Researchers discovered that fat overload can cause lysosomal acid lipase (LAL) ubiquitination, thus impairing its function and possibly reducing hepatic fat disposal and promoting nonalcoholic fatty liver disease (NAFLD) activity, according to a study published in Cell Disease & Death.

LAL deficiency (LAL-D) is a condition in which LAL activity is greatly reduced or absent altogether. This is typically caused by homozygous or heterozygous mutations in the LIPA gene.

The result? “Cholesteryl esters and triglycerides accumulate prevalently within lysosomes, and several complications arise due to both lipid overload at the target organ level and to dyslipidaemia,” Carotti et al wrote.

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Recent medical advancements have made it easier for scientists to determine the levels of LAL activity in a patient. Scientists have noted lower levels of LAL activity in adult patients with NAFLD. Carotti and colleagues thus decided to further explore the LAL protein, both in vitro and in vivo, to better understand how impairment in LAL activity affects NAFLD. 

Read more about LAL-D etiology 

For the in vitro portion of the study, the researchers experimented on fat-loaded hepatocyte-derived human carcinoma Huh7 cells. For the in vivo portion of the study, the researchers used male mice models that were divided into 4 groups: those fed with a normal diet for 4 months or for 8 months, and those fed with a high-fat diet for 4 months or for 8 months. At the end of the study, the liver tissues of these mice models were analyzed. 

The results showed that LAL activity is reduced in fat-loaded (high glucose/high lipid) in vivo experimental models of NAFLD. This coincided with an increase in ubiquitinated proteins. In addition, researchers also found that ubiquitinated/dysfunctional LAL accumulation could be observed in the liver of mice models fed with high-fat diets. 

The findings of these studies demonstrate how LAL activity is linked to NAFLD. “In the present study, fat overload in hepatocytes induced a significant impairment of LAL activity,” the research team wrote.

“Further studies are awaited in order to confirm our findings, and to verify whether inhibiting LAL ubiquitination or replacing LAL activity may prove beneficial in the treatment of NAFLD.”


Carotti S, Lettieri-Barbato D, Piemonte F, et al. Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liverCell Death Dis. Published online November 18, 2021. doi:10.1038/s41419-021-04382-4