225 In contrast, the mean mitochondrial diameter was higher in NASH compared Selleck Fulvestrant with fatty liver.225 Actually, some ultrastructural abnormalities of liver mitochondria could appear well before NASH.225,226 At the moment, there is no definite explanation for the progressive decline of MRC activity during NASH, although some hypotheses can be put forward (Fig. 4). Several MRC complexes including COX are sensitive to ROS and RNS.227,228 In addition, COX can be inhibited by low levels of NO229

and inactivated by 4-hydroxynonenal (4-HNE), a reactive aldehyde generated during lipid peroxidation.230 ROS overproduction within mitochondria could be favored by higher CYP2E1 expression and lower levels of mitochondrial GSH (mtGSH) (Fig. 4). TNF-α is able to impair MRC activity, possibly by inducing hypoxia inducible factor-1α (HIF-1α) and mtDNA damage.5,57,231,232 In addition, Kupffer cell-derived interferons could also impair MRC activity.20 Some lipid derivatives

such as FAs can directly inhibit several enzymes involved in MRC and OXPHOS.12,233,234 Moreover, saturated FAs are able to activate c-Jun N-terminal kinase and trigger INCB024360 in vitro the mitochondrial membrane permeability transition, thus inducing mitochondrial release of cytochrome c and apoptosis.40,235 Reduced adiponectin action in liver could be involved, since this adipokine seems to control MRC activity.236 Plasma adiponectin levels are indeed decreased in NAFLD, and especially in NASH.184,202,237 Moreover, lower hepatic expression of AdipoR1 and AdipoR2 is found in NASH,52,238-240 although other studies reported increased expression.237,241 Another mechanism could be higher activity of forkhead box O1 transcription factor (FoxO1), linked to IR.27 Indeed, FoxO1 activation is able to reduce the content of different MRC polypeptides, possibly by decreasing heme synthesis and impairing PGC1α activity.172 Reduced PGC1α activity could also be secondary to oxidative stress and inflammation, as previously mentioned (Fig. 4).197,198

Numerous drugs are currently tested in order selleck compound to alleviate fatty liver and NASH. These treatments can have different pharmacological effects including improvement of insulin sensitivity, stimulation of lipid oxidation, as well as reduction of DNL, oxidative stress, and inflammation.63,242,243 Regarding mtFAO, some investigations showed that fatty liver could be alleviated by further stimulating the already enhanced capacity for lipid oxidation.75,77 Drug-induced stimulation of mtFAO could have, however, deleterious consequence over the long term if this is not associated with concomitant improvement of MRC. Indeed, an imbalance between mtFAO and MRC activity induces ROS overproduction,5,7,17,63,171 as previously mentioned. Hence, it will be important in the future to find therapeutic strategies able to restore both mtFAO and MRC activity in a coordinated manner.