyzes lipid droplet-stored triglyceride and cholesteryl ester that are delivered to the lysosome from cytoplasmic droplets through autophagy. LAL regulates autophagy-dependent intracellular lipid catabolism in macrophages and hepatocytes through the mechanisms just described.
As for extracellular lipid catabolism, it was discovered that the human macrophage medium contains LAL that is catalytically active. When the human macrophage medium hydrolyzes LAL, it causes LDL fusion and the modification of LDL-induced lipid droplet formation in vascular and smooth muscle cells, sites that are vulnerable to atherosclerotic lesions. The modified LDL environment caused by LAL promotes vascular dysfunction and atherogenesis, causing organ damage in the long term.
What Is the Role of LAL in Atherosclerosis?
Atherosclerosis and its accompanying signs and symptoms are one of the most obvious characteristics of LAL-D. Macrophages found in atherosclerotic plaques have been discovered to have a lysosomal accumulation of free cholesterol and cholesteryl ester, thus strongly implicating LAL-D as a contributor to the buildup of atherosclerosis in the body.
However, the exact mechanisms of this process are disputed. Enhancing the degradative capacity of macrophages may yet be a useful therapeutic measure in combating atherosclerotic buildup. The therapeutic usefulness of enhancing macrophage LIPA expression and LAL-mediated lipolysis warrants further investigation.
Is the LIPA Gene Linked With Coronary Heart Disease?
Earlier in this article, we have outlined how LAL is encoded in the LIPA gene. Genome-wide association studies (GWAS) have identified LIPA as a novel locus for coronary heart disease (CHD).
In patients with CESD, hyperlipidemia and hepatomegaly are caused by rare mutations in the LIPA gene, causing some patients to develop premature atherosclerosis. Studies have also shown that greater LIPA expressions in monocytes and monocyte-derived macrophages increase the risk of developing CHD.
Read more about LAL-D prognosis
Conflicting molecular studies means that the functional impact and mechanisms of the casual variants at the LIPA locus deserve further research. The challenge now is to tighten the link (if it exists) between the gain of function (GOF) of LAL and the development of atherosclerosis, allowing for better therapies to be developed.
The Work Ahead Of Us
It is clear that a significant gap remains between the questions posed in this article and the answers that we readily possess. Molecular studies of rare diseases like LAL-D are incredibly valuable, and this study managed to shine a light on key areas that deserve future research. With a bit of luck, molecular breakthroughs in our understanding of diseases such as LAL-D can yield tremendous benefits to patients in terms of the development of better screening methods and therapies.
References
Zhang H. Lysosomal acid lipase and lipid metabolism. Curr Opin Lipidol. 2018;29(3):218-223. doi:10.1097/mol.0000000000000507
Tebani A, Sudrié-Arnaud B, Boudabous H, et al. Large-scale screening of lipase acid deficiency in at risk population. Clin Chim Acta. 2021;519:64-69. doi:10.1016/j.cca.2021.04.005
