Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
J Clin Endocrinol Metab. 2019 Jan 1;104(1):21-37. doi: 10.1210/jc.2018-01171.
Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death.
The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated.
DESIGN, SETTINGS, AND PARTICIPANTS: Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α-induced cell death was determined in vitro in human HepG2 hepatocytes.
Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-α-induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-α-activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR.
Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α-induced hepatocyte apoptosis, autophagy, and pyroptosis.
人类肥胖与循环 TNF-α水平升高有关，TNF-α是一种促炎细胞因子，可诱导肝细胞死亡。
本研究旨在探讨酰化和去酰化 ghrelin 通过抑制 TNF-α诱导的肝细胞凋亡、自噬性细胞死亡和焦亡，对肥胖患者非酒精性脂肪性肝病（NAFLD）向非酒精性脂肪性肝炎（NASH）进展的潜在有益作用。
设计、地点和参与者：在 158 名参与者中测量了血浆 ghrelin 同工型和 TNF-α，在 76 名接受减重手术的病态肥胖患者的肝活检中评估了肝细胞死亡，这些患者可进行肝超声和病理分析。在体外用人 HepG2 肝细胞测定酰化和去酰化 ghrelin 对基础和 TNF-α诱导的细胞死亡的影响。
肥胖和 NAFLD 患者的循环 TNF-α和酰化/去酰化 ghrelin 比值升高，而去酰化 ghrelin 水平降低。减重手术后 6 个月，发现酰化/去酰化 ghrelin 水平降低，肝功能改善。肥胖和 2 型糖尿病患者表现出肝 ghrelin O-酰基转移酶转录本增加，以及肝凋亡、焦亡增加和自噬受损。在 HepG2 肝细胞中，酰化和去酰化 ghrelin 治疗可降低 TNF-α诱导的细胞凋亡，表现为 caspase-8 和 caspase-3 裂解减少，TUNEL 阳性细胞和焦亡减少，caspase-1 激活和高迁移率族蛋白 1 表达降低。此外，酰化 ghrelin 通过 AMPK/mTOR 抑制 TNF-α激活的肝细胞自噬，表现为 LC3B-II/I 比值降低和 p62 积累增加。
ghrelin 是肝细胞死亡的保护因素。肥胖和 NAFLD 患者中升高的酰化/去酰化 ghrelin 比值可能构成一种代偿机制，以克服 TNF-α诱导的肝细胞凋亡、自噬和焦亡。
