Triacsin C reduces lipid droplet formation and induces mitochondrial biogenesis in primary rat hepatocytes

• Published in: Journal of bioenergetics and biomembranes Vol. 49; no. 5; pp. 399 - 411
• Main Authors: Dechandt, Carlos R. P., Zuccolotto-dos-Reis, Felippe H., Teodoro, Bruno G., Fernandes, Anna Maria A. P., Eberlin, Marcos N., Kettelhut, Isis C., Curti, Carlos, Alberici, Luciane C.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2017; Springer Nature B.V
• Subjects: Animal Anatomy; Animal Biochemistry; Animals; Apoptosis; Biochemistry; Bioorganic Chemistry; Biosynthesis; Carbonyl compounds; Carbonyls; Cells, Cultured; Chemistry; Chemistry and Materials Science; Dose-Response Relationship, Drug; Electron transport; Electron transport chain; Esterification; Fatty acids; Fatty liver; Hepatocytes; Hepatocytes - cytology; Histology; Lipid Droplets - drug effects; Lipid metabolism; Lipid Metabolism - drug effects; Lipid peroxidation; Lipids; Liver; Liver diseases; Membrane permeability; Metabolism; Mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondrial permeability transition pore; Morphology; Non-alcoholic Fatty Liver Disease - drug therapy; Organelle Biogenesis; Organic Chemistry; Oxidation; Pathogenesis; Rats; Reactive oxygen species; Rodents; TOR protein; Transcription; Triazenes - pharmacology; Triazenes - therapeutic use; Primary hepatocyte; Mitochondria; Reactive oxygen species; Biogenesis; Acyl-CoA synthetase; Triacsin C
• DOI: 10.1007/s10863-017-9725-9
• ISSN: 0145-479X

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 IC 50 (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-IC 50 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.