Abstract
Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug-induced steatosis.Methods: Human HepG2 cells were treated with drugs and changes in miRNA levels were measured by microarray and qRT-PCR. Drug-induced fat accumulation in HepG2 was analyzed by high-content screening and enzymatic methods. miRNA biomarkers were also analyzed in the sera of 44 biopsy-proven NAFLD patients and in 10 controls.Results: We found a set of 10 miRNAs [miR-22-5p, -3929, -24-2-5p, -663a, -29a-3p, -21 (5p and 3p), -27a-5p, -1260 and -202-3p] that were induced in human HepG2 cells and secreted to the culture medium upon incubation with model steatotic drugs (valproate, doxycycline, cyclosporin A and tamoxifen). Moreover, cell exposure to 17 common drugs for NAFLD patients showed that some of them (e.g., irbesartan, fenofibrate, and omeprazole) also induced these miRNAs and increased intracellular triglycerides, particularly in combinations. Finally, we found that most of these miRNAs (60%) were detected in human serum, and that NAFLD patients under fibrates showed both induction of these miRNAs and a more severe steatosis grade.Conclusion: Steatotic drugs induce a common set of hepatic miRNAs that could be used in drug screening during preclinical development. Moreover, most of these miRNAs are serum circulating biomarkers that could become useful in the diagnosis of iatrogenic steatosis.
Highlights
Drug-induced liver injury is the major reason for drug failure in clinical trials and for the withdrawal of commercialized drugs (Giacomini et al, 2007)
Unsupervised principal component analysis (PCA) analysis showed a separation between the dimethyl sulfoxide (DMSO) and cyclosporin A (CYCA) groups (Figure 1)
Results indicate that non-alcoholic fatty liver disease (NAFLD) patients under fibrate therapy have increased circulating levels of miRNA biomarkers of druginduced steatosis, as well as more severe fatty liver. These miRNAs are independent of serum TG levels. This is the first study searching for miRNA biomarkers of drug-induced hepatic steatosis in humans, which attempts to analyze the contribution of common drugs to NAFLD
Summary
Drug-induced liver injury is the major reason for drug failure in clinical trials and for the withdrawal of commercialized drugs (Giacomini et al, 2007). Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and predictive biomarkers are essential. These could be relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. Conclusion: Steatotic drugs induce a common set of hepatic miRNAs that could be used in drug screening during preclinical development Most of these miRNAs are serum circulating biomarkers that could become useful in the diagnosis of iatrogenic steatosis
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