The role of hepatic mitochondrial function and mitochondrial turnover in the development and progression of nonalcoholic fatty liver disease and lifestyle modifications to treat the disease

Abstract

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. Further, the mechanistic effects of weight loss induced by diet and exercise on histological outcomes of NAFLD/NASH are poorly understood. Data from this dissertation demonstrates a reduction in hepatic mitochondrial fatty acid oxidation and the rate limiting enzyme in [beta]-oxidation ([beta]-hydroxyacyl-CoA dehydrogenase activity) by ~50 percent in individuals with moderate [NAFLD activity score (NAS) = 3-4]; and severe (NAS [greater than or equal to] 5) NAFLD compared with no disease (NAS = 0). This coincided with increased hepatic mitochondrial reactive oxygen species production, as well as significant reductions in markers of mitochondrial biogenesis, autophagy, mitophagy, fission and fusion. Active treatment consisting of caloric restriction and exercise training to induce weight loss resulted in significant reductions in total NAS, intrahepatic lipid content, and hepatocellular ballooning. Changes in NAS significantly correlated with reduced body fat mass and increased aerobic capacity. Interestingly, hepatic fatty acid oxidation did not change at follow-up in response to weight loss induced by diet and exercise and did not correlate with changes in NAS or its components. The findings presented here suggest that compromised hepatic mitochondrial fatty acid oxidation and mitochondrial turnover are intimately linked to increasing NAFLD severity in humans with obesity. Further, lifestyle changes aimed at promoting weight loss through dietary caloric restriction and exercise leads to histological improvement sin NAFLD outcomes that are linked to improvements in body composition and aerobic capacity.