Cetti Federica, Ossoli Alice, Garavaglia Carola, Da Dalt Lorenzo, Norata Giuseppe Danilo, Gomaraschi Monica
Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
Ann Med. 2025 Dec;57(1):2497112. doi: 10.1080/07853890.2025.2497112. Epub 2025 Apr 28.
Lipid accumulation in hepatocytes is reduced by the activation of the peroxisome proliferator-activated receptor (PPAR) α, which is associated with increased lysosomal acid lipase (LAL) activity, transcription factor EB (TFEB) expression, and mitochondrial β-oxidation.Aim of the study was to assess whether the three isoforms of PPAR, i.e. α, δ and γ, share the same ability to reduce lipid accumulation in hepatocytes and to clarify the involvement of autophagy activation, lysosomal hydrolysis, and mitochondrial β-oxidation in lipid clearance induced by PPARs.
HepG2 cells were treated with oleate/palmitate (O/P) to induce lipid accumulation and exposed to the PPARα agonist fenofibric acid, the γ agonist pioglitazone, the δ agonist seladelpar, or the dual α/γ agonist saroglitazar.
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.
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.
过氧化物酶体增殖物激活受体（PPAR）α的激活可减少肝细胞中的脂质蓄积，这与溶酶体酸性脂肪酶（LAL）活性增加、转录因子EB（TFEB）表达以及线粒体β-氧化有关。本研究的目的是评估PPAR的三种亚型，即α、δ和γ，是否具有相同的减少肝细胞脂质蓄积的能力，并阐明自噬激活、溶酶体水解和线粒体β-氧化在PPAR诱导的脂质清除中的作用。
用油酸/棕榈酸（O/P）处理HepG2细胞以诱导脂质蓄积，并使其暴露于PPARα激动剂非诺贝特酸、γ激动剂吡格列酮、δ激动剂塞拉达帕或双α/γ激动剂沙罗格列扎。
用非诺贝特酸、吡格列酮、塞拉达帕或沙罗格列扎处理HepG2细胞可使O/P诱导的脂质蓄积减少一半。PPAR激动剂增加了TFEB、p62和LC3的表达，并挽救了O/P诱导的LAL损伤。此外，PPAR激动剂显著增加了线粒体质量以及参与线粒体动力学和脂肪酸分解代谢的基因的表达。有趣的是，当自噬通量、LAL活性或线粒体中的脂肪酸转运被特异性抑制剂阻断时，PPAR激动剂失去了减少脂质蓄积的能力。
所有PPAR激动剂均能够促进富含长链脂肪酸的细胞中的脂质清除。阐明了酸性水解在生成可在线粒体中分解代谢的脂肪酸中的关键作用，以及PPAR系统维持这一清除过程各阶段的能力。
