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

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.

Kaempferol exerts antioxidant effects in age‐related diminished ovarian reserve by regulating the HSP90/NRF2 pathway

“…To investigate whether kaempferol exerts a therapeutic effect on AR‐DOR via HSP90, we used the HSP90 agonist to perform the rescue experiment. Geranylgeranylacetone (GGA), a nontoxic antiulcer drug, has been unveiled to potently induce the transcriptional activation of HSP90 (Xie et al., 2021), which triggers a decrease in the generation of superoxide, resulting in an overall decline in oxidative stress within the cardiac and pulmonary tissues (Zhou et al., 2023). As expected, GGA reversed the effects of kaempferol on levels of AMH, E2, FSH (Figure 3b–d, p < .001), AFC (Figure 3f,g, p < .05), oxidative stress‐related indexes (Figure 4a–d, p < .001), and the HSP90/NRF2 axis (Figure 4e–g, p < .05).…”

“…Mice in the Con group and AR‐DOR group were intragastrically administered with 0.5% sodium carboxymethyl cellulose (CMC‐Na, HY‐Y1889A, MCE, China). Mice in the kaempferol group and the kaempferol + GGA group were intragastrically administered with 100 mg/kg kaempferol (dissolved with 0.5% CMC‐Na) alone or together with 200 mg/kg (Xie et al., 2021). GGA for 4 weeks.…”

Silibinin Targeting Heat Shock Protein 90 Represents a Novel Approach to Alleviate Nonalcoholic Fatty Liver Disease by Simultaneously Lowering Hepatic Lipotoxicity and Enhancing Gut Barrier Function

“…7,10 Clinical studies have revealed increased Hsp90α and Hsp90β levels in the serum of patients with NAFLD, which were positively correlated with the severity of hepatic steatosis. 36,37 Furthermore, the Hsp90 N-terminal inhibitor 17-AAG enhances hepatic albumosomal accumulation in mice, thereby inhibiting NAFLD progression. 38 PPARγ plays a dual role in the livers to facilitate the uptake and synthesis of both the fatty acids and prevent their catabolism, leading to lipid accumulation.…”

“…The multiple-hit hypothesis showed that hepatic steatosis initiated the subsequent cascade of intrahepatic detrimental events . Hsp90, a pivotal molecular chaperone protein, exhibits indispensable functions in lipid and glucose metabolism regulation, especially in hepatocytes. , Clinical studies have revealed increased Hsp90 α and Hsp90 β levels in the serum of patients with NAFLD, which were positively correlated with the severity of hepatic steatosis. , Furthermore, the Hsp90 N-terminal inhibitor 17-AAG enhances hepatic albumosomal accumulation in mice, thereby inhibiting NAFLD progression …”

Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance

“…Serum Hsp90α was increased in patients with metabolic-associated fatty liver disease (MAFLD). A positive correlation was found between age, glycosylated hemoglobin, serum Hsp90α, and grade of steatohepatitis [ 181 ]. Xie and colleagues showed that in a MAFLD mouse model, treatment with geranylgeranylacetone leads to decreased Hsp90α levels followed by improvement of steatohepatitis.…”