Impaired Hepatic Mitochondrial Capacity in Nonalcoholic Steatohepatitis Associated With Type 2 Diabetes
Research Design and Methods: We therefore examined obese persons with histologically proven NASH and without (OBE; n=30, body mass index 52±9 kg/m2) or with type 2 diabetes (T2D; n=15, 51±7 kg/m2) as well as healthy humans without liver disease (CON; n=14, 25±2 kg/m2). Insulin sensitivity was measured by euglycemic-hyperinsulinemic clamps with D-[6,6-2H2]glucose. Liver biopsies were used for assessing mitochondrial capacity by high-resolution respirometry and protein expression.
Results: T2D and OBE had comparable hepatic fat content, lobular inflammation and fibrosis. Oxidative capacity in liver tissue normalized for citrate synthase activity was 59% greater in OBE than in CON, whereas T2D presented with 33% lower complex II-linked oxidative capacity than OBE and higher H2O2 production than CON. Interestingly, people with NASH and hepatic fibrosis score ≥ 1 (F1+) had lower oxidative capacity and antioxidant defense than those without fibrosis (F0).
Conclusion: Loss of hepatic mitochondrial adaptation characterizes NASH and type 2 diabetes or hepatic fibrosis and may thereby favor accelerated disease progression.