| International Session（Symposium）3(JSGE・JSH・JSGS・JSGCS) |
| Fri. November 1st 9:30 - 11:30 Room 4: Portopia Hotel South Wing Portopia Hall |
| Identification of transcriptomic hepatic hypothyroidism in MASLD patients for resmetirom | |||
| Hirono Owa1, Naoto Fujiwara1, Hayato Nakagawa1 | |||
| 1Department of Gastroenterology and Hepatology, Mie University | |||
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| Background: Resmetirom, a selective thyroid hormone receptor beta (THRB) agonist, achieved significant fibrosis regression in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) in the phase 3 trial; however, its efficacy was observed only in 25% of patients. Methods: We first identified the molecular modulation by T3 via THRB based on hepatic transcriptome analysis of wild mice, T3-treated mice, and THRB-KO mice treated with T3 and defined downstream genes in the T3-THRB pathway as a THRB signature. Next, in hepatic transcriptome analysis from 82 MALSD patients, we evaluated the association between downregulated THRB signature in livers, i.e., hepatic hypothyroidism, and clinic-histological features. Results: T3-THRB pathway had anti-inflammatory effects by suppressing IL6-STAT3 and IL2-STAT5 pathways and reduced cholesterol synthesis in mice. Based on differential gene expression analysis, we defined a 360-gene THRB signature. T3-THRB pathway activation as well as THRB expression level was negatively correlated with histological liver fibrosis stage, inflammation and hepatocyte ballooning grade, and serum AFP levels. Indeed, among patients with fibrosis >F2, decreased T3-THRB pathway activation was observed in those with AFP >3ng/mL. Importantly, neither serum TSH nor T3 levels were associated with THRB activation, suggesting that fibrosis-related suppression of T3-THRB pathway was induced by reduced sensitivity to T3 through decreased THRB expression. Conclusion: MASLD patients with fibrosis and slightly elevated AFP levels demonstrated transcriptomic hepatic hypothyroidism and might be candidates for resmetirom. |
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Index Term 1: MAFLD Index Term 2: Resmetirom |
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