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

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 b-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.

MoLrp1-mediated signaling induces nuclear accumulation of MoMsn2 to facilitate fatty acid oxidation for infectious growth of the rice blast fungus

Fatty acid b-oxidation is critical for fatty acid degradation and cellular development.In the rice blast fungus Magnaporthe oryzae,fatty acid b-oxidation is reported to be important mainly for turgor generation in the appressorium.However,the role of fatty acid b-oxidation during invasive hyphal growth is rarely documented.We demonstrated that blocking peroxisomal fatty acid b-oxidation impaired lipid droplet(LD)degradation and infectious growth of M.oryzae.We found that the key regulator of pathogenesis,MoMsn2,which we identified previously,is involved in fatty acid b-oxidation by targeting MoDCI1(encoding dienoyl-coenzyme A[CoA]isomerase),which is also important for LD degradation and infectious growth.Cytological observations revealed that MoMsn2 accumulated from the cytosol to the nucleus during early infection or upon treatment with oleate.We determined that the low-density lipoprotein receptor-related protein MoLrp1,which is also involved in fatty acid b-oxidation and infectious growth,plays a critical role in the accumulation of MoMsn2 from the cytosol to the nucleus by activating the cyclic AMP signaling pathway.Our results provide new insights into the importance of fatty acid oxidation during invasive hyphal growth,which is modulated by MoMsn2 and its related signaling pathways in M.oryzae.