A new study has uncovered a novel molecular mechanism that promotes the clearance of cholesteryl esters from the brain, which could have important implications for those with lysosomal acid lipase deficiency (LAL-D).

LAL-D is a pathological condition associated with disruption of intralysosomal degradation and the consequent accumulation of cholesteryl esters and triglycerides. The study was published in iScience.

The mechanism involves the PDZ domain-containing protein 8 (PDZD8), a Rab7 effector protein involved in endosome maturation and maintenance of neuronal integrity. “PDZD8 transfers cholesterol from ER [endoplasmic reticulum] to LEs/Lys [late endosomes and lysosomes] and thereby promotes endosome maturation, leading to lysosome maturation and fusion with LDs [lipid droplets] and consequent CE [cholesteryl ester] degradation by lipophagy,” the study’s authors explained.


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PDZD8-deficient mice showed abnormal accumulation of cholesteryl esters in the basal ganglia and cortex, although less pronounced in the cortex, when compared with control animals. Such abnormal accumulation of cholesteryl esters in the PDZD8-deficient brain resulted from an impairment of lipophagy and was shown to be diet-independent.

Read about LAL-D etiology

In contrast to the brain, the liver of PDZD8-deficient mice did not show abnormal accumulation of cholesteryl esters. The levels of cholesteryl esters and triglycerides increased in response to a high-fat diet in both PDZD8-deficient mice and control animals.

Moreover, PDZD8-deficient mice also presented with defects in the degradation of lipid droplets in the brain. On the other hand, the amounts of other lipids such as triglyceride and fatty acids were largely unaffected. The explanation for the specific accumulation of cholesteryl esters in PDZD8-deficient brain and not other lipids remains to be elucidated.

This study had limitations. For instance, it used neuronal cell lines and mouse brains as study models. Therefore, future studies should clarify the role of PDZD8 in promoting lipophagy in humans, as well as the impact of PDZD8 on dyslipidemia.

Reference

Morita K, Wada M, Nakatani K, et al. PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy. iScience. 2022:105612. doi:https://doi.org/10.1016/j.isci.2022.105612