79 Increased hepatic FAO and/or higher expression of FAO genes were not always found in patients and rodents with fatty liver (Table 1).71,82-86 Different factors could explain this discrepancy: First, different methods were used to assess FAO. For instance, some studies reported increased mtFAO in liver homogenates but normal (or reduced) mtFAO in isolated mitochondria, which could be explained by higher mitochondrial mass.64,74,76 Second, mitochondrial adaptations could vary during the development of NAFLD and IR79,87,88 and could also depend on nutritional factors such as dietary lipids89-92 and fructose.83,93 Finally, the capacity of liver mitochondria to oxidize substrates and to adapt
to nutrient excess is under complex genetic control in mice94,95 and in human, as mentioned previously. The
precise mechanisms responsible for higher mtFAO in NAFLD are poorly understood but several hypotheses can be put forward (Fig. 3): Increased PD98059 levels of NEFAs. When IR occurs in WAT, the mere expansion of the pool of NEFAs in plasma can augment the global rate of mtFAO in liver.96,97 Higher FA levels in liver can also activate PPARα, as discussed later on. Higher production of hormones and cytokines. mtFAO in liver could be favored by increased levels of hormones and other circulating factors such as leptin,5,98-100 FGF21,101-104 and interleukin 6 (IL6).105,106 Hepatic IR. Little is known regarding the impact of IR on mtFAO. However, some investigations suggest that FAO and ketogenesis are overall up-regulated during IR,68,71 although insulin-induced down-regulation of lipid oxidation can still occur in the insulin-resistant fatty liver.13,68,71,107 Selleckchem STI571 The paradoxical coexistence of increased FAO and higher DNL in fatty liver will be discussed below. Activation of hepatic PPARα. Numerous studies showed Protein tyrosine phosphatase increased expression of PPARα in fatty liver.73,86,108-113 Different cues such as FAs, leptin, and IL6 could activate PPARα and its target genes involved in mtFAO (CPT1, MCAD), peroxisomal FAO (acyl-CoA oxidase),
and VLDL production (microsomal triglyceride transfer protein).114-116 In contrast, hepatic PPARα expression was either unchanged, or even reduced, in some investigations.88,101,117,118 Increased hepatic CPT1 expression and activity. Hepatic CPT1 expression and/or activity is often enhanced in rodents and patients during NAFLD and obesity.56,75,77,86,101,108,110,119-121 Increased CPT1 expression can be due to PPARα activation, but some studies also suggest a PPARα-independent mechanism.5,56 Expression and/or activity of other mtFAO enzymes can be increased during fatty liver, such as different dehydrogenases.108,111,120,122,123 Since CPT1 activity is inhibited by the lipogenic precursor malonyl-CoA, there are at least two hypotheses that can explain how CPT1 could still be active with high malonyl-CoA levels. First, hepatic CPT1 could be less inhibitable by this endogenous metabolite.