肥胖是現今社會重大的疾病。肥胖往往牽涉了代謝失調，因而導致脂肪肝，心血管疾病，各種類的癌症等其他疾病。據世界衛生組織在2022年的統計，全球超過約十億人患有肥胖症，但目前卻缺乏了有效治療肥胖症導致的代謝失調和脂肪肝的藥物。實驗室早期的結果發現剔除USP24會在小鼠中引發自噬作用，且小鼠體重及體脂肪較低。據此推測USP24可能在脂質代謝中扮演重要的角色。爲深入探討USP24在脂質代謝中的角色，本研究利用新穎USP24抑制劑治療高脂肪飼料誘導肥胖的小鼠，發現USP24抑制劑有效的降低小鼠體重，肝臟脂肪和體脂肪細胞大小。本研究對剔除USP24肥胖小鼠的肝臟進行次世代RNA定序分析，發現USP24剔除顯著降低肝臟的脂肪酸代謝，不飽和脂肪酸新合成及發炎反應的基因表達，顯示USP24可能參與在脂肪肝的發展。最後，USP24在3T3-L1細胞脂肪新生中表現量增加，抑制USP24則阻斷脂肪新生過程。進一步探討發現USP24可能透過增加CREB的磷酸化和穩定p300蛋白，增加CREB的轉錄活性，透過CREB-C/EBPβ-PPARγ途徑增加脂肪新生。本研究願透過瞭解USP24在脂質代謝和脂肪新生的角色和分子機制，以USP24為標靶，研發有效治療肥胖症，脂肪肝和脂肪肝炎的藥物。

Obesity is a major health concern affecting billions worldwide. Obesity is associated with metabolic dysregulation and may increase risks of fatty liver, cardiovascular disease, and various forms of cancers. However, there is currently little pharmacological method to treat obesity related metabolic diseases and fatty liver diseases. Our previous data showed that USP24 knockout mice exhibit enhanced autophagic activity, lower body weight and body fat content, we hypothesize that USP24 may play a major role in lipid metabolism. First, in this study, USP24 inhibition using novel USP24 inhibitor significantly decreased body weight and body fat content in mice, consistent with results from USP24 knockout mice. Furthermore, USP24 inhibitor treatment decreased white adipocyte cell size and reduced lipid droplet accumulation in high fat diet mice, indicating USP24 involvement in lipid metabolism. Next, RNA sequencing of liver tissues in USP24 knockout high fat diet mice revealed significant downregulation of fatty acid metabolic genes and inflammatory genes compared to USP24 wild type mice, indicating attenuation of NALFD and NASH symptoms. Finally, this study showed that USP24 is upregulated during 3T3-L1 adipogenesis and inhibition of USP24 prevented adipocyte differentiation. USP24 positively regulates early stages of differentiation through involvement in the CREB-C/EBPβ-PPARγ axis via increase in phospho-CREB protein and stabilizing p300, thereby increasing the transcriptional activity of CREB. This study seeks to elucidate the detailed role and molecular mechanism of USP24 in lipid metabolism and showed that targeting USP24 to be a potential treatment for obesity, NAFLD and NASH.

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