147 Higher LCFA oxidation was found in liver mitochondria and peroxisomes isolated from ob/ob mice (Table 1).57,149,152,153 Increased mtFAO capacity in ob/ob liver was associated with enhanced CPT activity and/or CPT1 expression,109,152,154 and higher expression PI3K Inhibitor high throughput screening of other mtFAO enzymes.119,154-157 Moreover,
PPARα expression is augmented in ob/ob liver,109,154,158 although some studies found normal or reduced PPARα expression.157,159 In db/db mice, mtFAO was enhanced in one study,160 whereas total hepatic FAO was decreased in another report (Table 1).161 PPARα expression in db/db liver was either increased,109,162,163 unchanged,164-166 or decreased.167,168 In ob/ob mice, hepatic mitochondrial oxidation of glutamate (providing electrons to complex I) was either unchanged or increased, whereas that of succinate (providing electrons to complex II) was consistently enhanced (Table 1).152,169-171 In db/db liver, glutamate and succinate-driven mitochondrial respiration was increased.170 However, the activity of different hepatic MRC complexes was significantly reduced in ob/ob57,58,172,173 and db/db mice (Table 1).172,174,175 These data, reporting higher (or normal) rates of oxygen consumption and reduced activity of different MRC complexes, are not necessarily www.selleckchem.com/products/cobimetinib-gdc-0973-rg7420.html discordant. Indeed, mitochondrial respiration is significantly impaired only when
the activity of MRC complexes is severely inhibited.176 An important ATP depletion was observed in ob/ob liver,171,177 which could be due to OXPHOS uncoupling.171,178 Finally, electron microscopic analysis of ob/ob liver showed enlarged mitochondria with abnormal cristae organization
and granular matrix, but without crystalline inclusions.153 Taken together, these data in ob/ob and db/db indicated higher MCE公司 oxidative capacity of liver mitochondria with different respiratory substrates including FAs, but impaired activity of different MRC complexes. These mitochondrial alterations are leading to ROS overproduction since more substrate-derived electrons are entering the MRC and leak from complexes I and III.5,7,17,63,171 Increased hepatic mtFAO in ob/ob and db/db mice was associated with higher, normal, or even reduced PPARα expression. The exact reasons of this discrepancy are not known, but differences in age and diet could be involved. Three studies assessed whole-body 13C-octanoate oxidation in patients with NASH. In one study, patients with NASH had higher whole-body 13C-octanoate oxidation when compared to the controls,72 whereas the other studies showed no difference (Table 1).179,180 Using indirect calorimetry and KB production as surrogate markers of mtFAO, other investigations found higher fat oxidation in patients with NASH.42,71,97,181 In contrast, reduced PPARα mRNA expression was found in patients with NASH compared to patients with simple fatty liver,111,113,182 thus suggesting that PPARα induction progressively declines when fatty liver progresses to NASH.