BRUCE liver-deficiency potentiates MASLD/MASH in PTEN liver-deficient background by impairment of mitochondrial metabolism in hepatocytes and activation of STAT3 signaling in hepatic stellate cells

Lixiao Che, Camille K. Stevenson, David R. Plas, Jiang Wang, Chunying Du
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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common liver disease, affecting up to 25% of people worldwide, featuring excessive fat accumulation in hepatocytes. Its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), is a serious disease with hepatic inflammation and fibrosis, increasing the need for liver transplants. However, the pathogenic mechanism of MASLD and MASH is not fully understood. We reported that BRUCE (BIRC6) is a liver cancer suppressor and is downregulated in MASLD/MASH patient liver specimens, though the functional role of BRUCE in MASLD/MASH remains to be elucidated. To this end, we generated liver-specific double KO (DKO) mice of BRUCE and PTEN, a major tumor suppressor and MASLD/MASH suppressor. By comparing liver histopathology among 2-3-month-old mice, there were no signs of MASLD or MASH in BRUCE liver-KO mice and only onset of steatosis in PTEN liver-KO mice. Interestingly, DKO mice had developed robust hepatic steatosis with inflammation and fibrosis. Further analysis of mitochondrial function with primary hepatocytes found moderate reduction of mitochondrial respiration, ATP production and fatty acid oxidation in BRUCE KO and the greatest reduction in DKO hepatocytes. Moreover, aberrant activation of pro-fibrotic STAT3 signaling was found in hepatic stellate cells (HSCs) in DKO mice which was prevented by administered STAT3-specific inhibitor (TTI-101). Collectively, the data demonstrates by maintaining mitochondrial metabolism BRUCE works in concert with PTEN to suppress the pro-fibrogenic STAT3 activation in HSCs and consequentially prevent MASLD/MASH. The findings highlight BRUCE being a new co-suppressor of MASLD/MASH.
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在 PTEN 肝缺陷背景下,BRUCE 肝缺陷通过损害肝细胞的线粒体代谢和激活肝星状细胞中的 STAT3 信号,增强 MASLD/MASH 的作用
代谢功能障碍相关性脂肪性肝病(MASLD)是目前最常见的肝病,影响着全球多达 25% 的人,其特点是肝细胞内脂肪过度堆积。其晚期形式,即代谢功能障碍相关性脂肪性肝炎(MASH),是一种严重的肝脏炎症和纤维化疾病,增加了肝移植的需求。然而,MASLD 和 MASH 的致病机制尚不完全清楚。我们曾报道,BRUCE(BIRC6)是一种肝癌抑制因子,在MASLD/MASH患者肝脏标本中下调,但BRUCE在MASLD/MASH中的功能作用仍有待阐明。为此,我们培育了肝脏特异性双KO(DKO)小鼠,它们分别是BRUCE和PTEN(一种主要的肿瘤抑制因子和MASLD/MASH抑制因子)。通过比较2-3月龄小鼠的肝脏组织病理学,BRUCE肝脏KO小鼠没有MASLD或MASH的迹象,而PTEN肝脏KO小鼠仅出现脂肪变性。有趣的是,DKO 小鼠出现了严重的肝脏脂肪变性,并伴有炎症和纤维化。用原代肝细胞对线粒体功能进行进一步分析发现,BRUCE KO 的线粒体呼吸、ATP 生成和脂肪酸氧化中度降低,而 DKO 肝细胞的降低幅度最大。此外,在 DKO 小鼠的肝星状细胞(HSCs)中发现了促纤维化 STAT3 信号的异常激活,而 STAT3 特异性抑制剂(TTI-101)可以阻止这种激活。总之,这些数据表明,通过维持线粒体代谢,BRUCE 可与 PTEN 协同作用,抑制造血干细胞中促纤维化的 STAT3 激活,从而预防 MASLD/MASH。这些发现突显了 BRUCE 是 MASLD/MASH 的一个新的共抑制因子。
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