Impaired Hepatic Mitochondrial Capacity in Nonalcoholic Steatohepatitis Associated With Type 2 Diabetes

Objective: Persons with type 2 diabetes are at higher risk of progression of non-alcoholic fatty liver (steatosis) to steatohepatitis (NASH), fibrosis and cirrhosis. Obese humans adapt their hepatic metabolism by upregulation of mitochondrial capacity, which may be lost during the progression of steatosis. However, the role of type 2 diabetes for hepatic mitochondrial function in NASH remains unclear.

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.