Endocrine Abstracts

Objective: Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the main hepatic metabolic alterations, often associated with elevated high-fat diet (HFD) consumption. Hepatic lipid accumulation may progress in metabolic alterations involving increased production of reactive oxygen species (ROS). The main intracellular source of ROS are mitochondria, which are also responsible for lipid metabolism. Thus, alterations of mitochondrial machinery are widely recognized as central players in the development of liver steatosis. Thyroid Hormones (TH) are master regulators of energy and lipid homeostasis: 3,5,3′-triiodo-L-thyronine (T3) is known to prevent HFD metabolic side effects by modulating, among several pathways, mitochondrial dynamics, biogenesis and mitophagy, collectively known as mitochondrial quality control (MQC). Recent studies in rodents revealed that 3,5-diiodo-L-thyronine (3,5-T2), a naturally occurring TH metabolite, elicits hypolipidemic effects by increasing the resting metabolic rate without being thyrotoxic. However, until now, literature has been lacking of studies that correlate directly 3,5-T2 to MQC. Here, using a mouse model of HFD-associated NAFLD, we aim to characterize the role of 3,5-T2 administration by focusing on the liver MQC system in a context of metabolic alterations.

Methods: Male mice were fed a 60% fat diet for 19 weeks. During the last 10 days of treatment, 3,5-T2 or T3 were injected at the dose of 200 µg and 15 µg for 100 g body weight, respectively. Factors linked to mitochondrial biogenesis (mtDNA copy number, PGC1α) dynamics (for fusion MFN2 and for fission DRP1) and mitophagy (PINK1 and PARKIN) were investigated. Moreover, analysis of mtDNA oxidative damage and mitochondrial base excision repair (BER) system were performed.

Results: HFD mice developed obesity and liver steatosis. Moreover, they showed a significant accumulation of mtDNA oxidative damage and a downregulation of the BER system. Both iodothyronines showed hypolipidemic actions and reverted the HFD-induced mtDNA damage by stimulating the BER system. As far as the MQC is concerned, only T3 stimulated mitochondrial biogenesis. Both iodothyronines modulated mitochondrial dynamics, with 3,5-T2 stimulating fusion while T3 pushed dynamics balance towards fission. Finally, both iodothyronines strongly increased the PINK1 and PARKIN expression, indicating an activation of mitophagy.

Conclusions: Results represent a first step to shed light on how 3,5-T2 modulates the MQC. Further efforts are needed as 3,5-T2’s ability to regulate these mechanisms could be used for the treatment of HFD-induced hepatic metabolic dysfunctions in the near future.