DataSheet_1_Predictive Modeling of MAFLD Based on Hsp90α and the Therapeutic Application of Teprenone in a Diet-Induced Mouse Model.docx

Background and AimsThe heat shock protein (Hsp) 90α is induced by stress and regulates inflammation through multiple pathways. Elevated serum Hsp90α had been found in nonalcoholic steatohepatitis (NASH). Geranylgeranylacetone (GGA, also called teprenone) is a terpenoid derivative. It was reported to induce Hsp and alleviate insulin resistance. We aimed to evaluate the Hsp90α as a biomarker in predicting metabolic-associated fatty liver disease (MAFLD) and define the therapeutic effects of geranylgeranylacetone for the disease.
MethodsA clinical study was conducted to analyze the elements associated with Hsp90α, and a predictive model of MAFLD was developed based on Hsp90α. The histopathological correlation between Hsp90α and MAFLD was investigated through a diet-induced mouse model. Furthermore, GGA was applied to the mouse model.
ResultsSerum Hsp90α was increased in patients with MAFLD. A positive linear relationship was found between age, glycosylated hemoglobin (HbA1c), MAFLD, and serum Hsp90α. Meanwhile, a negative linear relationship with body mass index (BMI) was found. A model using Hsp90α, BMI, HbA1c, and ALT was established for predicting MAFLD. The area under the receiver operating characteristic (ROC) curves was 0.94 (95% CI 0.909–0.971, p = 0.000). The sensitivity was 84.1%, and the specificity was 93.1%. In vitro experiments, GGA induced Hsp90α in steatosis cells. In the mice model, Hsp90α decreased in the GGA treatment group. Hepatic steatosis, inflammation, insulin resistance, and glucose intolerance were improved in the GGA-treated group. Serum Hsp90α was positively correlated with steatohepatitis activity according to hepatic histopathology.
ConclusionsSerum Hsp90α was elevated in MAFLD, and a positive correlation between serum Hsp90α and the grade of activity of steatohepatitis was observed. The model using BMI, HbA1c, and alanine aminotransferase (ALT) had a good value to predict MAFLD. The findings also revealed the effectiveness of GGA in the treatment of MAFLD.

背景与目的
热休克蛋白90α（Hsp90α）可由应激诱导，并通过多条通路调控炎症反应。临床已在非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）患者中发现血清Hsp90α水平升高。吉格列汀酮（geranylgeranylacetone, GGA，又称替普瑞酮）是一种萜类衍生物，已有研究表明其可诱导热休克蛋白表达，并改善胰岛素抵抗。本研究旨在评估Hsp90α作为生物标志物在预测代谢相关脂肪性肝病（metabolic-associated fatty liver disease, MAFLD）中的价值，并明确GGA对该病的治疗效果。

方法
本研究开展临床分析以探究与Hsp90α相关的影响因素，并基于Hsp90α构建MAFLD预测模型。通过饮食诱导的小鼠模型，探究Hsp90α与MAFLD的组织病理学关联。此外，将GGA应用于该小鼠模型。

结果
MAFLD患者的血清Hsp90α水平升高。年龄、糖化血红蛋白（glycosylated hemoglobin, HbA1c）水平与MAFLD及血清Hsp90α水平呈正线性相关，而体质量指数（body mass index, BMI）与血清Hsp90α水平呈负线性相关。本研究构建了包含Hsp90α、BMI、HbA1c及丙氨酸氨基转移酶（alanine aminotransferase, ALT）的MAFLD预测模型，其受试者工作特征（receiver operating characteristic, ROC）曲线下面积为0.94（95%置信区间（confidence interval, CI）：0.909~0.971，P值（probability, P）=0.000），模型灵敏度为84.1%，特异度为93.1%。体外实验显示，GGA可诱导脂肪变性细胞表达Hsp90α。在小鼠模型中，GGA干预组的血清Hsp90α水平降低，该组小鼠的肝脏脂肪变性、炎症反应、胰岛素抵抗及糖耐量异常均得到改善。肝脏组织病理学分析显示，血清Hsp90α水平与脂肪性肝炎活动度呈正相关。

结论
MAFLD患者血清Hsp90α水平升高，且血清Hsp90α水平与脂肪性肝炎活动度呈正相关。包含BMI、HbA1c及丙氨酸氨基转移酶（ALT）的预测模型对MAFLD具有良好的预测价值。本研究结果同时证实了GGA治疗MAFLD的有效性。