Experimental investigations also pointed to a progressive reduction of MRC activity during NAFLD, which could impair energy output

and aggravate ROS overproduction by the damaged MRC. Hence, developing drugs that further increase mtFAO and restore MRC activity in a coordinated manner could ameliorate steatosis, but also necroinflammation and fibrosis by reducing oxidative stress. In contrast, physicians should be aware that numerous drugs in the current pharmacopoeia are able to induce mitochondrial dysfunction, which could aggravate NAFLD in some patients. (Hepatology 2013;58:1497–1507) Most obese people develop fatty liver, which is characterized by the presence of large vacuoles of lipids (mainly triacylglycerol) within the cytosol. Although fatty liver is a benign condition, it can progress in the long term Everolimus to nonalcoholic steatohepatitis (NASH) in 10% to 20% of patients. In addition to macrovacuolar steatosis, NASH is characterized by microvesicular steatosis, inflammation, fibrosis, and the presence of hepatocyte injury in the forms of ballooning and apoptosis.[1, 2] Even though NASH is not by itself a severe hepatic lesion, it can progress to cirrhosis and liver cancer.[3] Selleck GSK458 Collectively, the large spectrum of conditions ranging from fatty liver to NASH is referred to as nonalcoholic liver disease (NAFLD). In order to better assess the histological changes in NAFLD, in particular

during therapeutic trials, the Pathology Committee of the NASH Clinical Research Network designed and validated see more the NAFLD activity score (NAS) system, derived from the sum of individual scores for steatosis, lobular inflammation, and hepatocellular ballooning.[2, 4] During NAFLD, several metabolic adaptations are set up in order to curb fat accumulation. In particular, increased mitochondrial fatty acid oxidation (mtFAO) plays a significant role, but this adaptation secondarily induces oxidative stress.5,6 This could participate in the progressive reduction in mitochondrial respiratory chain (MRC) activity, which further aggravates oxidative

stress and impairs energy output.5-7 Before considering mitochondrial adaptations and dysfunctions in NAFDL, we will recall key features of lipid and carbohydrate homeostasis and the role of mitochondria in FAO and energy production. Hepatic fatty acids (FAs) can be: (1) taken up from the pool of plasma nonesterified FAs (NEFAs) released by white adipose tissue (WAT); (2) generated from the hydrolysis of chylomicrons coming from the intestine; and (3) synthesized through de novo lipogenesis (DNL).8,9 Depending on the nutritional/hormonal status, hepatic FAs either enter mitochondria to undergo β-oxidation or are esterified into triacylglycerol (TAG), usually secreted in plasma as very low density lipoproteins (VLDL).10 Alternatively, the TAG molecules can accumulate as fat droplets surrounded by proteins belonging to the PAT family.