[5] However, any significant reduction of MRC activity can induce

ROS overproduction, thus triggering oxidative stress.5,7,17 Thirteen MRC polypeptides are encoded by mitochondrial DNA (mtDNA), a small circular DNA present in several copies within the matrix (Fig. 1),12,17 and sensitive to oxidative damage.5,19 The oxidative attack of mtDNA can generate 8-hydroxydeoxyguanosine, point mutations, and deletions. In addition to ROS, reactive nitrogen species (RNS) and lipid peroxidation products are able to damage mtDNA.20,21 Irreparable damages to mtDNA can induce its Navitoclax manufacturer degradation by nucleases, thus leading to mtDNA depletion.19,22 Mitochondria also contain nuclear-encoded proteins required for mtDNA maintenance including mitochondrial transcription factor A (Tfam) involved in mtDNA transcription and mtDNA repair enzymes. Importantly, expression of Tfam and several MRC polypeptides is controlled by nuclear respiratory factors 1 and 2 (NRF1 and 2). Moreover, PGC1α interacts in the nucleus with NRF1, NRF2, and PPARα in order to coordinate the expression of nuclear genes governing mitochondrial function and biogenesis.16,23 Insulin resistance (IR) in muscle and WAT plays a central role in the pathogenesis of fatty liver (Fig. 2).8,24

In particular, IR in WAT favors TAG lipolysis, thus leading to uncontrolled NEFA release into the circulation.9,25 Because NEFA uptake by the hepatocytes is concentration-dependent, IR greatly increases the amount of NEFAs entering the liver.26 FAs are also click here synthesized more actively in liver during IR (Fig. Pyruvate dehydrogenase lipoamide kinase isozyme 1 2), since hyperinsulinemia overactivates SREBP1c.5,26 Excess of fat in liver can in turn cause IR in this organ.5,27 Intriguingly, IR in liver only affects some, but not all, insulin-sensitive metabolic pathways.28,29 For instance, whereas

gluconeogenesis is less inhibited by insulin, DNL is overactivated by hyperinsulinemia.5,29 However, the mechanisms responsible for mixed hepatic insulin sensitivity and resistance are not fully understood, although different hypotheses have been put forward.29-34 Hyperglycemia contributes to fatty liver during type 2 diabetes, in particular by overactivating ChREBP.5,35 Furthermore, high glucose levels promote ROS overproduction within hepatocytes, thus favoring oxidative stress and mitochondrial dysfunction.5,36 Type 2 diabetes can also be associated with high glucagonemia, which contributes to hyperglycemia and ketoacidosis.37 High glucagonemia could also impair hepatic function,38 possibly by increasing the expression of cytochrome P450 2E1 (CYP2E1).39 At least three major events are involved in the progression of fatty liver to NASH, including overproduction of ROS and RNS, lipotoxicity, and increased release of proinflammatory and profibrogenic cytokines.