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<p>Lipid metabolism disorders, which are closely linked to obesity, are significantly modulated by the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a key regulator of glucocorticoid (GC) activation. This study explored the therapeutic potential of H8, a curcumin analog and selective inhibitor of 11β-HSD1, in mitigating these disorders. Employing an in vitro model of GC-induced differentiation in 3T3-L1 adipocytes and an in vivo C57BL/6 mice model characterized by 11β-HSD1 overexpression, we demonstrated that treatment with H8 effectively reduced GC levels in both serum and cultured cells. Lipid accumulation, evaluated through Oil Red O and hematoxylin and eosin (HE) staining, was significantly diminished by H8 in both cellular and animal models. Mechanistic investigations revealed that H8 modulated lipid metabolism through dual mechanisms: inhibition of 11β-HSD1 and activation of the AMP-activated protein kinase (AMPK) signaling pathway. Immunohistochemical and immunofluorescence analyses corroborated these lipid-modulating effects, while RNA and protein profiling identified significant alterations in markers of lipid synthesis. Further examination of the interplay between 11β-HSD1 and AMPK led us to hypothesize that H8 ameliorates lipid metabolism disorders primarily through its inhibitory effects.</p>

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11β-HSD1 inhibitor alleviates lipid metabolism disorder by activating the AMPK signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Yang Han,
  • Lingyu Li,
  • Xiaohuan Yuan,
  • Haihua Bao

摘要

Lipid metabolism disorders, which are closely linked to obesity, are significantly modulated by the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a key regulator of glucocorticoid (GC) activation. This study explored the therapeutic potential of H8, a curcumin analog and selective inhibitor of 11β-HSD1, in mitigating these disorders. Employing an in vitro model of GC-induced differentiation in 3T3-L1 adipocytes and an in vivo C57BL/6 mice model characterized by 11β-HSD1 overexpression, we demonstrated that treatment with H8 effectively reduced GC levels in both serum and cultured cells. Lipid accumulation, evaluated through Oil Red O and hematoxylin and eosin (HE) staining, was significantly diminished by H8 in both cellular and animal models. Mechanistic investigations revealed that H8 modulated lipid metabolism through dual mechanisms: inhibition of 11β-HSD1 and activation of the AMP-activated protein kinase (AMPK) signaling pathway. Immunohistochemical and immunofluorescence analyses corroborated these lipid-modulating effects, while RNA and protein profiling identified significant alterations in markers of lipid synthesis. Further examination of the interplay between 11β-HSD1 and AMPK led us to hypothesize that H8 ameliorates lipid metabolism disorders primarily through its inhibitory effects.