Cetti_2025_Ann.Med_57_2497112

BACKGROUND AND AIM: Lipid accumulation in hepatocytes is reduced by the activation of the peroxisome proliferator-activated receptor (PPAR) alpha, which is associated with increased lysosomal acid lipase (LAL) activity, transcription factor EB (TFEB) expression, and mitochondrial beta-oxidation.Aim of the study was to assess whether the three isoforms of PPAR, i.e. alpha, delta and gamma, share the same ability to reduce lipid accumulation in hepatocytes and to clarify the involvement of autophagy activation, lysosomal hydrolysis, and mitochondrial beta-oxidation in lipid clearance induced by PPARs. METHODS: HepG2 cells were treated with oleate/palmitate (O/P) to induce lipid accumulation and exposed to the PPARalpha agonist fenofibric acid, the gamma agonist pioglitazone, the delta agonist seladelpar, or the dual alpha/gamma agonist saroglitazar. RESULTS: The treatment of HepG2 cells with fenofibric acid, pioglitazone, seladelpar, or saroglitazar halved lipid accumulation induced by O/P. PPAR agonists increased TFEB, p62, and LC3 expression and rescued LAL impairment induced by O/P. Moreover, PPAR agonists significantly increased mitochondrial mass and the expression of genes involved in mitochondrial dynamics and fatty acid catabolism. Interestingly, PPAR agonists lost their ability to reduce lipid accumulation when autophagic flux, LAL activity, or fatty acid transport in the mitochondria were blocked by specific inhibitors. CONCLUSION: All PPAR agonists were able to promote the clearance of lipids in cells loaded with long-chain fatty acids. The key role of acid hydrolysis to generate fatty acids, which can be then catabolized in the mitochondria, and the ability of the PPAR system to sustain each phase of this clearing process were elucidated.