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

Author(s)

Dechandt, Carlos R. P. ^[1] ; Zuccolotto-dos-Reis, Felippe H. ^[1] ; Teodoro, Bruno G. ^[1] ; Fernandes, Anna Maria A. P. ^[2] ; Eberlin, Marcos N. ^[2] ; Kettelhut, Isis C. ^[3] ; Curti, Carlos ^[1] ; Alberici, Luciane C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Estadual Campinas, Inst Quim, Lab Thomson Espectrometria Massas, Rua Sergio Buarque Holanda S-N, BR-13083970 Campinas, SP - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Journal of Bioenergetics and Biomembranes; v. 49, n. 5, p. 399-411, OCT 2017.
• Web of Science Citations: 2

Abstract

Intracellular long-chain acyl-CoA synthetases (ACSL) activate fatty acids to produce acyl-CoA, which undergoes beta-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 mu M) for LD formation: (i) diminished LD number in a concentration-dependent manner; (ii) increased mitochondrial amount; (iii) markedly improved mitochondrial metabolism by enhancing the beta-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-1 alpha or the content of mTOR and phosphorylated AMPK. Triacsin C at 10 mu M 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. (AU)

• FAPESP's process: 10/17259-9 - Studies on mechanisms of mitochondrial uncoupling by non-esterified fatty acids as a strategy for prevention / treatment of obesity
• Grantee: Luciane Carla Alberici
• Support Opportunities: Research Grants - Young Investigators Grants