Triacsin C reduces lipid droplet formation and induces mitochondrial biogenesis in primary rat hepatocytes
| Autor: | Bruno G. Teodoro, Isis do Carmo Kettelhut, Felippe Henrique Zuccolotto-Dos-Reis, Carlos Curti, Anna Maria A. P. Fernandes, Carlos Roberto Porto Dechandt, Marcos N. Eberlin, Luciane C. Alberici |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Physiology Mitochondria Liver Oxidative phosphorylation Mitochondrion Biology 03 medical and health sciences chemistry.chemical_compound Lipid oxidation FÍGADO GORDUROSO Non-alcoholic Fatty Liver Disease Lipid droplet medicine Animals Cells Cultured Organelle Biogenesis Dose-Response Relationship Drug Lipid Droplets Cell Biology Lipid Metabolism Rats Cell biology Triacsin C 030104 developmental biology medicine.anatomical_structure Mitochondrial biogenesis Mitochondrial permeability transition pore Biochemistry chemistry Hepatocyte Hepatocytes Triazenes |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | Intracellular long-chain acyl-CoA synthetases (ACSL) activate fatty acids to produce acyl-CoA, which undergoes β-oxidation and participates in the synthesis of esterified lipids such as triacylglycerol (TAG). Imbalances in these metabolic routes are closely associated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Triacsin C is one of the few compounds that inhibit TAG accumulation into lipid droplets (LD) by suppressing ACSL activity. Here we report that treatment of primary rat hepatocytes with triacsin C at concentrations lower than the IC50 (4.1 μM) for LD formation: (i) diminished LD number in a concentration-dependent manner; (ii) increased mitochondrial amount; (iii) markedly improved mitochondrial metabolism by enhancing the β-oxidation efficiency, electron transport chain capacity, and degree of coupling - treatment of isolated rat liver mitochondria with the same triacsin C concentrations did not affect the last two parameters; (iv) decreased the GSH/GSSG ratio and elevated the protein carbonyl level, which suggested an increased reactive oxygen species production, as observed in isolated mitochondria. The hepatocyte mitochondrial improvements were not related to either the transcriptional levels of PGC-1α or the content of mTOR and phosphorylated AMPK. Triacsin C at 10 μM induced hepatocyte death by necrosis and/or apoptosis through mechanisms associated with mitochondrial permeability transition pore opening, as demonstrated by experiments using isolated mitochondria. Therefore, triacsin C at sub-IC50 concentrations modulates the lipid imbalance by shifting hepatocytes to a more oxidative state and enhancing the fatty acid consumption, which can in turn accelerate lipid oxidation and reverse NAFLD in long-term therapies. |
| Databáze: | OpenAIRE |
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