Dewidar 2023 EBioMedicine
| Dewidar B, Mastrototaro L, Englisch C, Ress C, Granata C, Rohbeck E, Pesta D, Heilmann G, Wolkersdorfer M, Esposito I, Reina Do Fundo M, Zivehe F, Yavas A, Roden M (2023) Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases. https://doi.org/10.1016/j.ebiom.2023.104714 |
» EBioMedicine 94:104714. PMID: 37454552 Open Access
Dewidar Bedair, Mastrototaro Lucia, Englisch Cornelia, Ress Claudia, Granata Cesare, Rohbeck Elisabeth, Pesta Dominik, Heilmann Geronimo, Wolkersdorfer Martin, Esposito Irene, Reina Do Fundo Michelle, Zivehe Fariba, Yavas Aslihan, Roden Michael (2023) EBioMedicine
Abstract: Disturbed hepatic energy metabolism contributes to non-alcoholic fatty liver (NAFLD), but the development of changes over time and obesity- or diabetes-related mechanisms remained unclear.
Two-day old male C57BL/6j mice received streptozotocin (STZ) or placebo (PLC) and then high-fat (HFD) or regular chow diet (RCD) from week 4 (W4) to either W8 or W16, yielding control [CTRL = PLC + RCD], diabetes [DIAB = STZ + RCD], obesity [OBES = PLC + HFD] and diabetes-related non-alcoholic steatohepatitis [NASH = STZ + HFD] models. Mitochondrial respiration was measured by high-resolution respirometry and insulin-sensitive glucose metabolism by hyperinsulinemic-euglycemic clamps with stable isotope dilution.
NASH showed higher steatosis and NAFLD activity already at W8 and liver fibrosis at W16 (all p < 0.01 vs CTRL). Ballooning was increased in DIAB and NASH at W16 (p < 0.01 vs CTRL). At W16, insulin sensitivity was 47%, 58% and 75% lower in DIAB, NASH and OBES (p < 0.001 vs CTRL). Hepatic uncoupled fatty acid oxidation (FAO)-associated respiration was reduced in OBES at W8, but doubled in DIAB and NASH at W16 (p < 0.01 vs CTRL) and correlated with biomarkers of unfolded protein response (UPR), oxidative stress and hepatic expression of certain enzymes (acetyl-CoA carboxylase 2, Acc2; carnitine palmitoyltransferase I, Cpt1a). Tricarboxylic acid cycle (TCA)-driven respiration was lower in OBES at W8 and doubled in DIAB at W16 (p < 0.0001 vs CTRL), which positively correlated with expression of genes related to lipolysis.
Hepatic mitochondria adapt to various metabolic challenges with increasing FAO-driven respiration, which is linked to dysfunctional UPR, systemic oxidative stress, insulin resistance and altered lipid metabolism. In a diabetes model, higher TCA-linked respiration reflected mitochondrial adaptation to greater hepatic lipid turnover. • Keywords: Fatty liver, High-resolution respirometry, Insulin resistance, Mitochondria, Type 1 diabetes, Type 2 diabetes, Unfolded protein response • Bioblast editor: Plangger M • O2k-Network Lab: DE Duesseldorf Roden M, DE Cologne Pesta D
Labels: MiParea: Respiration
Pathology: Diabetes, Obesity, Other
Organism: Mouse Tissue;cell: Skeletal muscle, Liver Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET
Pathway: F, N, NS, ROX
HRR: Oxygraph-2k
2023-07
