1165-P: Alterations of Hepatic Mitochondrial Respiration in Murine Models of Diabetes and Nonalcoholic Fatty Liver Disease (NAFLD)

Abstract

Diabetes mellitus (DM) accelerates progression of fatty liver to nonalcoholic steatohepatitis (NASH) and fibrosis. Mitochondrial function is also frequently impaired in DM, but maybe differently regulated in NAFLD. Thus, we examined hepatic mitochondrial respiration during DM and NAFLD development. Two-days old male C57BL/6j mice received streptozotocin (STZ) or vehicle (placebo, PLC) and then high-fat diet (HFD) or continued regular chow diet (RCD) from week 4 to 12, yielding 4 models (n=8 each): obesity [PLC+HFD], DM [STZ+RCD], NASH [STZ+HFD] and control [PLC+RCD]. Histology and immunohistochemistry were performed to describe NAFLD, including the NAFLD activity score (NAS) derived from steatosis, lobular inflammation and hepatocellular ballooning. High-resolution respirometry and hyperinsulinemic-euglycemic clamps were used to measure mitochondrial respiration and insulin sensitivity. DM and NASH showed >200% higher blood glucose levels (p<0.0001 vs. control). The NAS (mean±SEM) was not different in obese (1.38±0.32; p>0.99), gradually higher in DM (2.50±0.42; p=0.063) and markedly increased in NASH (3.25±0.45; p<0.01) compared to control (1.00±0.27). Main contributors to NAS were steatosis and hepatocellular ballooning in NASH (p<0.001 and p<0.05 vs. control) and hepatocellular ballooning in DM (p<0.01 vs. control). Maximal uncoupled β-oxidation-associated respiration was 1.6-, 1.7-, and 1.9-fold higher in obesity, DM and NASH compared to control (all p<0.01). Mitochondrial density was decreased in both DM and NASH (p<0.05 vs. control), whereas β-oxidation-dependent mitochondrial leak control ratio was not different between all groups. Insulin-stimulated glucose disposal was 44% and 66% lower in obesity and NASH (both p<0.001 vs. control). In conclusion, hyperglycemia and high-fat diet feeding associate with higher respiration but lower content of hepatic mitochondria, which may both contribute to progression of NAFLD. Disclosure B. Dewidar: None. M. Reinadofundo: None. C. Englisch: None. L. Mastrototaro: None. D. Pesta: None. C. Ress: None. I. Esposito: None. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.