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Inhibition of mitochondrial fatty acid oxidation in drug-induced hepatic steatosis

Abstract : Mitochondrial fatty acid oxidation (mtFAO) is a key metabolic pathway required for energy production in the liver, in particular during periods of fasting. One major consequence of drug-induced impairment of mtFAO is hepatic steatosis, which is characterized by an accumulation of triglycerides and other lipid species, such as acyl-carnitines. Actually, the severity of this liver lesion is dependent on the residual mitochondrial β-oxidation flux. Indeed, a severe inhibition of mtFAO leads to microvesicular steatosis, hypoglycemia and liver failure. In contrast, moderate impairment of mtFAO can cause macrovacuolar steatosis, which is a benign lesion in the short term. Because some drugs can induce both microvesicular and macrovacuolar steatosis, it is surmised that severe mitochondrial dysfunction could be favored in some patients by non-genetic factors (e.g., high doses and polymedication), or genetic predispositions involving genes that encode proteins playing directly or indirectly a role in the mtFAO pathway. Example of drugs inducing steatosis include acetaminophen (APAP), amiodarone, ibuprofen, linezolid, nucleoside reverse transcriptase inhibitors, such as stavudine and didanosine, perhexiline, tamoxifen, tetracyclines, troglitazone and valproic acid. Because several previous articles reviewed in depth the mechanism(s) whereby most of these drugs are able to inhibit mtFAO and induce steatosis, the present review is rather focused on APAP, linezolid and troglitazone. These steatogenic drugs are indeed rarely discussed in the literature as regards their ability to impair mtFAO. © 2019 The Third Affiliated Hospital of Sun Yat-sen University
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B. Fromenty. Inhibition of mitochondrial fatty acid oxidation in drug-induced hepatic steatosis. Liver Research, KeAi, 2019, 3 (3-4), pp.157-169. ⟨10.1016/j.livres.2019.06.001⟩. ⟨hal-02443758⟩

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