Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Biomed Pharmacother. 2024 May;174:116595. doi: 10.1016/j.biopha.2024.116595. Epub 2024 Apr 19.
Fatty liver is the earliest response of the liver to excessive alcohol consumption. Previously we identified that chronic alcohol administration increases levels of stomach-derived hormone, ghrelin, which by reducing circulating insulin levels, ultimately contributes to the development of alcohol-associated liver disease (ALD). In addition, ghrelin directly promotes fat accumulation in hepatocytes by enhancing de novo lipogenesis. Other than promoting ALD, ghrelin is known to increase alcohol craving and intake. In this study, we used a ghrelin receptor (GHSR) knockout (KO) rat model to characterize the specific contribution of ghrelin in the development of ALD with emphasis on energy homeostasis. Male Wistar wild type (WT) and GHSR-KO rats were pair-fed the Lieber-DeCarli control or ethanol diet for 6 weeks. At the end of the feeding period, glucose tolerance test was conducted, and tissue samples were collected. We observed reduced alcohol intake by GHSR-KOs compared to a previous study where WT rats were fed ethanol diet ad libitum. Further, when the WTs were pair-fed to GHSR-KOs, the KO rats exhibited resistance to develop ALD through improving insulin secretion/sensitivity to reduce adipose lipolysis and hepatic fatty acid uptake/synthesis and increase fatty acid oxidation. Furthermore, proteomic data revealed that ethanol-fed KO exhibit less alcohol-induced mitochondrial dysfunction and oxidative stress than WT rats. Proteomic data also confirmed that the ethanol-fed KOs are insulin sensitive and are resistant to hepatic steatosis development compared to WT rats. Together, these data confirm that inhibiting ghrelin action prevent alcohol-induced liver and adipose dysfunction independent of reducing alcohol intake.
脂肪肝是肝脏对过量饮酒的最早反应。此前我们发现，慢性酒精摄入会增加胃源性激素——ghrelin 的水平，ghrelin 通过降低循环胰岛素水平，最终导致酒精相关性肝病 (ALD) 的发生。此外，ghrelin 通过增强从头合成脂肪，直接促进肝细胞脂肪堆积。除了促进 ALD 外，ghrelin 还被认为会增加对酒精的渴望和摄入。在这项研究中，我们使用 ghrelin 受体 (GHSR) 敲除 (KO) 大鼠模型来描述 ghrelin 在 ALD 发展中的特定作用，重点是能量平衡。雄性 Wistar 野生型 (WT) 和 GHSR-KO 大鼠分别用 Lieber-DeCarli 对照或乙醇饮食喂养 6 周。在喂养期结束时，进行葡萄糖耐量试验，并收集组织样本。与之前 WT 大鼠自由摄取乙醇饮食的研究相比，GHSR-KO 大鼠的酒精摄入量减少。此外，当 WT 大鼠与 GHSR-KO 大鼠进行配对喂养时，KO 大鼠通过改善胰岛素分泌/敏感性来减少脂肪分解和肝脏脂肪酸摄取/合成，增加脂肪酸氧化，从而抵抗 ALD 的发生。此外，蛋白质组学数据显示，与 WT 大鼠相比，乙醇喂养的 KO 大鼠表现出较少的酒精诱导的线粒体功能障碍和氧化应激。蛋白质组学数据还证实，与 WT 大鼠相比，乙醇喂养的 KO 大鼠对胰岛素敏感，并且抵抗肝脂肪变性的发展。总之，这些数据证实，抑制 ghrelin 的作用可预防酒精引起的肝脏和脂肪组织功能障碍，而与减少酒精摄入无关。
