Resumen de SGAs induced mitochondrial dysfunction enhances its liver toxicity
The prevalence of metabolic syndrome (MetS) is increasing dramatically. Recent studies have illustrated that long-term treatment with second-generation antipsychotics (SGA), the first-line treatment for schizophrenia, with which between 1 and 2% of the total population is treated chronically, depending on the country, it strongly increases the risk of developing metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). It is therefore necessary to identify factors that allow evaluating the risk associated with its chronic intake for the development of liver disease before starting treatment with a drug.
It has been proposed that reactive oxygen species (ROS), which are produced as a consequence of hepatic catabolism of drugs, may contribute to the development of liver disease. The systems responsible for drug catabolism and ROS detoxification are strongly regulated at the transcriptional level by the transcriptional coactivator PGC-1α and depend largely on active mitochondrial metabolism. Recent studies show the frequent accumulation of drugs in mitochondrial membranes and their interference with mitochondrial activity, suggesting that this may be a key factor in chronic liver toxicity resulting from drug administration.
Taking into account the relevance of the problem, in particular for the case of SGAs, we decided to evaluate the contribution of mitochondrial function to the development of NAFLD induced by treatment with SGAs in order to determine if it can serve as a risk predictor. Two widely used SGAs with different metabolic profiles were selected as models. Olanzapine (Ola), very obesogenic and sedative, and Aripiprazole (Ari), whose consumption in humans is not associated with weight gain or sedation.
To this end, we studied the effect of short- and long-term treatment with Ari and Ola in wild-type and PGC-1α-deficient mice, a model of mitochondrial dysfunction, and in human volunteers, in short-term treatments.
Ari and Ola were found to accumulate in mitochondrial membranes isolated from the liver of treated mice, and inhibit respiration in mice, while a generalized reduction in complex I protein expression was observed of ETC in the liver of mice treated for 5 days with Ari, an indicator of loss of mitochondrial functionality.
In line with these observations, treatment for 6 months with Ari and Ola resulted in weight gain, glucose intolerance, and accumulation of fat in the liver. However, progression to NAFLD, with the presence of fibrosis, was only significant in PGC-1α-deficient mice treated with Ari, confirming the relevance of mitochondrial function in SGAs-induced liver toxicity, especially in response to treatment with Ari.
Human respiration and gene expression studies also confirmed the presence of mitochondrial dysfunction in Ari and Ola-treated PBMCs, and suggested increased Ari toxicity and compensatory capacity in response to Ola, possibly through increased anaerobic catabolism of Ola carbohydrates.
These results suggest that the evaluation of mitochondrial function in patients before treatment and of the effect of drugs on the mitochondria can be used to predict the risk of developing liver disease derived from chronic drug intake. In addition, they point out the greater toxicity of Ari compared to Ola, when up to now Ari has been considered a safer drug metabolically speaking as it does not induce weight gain or sedation in subjects treated with the drug. Finally, the data obtained highlight the protective role of PGC-1α in liver function and against drug-induced toxicity.
