Considerable ambiguity exists in the literature regarding the role of hepatic mitochondrial dysfunction in the pathological progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) and fibrosis. To investigate this relationship, liver biopsies were obtained from patients with morbid obesity undergoing bariatric surgery [n=110, age 44.7±11.7 y, weight 136.3±25.5 kg, BMI 48.7±7.4 kg/m2, AST 35.6±32.1 U/L, ALT 41.0±35.6 U/L, NAFLD activity score 3±2 (NAS; liver injury score: steatosis, ballooning, and inflammation; range: 0-8), fibrosis score 0.5±1.0 (range: 0-4), glucose 104±33 mg/dL] and assessments of mitochondrial function and turnover performed. Data were clustered into four groups based on NAS (No Disease, NAS=0, n=13; Mild NAS=1-2, n=28; Moderate NAS=3-4, n=41; and Severe NAS≥5, n=28). Complete hepatic mitochondrial oxidation of palmitate to CO2 was reduced by ∼50% with Moderate and Severe NAS vs. no disease (p<0.05). This was accompanied by a 50% decrease in hepatic β-HAD activity in all groups with NAFLD (p<0.01), without any differences in citrate synthase activity (p>0.05). In addition to reduced hepatic mitochondrial function, elevated NAS was associated with reduced hepatic mitochondrial biogenesis (PGC1α, SIRT1, PPARα, and AMPKα1 mRNA; p<0.05) and mitochondrial turnover (BNIP3, PARKIN mRNA; p<0.05) markers. Furthermore, hepatic mitochondrial H2O2 emission was elevated in Severe NAS (p<0.01) and positively related to lobular inflammation (r=0.336, p<0.01) and hepatocellular ballooning (r=0.379, p<0.001). Here, we provide novel insight into the relationship between NAFLD severity and hepatic mitochondrial dysfunction. Our findings suggest that compromised hepatic mitochondrial fatty acid metabolism and reduced hepatic mitochondrial biogenesis/turnover may be linked to NAFLD progression in patients with morbid obesity.
M.P. Moore: None. R. Cunningham: None. G.M. Meers: None. S.A. Johnson: None. A.A. Wheeler: None. R. Ganga: None. J. Pitt: None. N. Spencer: None. A.A. Diaz-Arias: None. A. Swi: None. J.A. Ibdah: None. E.J. Parks: None. R.S. Rector: None.
National Institutes of Health (R01DK113701); U.S. Department of Veterans Affairs (I01BX003271)