Abstract
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.
Highlights
Metabolic-associated fatty liver disease (MAFLD), known as nonalcoholic fatty liver disease (NAFLD), is closely associated with type 2 diabetes mellitus (T2DM), cardiovascular disease, and chronic kidney disease (CKD)
MAFLD was diagnosed according to the criteria proposed by an international expert panel [1, 2]: evidence of hepatic steatosis was provided by liver biopsies, imaging, or blood biomarkers with one of the following conditions: [1] overweight or obesity (BMI ≥23 kg/m2), [2] type 2 diabetes (2021 American Diabetes Association), and [3] metabolic dysfunction
Body mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), TG, low-density lipoprotein cholesterol (LDL-C), uric acid (UA), and glycosylated hemoglobin (HbA1c) were higher in MAFLD patients than in healthy subjects
Summary
Metabolic-associated fatty liver disease (MAFLD), known as nonalcoholic fatty liver disease (NAFLD), is closely associated with type 2 diabetes mellitus (T2DM), cardiovascular disease, and chronic kidney disease (CKD). As suggested in the consensus statement, the diagnosis of MAFLD is based on evidence of fat accumulation in the liver (hepatic steatosis) and one of the following three criteria: overweight/obesity, the presence of T2DM, or metabolic dysregulation [2]. Compared with the NAFLD diagnostic criteria, the prevalence of MAFLD is less than NAFLD in patients with fatty liver disease. The definition of MAFLD is more practical for identifying patients with fatty liver disease with a high risk of metabolic comorbidities [3]. Cytokeratin 18 (CK-18) fragment level is the more recognized noninvasive biomarker for evaluating steatohepatitis, but the predicted value of CK-18 was reported as not satisfactory [6]. We aimed to evaluate the Hsp90a as a biomarker in predicting metabolicassociated fatty liver disease (MAFLD) and define the therapeutic effects of geranylgeranylacetone for the disease
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