| Abstract: | BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) and its more advanced form steatohepatitis (NASH) is associated with obesity and is an independent risk factor for cardiovascular, liver-related, and all-cause mortality. Available human data examining hepatic mitochondrial fatty acid oxidation and hepatic mitochondrial turnover in NAFLD and NASH are scant. To investigate this relationship, liver biopsies were obtained from patients with obesity undergoing bariatric surgery and data clustered into four groups based on hepatic histopathological classification: Control (no disease), NAFL (steatosis only), Borderline-NASH (steatosis with lobular inflammation or hepatocellular ballooning), and Definite-NASH (steatosis, lobular inflammation, and hepatocellular ballooning). RESULTS: Hepatic mitochondrial complete fatty acid oxidation to CO2 and the rate limiting enzyme in β-oxidation (β-hydroxyacyl-CoA dehydrogenase activity) were reduced by ~40-50% with D-NASH compared with Control. This corresponded with increased hepatic mitochondrial reactive oxygen species production, as well as dramatic reductions in markers of mitochondrial biogenesis, autophagy, mitophagy, fission and fusion in NAFL and NASH. CONCLUSIONS: These findings suggest that compromised hepatic fatty acid oxidation and mitochondrial turnover are intimately linked to increasing NAFLD severity in patients with obesity. |
