PPAR-mediated reduction of lipid accumulation in hepatocytes involves the autophagy-lysosome-mitochondrion axis

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, gamma and delta, 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 almost 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 a panel of genes involved in mitochondrial dynamics and in fatty acid catabolism. Interestingly, PPAR agonists completely 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.