**5.3 Hepatic FAs oxidation**

Hepatic FAs oxidation (FAO), commonly induced by low-circulating glucose concentrations, occurs mainly in the mitochondria to provide energy, which is controlled by PPARα [75]. FAs are transported into the mitochondria *via* CPT1 situated in the outer mitochondrial membrane and preferably metabolized *via* peroxisomal β-oxidation.

The action of PPARα is upregulated by FAs and glucagon and suppressed by insulin. PPARα activation could induce the transcription of FAO-related genes in the mitochondria, peroxisomes, and cytochromes, which therefore reduces the level of hepatic lipids [76]. PPARα knockout could lead to hepatic steatosis in mice, emphasizing the critical role of PPARα in promoting FAO and preventing hepatic lipid accumulation [77]. However, studies of FAO are conflicting in patients with NAFLD. Increased FAO might be a compensatory response in NAFLD to reduce the lipids accumulation and lipotoxicity, which could also produce ROS to induce oxidative stress. Compared to patients with less severe steatosis or non-steatotic controls, the expression of β-oxidation-related genes was higher in patients with more severe steatosis [78]. Combination of stable isotope-labeled tracers identified that fasting mitochondrial oxidation was twice as high in patients with NAFLD than in those without NAFLD [79]. FAs oxidation and its oxidative damage to mitochondrial DNA occur in NAFLD, which could further impair mitochondrial function, resulting in a vicious cycle and alteration of mitochondrial ultrastructure [79]. Study found that FAO and the rate-limiting enzyme in β-oxidation of hepatic mitochondrial were reduced in definite NASH compared with no disease controls [80]. In addition, FAs-metabolizing enzyme located in the cytochromes such as CYP2E1 and CYP4A11 elevates in the context of NAFLD. Increased FAO in cytochromes may induce excess accumulation of ROS and exacerbation of hepatic oxidative stress, which could lead to hepatic steatosis.
