1816-P: Hepatic Mitochondrial Alterations in a Murine Model of Combined Diabetes and Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is tightly associated with obesity and type 2 diabetes. There is evidence that mitochondrial function is altered in both diseases. Here, we examined hepatic mitochondria during different stages of NAFLD in mice with experimental diabetes.

Two-days old male C57BL/6j mice received 200 µg streptozotocin (STAM) or vehicle (CTRL). From 4 weeks on, they were on high-fat diet for either 4 w or 8 w to induce steatosis or nonalcoholic steatohepatitis (NASH). Liver histology was performed to quantify steatosis, inflammation and fibrosis. Mitochondrial respiration was assessed in liver tissues using high-resolution respirometry with different substrate protocols. Citrate synthase activity (CSA) served as a surrogate marker for mitochondrial content. Immunoblotting was used to quantify mitochondrial complexes.

Compared to CTRL, STAM mice showed 140% and 54% higher blood glucose and liver/body weight. Hepatic steatosis increased from 2% to 15% at 4 w and decreased to 5% at 8 w. NAFLD activity score was 0.25 in CTRL and increased to 2.5 at 4 w and 8 w in STAM. STAM mice had lower CSA, indicating lower mitochondrial content at both time points, whereas complex III protein content was decreased only at 8 w. Of note, maximal uncoupled β-oxidation-associated respiration, normalized to CSA, was 1.7- and 2.7-fold higher in livers of STAM mice after 4 w and 8 w, respectively, as compared to CTRL.

In conclusion, combined diabetes and NASH decreased mitochondrial content but resulted in greater maximal oxidative capacity per mitochondrion, possibly reflecting an adaptation of mitochondrial function during NAFLD progression in adult mice.