Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany.
Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory for Insulin Resistance, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
EBioMedicine. 2023 Aug;94:104714. doi: 10.1016/j.ebiom.2023.104714. Epub 2023 Jul 16.
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.
Funding bodies that contributed to this study were listed in the acknowledgements section.
非酒精性脂肪肝（NAFLD）与肝能量代谢紊乱有关，但随着时间的推移，这种变化的发展以及肥胖症或糖尿病相关的机制仍不清楚。
2 天大的雄性 C57BL/6j 小鼠接受链脲佐菌素（STZ）或安慰剂（PLC），然后从第 4 周（W4）开始给予高脂肪（HFD）或普通饮食（RCD），持续至第 8 周（W8）或第 16 周（W16），得到对照[CTRL=PLC+RCD]、糖尿病[DIAB=STZ+RCD]、肥胖症[OBES=PLC+HFD]和糖尿病相关非酒精性脂肪性肝炎[NASH=STZ+HFD]模型。通过高分辨率呼吸测量法测定线粒体呼吸，通过稳定同位素稀释的高胰岛素-正常血糖钳夹技术测定胰岛素敏感的葡萄糖代谢。
NASH 在 W8 时已显示出更高的脂肪变性和 NAFLD 活性，在 W16 时出现肝纤维化（均 p<0.01 比对照）。气球样变增加在 W16 时的 DIAB 和 NASH 中（p<0.01 比对照）。在 W16 时，DIAB、NASH 和 OBES 的胰岛素敏感性分别降低了 47%、58%和 75%（p<0.001 比对照）。OBES 在 W8 时脂肪酸氧化（FAO）相关的去偶呼吸减少，但 DIAB 和 NASH 在 W16 时增加了一倍（p<0.01 比对照），与未折叠蛋白反应（UPR）、氧化应激和某些酶（乙酰辅酶 A 羧化酶 2，Acc2；肉碱棕榈酰转移酶 I，Cpt1a）的肝表达相关。OBES 在 W8 时三羧酸循环（TCA）驱动的呼吸减少，在 DIAB 时增加了一倍（p<0.0001 比对照），这与与脂肪分解相关的基因表达呈正相关。
肝脏线粒体通过增加 FAO 驱动的呼吸来适应各种代谢挑战，这与功能失调的 UPR、全身氧化应激、胰岛素抵抗和改变的脂质代谢有关。在糖尿病模型中，更高的 TCA 相关呼吸反映了线粒体对更大的肝脂质周转率的适应。
参与本研究的资助机构在致谢部分列出。
