Lipid accumulation impairs lysosomal acid lipase activity in hepatocytes: Evidence in NAFLD patients and cell cultures.

Abstract

AIMS:

It has been hypothesized that the activity of lysosomal acid lipase (LAL), a key enzyme involved in lipid metabolism, is involved in the NAFLD phenotype. To clarify the role of LAL in NAFLD, we studied 164 consecutive patients with biopsy-proven NAFLD and fat-loaded HepG2 cells.

METHODS:

LAL activity was measured (i) on dried blood spots (DBS) from NAFLD patients and dyslipidemic subjects without fatty liver and (ii) on liver biopsies from NAFLD patients. LAL activity and expression were evaluated in HepG2 cells cultured in the presence of free fatty acids (FAs), with or without a PPAR-alpha agonist.

RESULTS:

LAL activity was significantly reduced in patients with NAFLD compared to dyslipidemic subjects. LAL activity measured in liver biopsies from NAFLD patients was highly correlated to that measured on DBS and was independent of LAL expression in the liver. In a fully adjusted model, LAL activity on DBS was associated only with platelets and, when normalized by platelet count, it did not differ according to fibrosis stage. In vitro, FA loading of HepG2 fully replicated the impairment of LAL activity observed in NALFD patients. In these cells, the activation of PPAR-alpha receptors prevented and corrected FA-induced LAL impairment, by stimulating FA oxidation and LAL expression.

CONCLUSIONS:

LAL activity is reduced in NAFLD patients, independently from disease progression. In vitro, impaired LAL activity induced by FA loading was rescued by PPAR-alpha activation. These data suggest that the pharmacological modulation of LAL should be explored in the management of NAFLD patients.

• Authors: Monica Gomaraschi, Anna Ludovica Fracanzani, Paola Dongiovanni, Chiara Pavanello, Eleonora Giorgio, Lorenzo Da Dalt, Giuseppe Danilo Norata, Laura Calabresi, Dario Consonni, Rosa Lombardi, Adriana Branchi, Silvia Fargion
• Journal: Biochimica et biophysica acta. Molecular and cell biology of lipids (Biochim Biophys Acta Mol Cell Biol Lipids) Vol. 1864 Issue 12 Pg. 158523 (12 2019) ISSN: 1879-2618 [Electronic] Netherlands
• PMID: 31505261 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Fatty Acids
• PPAR alpha
• LIPA protein, human
• Sterol Esterase

Topics

• Adult
• Fatty Acids (metabolism)
• Female
• Hep G2 Cells
• Hepatocytes (metabolism, pathology)
• Humans
• Lipid Metabolism
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease (metabolism, pathology)
• PPAR alpha (metabolism)
• Sterol Esterase (metabolism)