In patients with the rare inherited autosomal recessive metabolic disorder lysosomal acid lipase deficiency (LAL-D), a defective breakdown in body lipids is reported, with oxidized cholesteryl ester shown to induce exocytosis of dysfunctional lysosomes in lipidotic macrophages.

Macrophages that are exposed to cholesteryl hemiazelate (ChA)—a common byproduct of low-density lipoprotein-derived cholesteryl ester oxidation—exhibit enlarged peripheral dysfunctional lysosomes that appear to be replete with undigested ChA and neutral lipids.

Atherosclerosis is one of the key characteristics of LAL-D.  The factors that impact the initiation and progression of atherosclerotic lesions are complex and remain to be elucidated. An early manifestation of atherogenesis is the sequestration of lipids by macrophages in the arterial intima. This event is associated with macrophage ingestion of low-density lipoproteins that accumulate in the vascular wall.

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The researchers of the current analysis sought to clarify the precise chemical etiology of atherogenesis, as well as the cellular and molecular mechanisms that are responsible for the impairment of lysosome function in plaque macrophages. Their findings were published in the journal Traffic.

Read more about approved therapies for LAL-D

ChA was prepared via a process used for the synthesis of cholesteryl hemisuccinate. Next, the ChA was synthesized from the reaction of commercially available cholesterol with freshly prepared azelaic anhydride. The cholesterol was stimulated with 2.6 molar equivalents of azelaic anhydride in dry pyridine under reflux for a period of 7 hours.

The following findings regarding the atherogenic properties of ChA toward macrophages were derived from this analysis:

  • ChA is toxic to macrophages; it induces lipid accumulation and the formation of peripheral enlarged lysosomes;
  • Lysosomes in ChA-treated macrophages are dysfunctional;
  • The lysosomes are shifted toward the cell periphery in ChA-treated cells;
  • The peripheral enlarged lysosomes are more exocytic in ChA-treated cells;
  • ChA drives lysosome biogenesis in macrophages;
  • The ChA-generated lysosomal phenotype is mediated partially by transcription factor EB (TFEB) and/or transcription factor E3 (TFE3); and
  • The additional promotion of TFEB translocation lessens lysosomal hypertrophy and prevents the development of atherogenic phenotypes.

The low-density lipoprotein-cholesterol level in the blood is a major indicator of risk for cardiovascular disease. The results of the present study show that ChA is one of the primary end products of cholesteryl linoleate oxidation, which is increased in the plasma of patients with cardiovascular disease.

A key finding of the current study is that the peripheral enlarged dysfunctional lysosomes are more prone to fuse with the plasma membrane. Thus, it seems logical to predict that lysosome exocytosis and de novo biogenesis of these organelles are the cellular responses intended to cope with atypical lysosomes upon ChA treatment.

“In sum, our data show that ChA is involved in the etiology of lysosome dysfunction and promotes the exocytosis of these organelles,” the researchers explained. “This latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis,” they highlighted. “The data reported here reinforce that the development of new therapeutical interventions aiming to restore lysosomal function may be useful in atherosclerosis treatment,” the authors concluded.


Domingues N, Marques ARA, Calado RDA, et al. Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages. Traffic. Published online May 2, 2023. doi:10.1111/tra.12888