Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
Int J Obes (Lond). 2020 Feb;44(2):475-487. doi: 10.1038/s41366-019-0420-2. Epub 2019 Jul 19.
BACKGROUND/OBJECTIVES: Bariatric surgery improves nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain elusive. We evaluated the potential role of ghrelin isoforms in the amelioration of hepatic inflammation after sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB).
SUBJECTS/METHODS: Plasma ghrelin isoforms were measured in male Wistar rats (n = 129) subjected to surgical (sham operation, sleeve gastrectomy, or RYGB) or dietary interventions [fed ad libitum a normal (ND) or a high-fat diet (HFD) or pair-fed diet]. The effect of acylated and desacyl ghrelin on markers of inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in primary rat hepatocytes under palmitate-induced lipotoxic conditions was assessed.
Plasma desacyl ghrelin was decreased after sleeve gastrectomy and RYGB, whereas the acylated/desacyl ghrelin ratio was augmented. Both surgeries diminished obesity-associated hepatic steatosis, CD68- and apoptotic cells, proinflammatory JNK activation, and Crp, Tnf, and Il6 transcripts. Moreover, a postsurgical amelioration in the mitochondrial DNA content, oxidative phosphorylation (OXPHOS) complexes I and II, and ER stress markers was observed. Specifically, following bariatric surgery GRP78, spliced XBP-1, ATF4, and CHOP levels were reduced, as were phosphorylated eIF2α. Interestingly, acylated and desacyl ghrelin inhibited steatosis and inflammation of palmitate-treated hepatocytes in parallel to an upregulation of OXPHOS complexes II, III, and V, and a downregulation of ER stress transducers IRE1α, PERK, ATF6, their downstream effectors, ATF4 and CHOP, as well as chaperone GRP78.
Our data suggest that the increased relative acylated ghrelin levels after bariatric surgery might contribute to mitigate obesity-associated hepatic inflammation, mitochondrial dysfunction, and ER stress.
背景/目的：减重手术可改善非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH），但其潜在机制仍难以捉摸。我们评估了胃袖状切除术和 Roux-en-Y 胃旁路术（RYGB）后生长激素释放肽（ghrelin）同工型在改善肝炎症中的潜在作用。
研究对象/方法：对接受手术（假手术、胃袖状切除术或 RYGB）或饮食干预（自由进食正常饮食（ND）或高脂肪饮食（HFD）或等热量饮食）的雄性 Wistar 大鼠（n=129）测量血浆生长激素释放肽同工型。评估棕榈酸诱导的脂毒性条件下，酰基化和去酰基化 ghrelin 对原代大鼠肝细胞中炎症标志物、线粒体功能障碍和内质网（ER）应激的影响。
胃袖状切除术和 RYGB 后血浆去酰基 ghrelin 减少，而酰基/去酰基 ghrelin 比值增加。两种手术均减轻肥胖相关的肝脂肪变性、CD68-和凋亡细胞、促炎 JNK 激活以及 Crp、Tnf 和 Il6 转录物。此外，还观察到手术后线粒体 DNA 含量、氧化磷酸化（OXPHOS）复合物 I 和 II 以及 ER 应激标志物的改善。具体而言，减重手术后 GRP78、剪接 XBP-1、ATF4 和 CHOP 水平降低，磷酸化 eIF2α 减少。有趣的是，酰基化和去酰基化 ghrelin 可抑制棕榈酸处理的肝细胞的脂肪变性和炎症，同时上调 OXPHOS 复合物 II、III 和 V，并下调 ER 应激转导子 IRE1α、PERK、ATF6、其下游效应子 ATF4 和 CHOP 以及伴侣蛋白 GRP78。
我们的数据表明，减重手术后相对增加的酰基化 ghrelin 水平可能有助于减轻肥胖相关的肝炎症、线粒体功能障碍和 ER 应激。
