Integrator complex subunit 6 promotes hepatocellular steatosis via β-catenin-PPARγ axis

IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et biophysica acta. Molecular and cell biology of lipids Pub Date : 2024-07-07 DOI:10.1016/j.bbalip.2024.159532
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Abstract

Hepatic adipogenesis has common mechanisms with adipocyte differentiation such as PPARγ involvement and the induction of adipose tissue-specific molecules. A previous report demonstrated that integrator complex subunit 6 (INTS6) is required for adipocyte differentiation. This study aimed to investigate INTS6 expression and its role in hepatic steatosis progression. The expression of INTS6 and PPARγ was examined in the liver of a mouse model of steatohepatitis and in paired liver biopsy samples from 11 patients with severe obesity and histologically proven metabolic dysfunction associated steatohepatitis (MASH) before and one year after bariatric surgery. To induce hepatocellular steatosis in vitro, an immortalized human hepatocyte cell line Hc3716 was treated with free fatty acids. In the steatohepatitis mouse model, we observed hepatic induction of INTS6, PPARγ, and adipocyte-specific genes. In contrast, β-catenin which negatively regulates PPARγ was reduced. Biopsied human livers demonstrated a strong positive correlation (r2 = 0.8755) between INTS6 and PPARγ mRNA levels. After bariatric surgery, gene expressions of PPARγ, FABP4, and CD36 were mostly downregulated. In our in vitro experiments, we observed a concentration-dependent increase in Oil Red O staining in Hc3716 cells after treatment with the free fatty acids. Alongside this change, the expression of INTS6, PPARγ, and adipocyte-specific genes was induced. INTS6 knockdown using siRNA significantly suppressed cellular lipid accumulation together with induction of β-catenin and PPARγ downregulation. Collectively, INTS6 expression closely correlates with PPARγ. INTS6 suppression significantly reduced hepatocyte steatosis via β-catenin-PPARγ axis, indicating that INTS6 could be a novel therapeutic target for treating MASH.

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整合器复合体亚基 6 通过 β-catenin-PPARγ 轴促进肝细胞脂肪变性
肝脏脂肪生成与脂肪细胞分化有共同的机制,如 PPARγ 参与和诱导脂肪组织特异性分子。之前的一项研究表明,整合子复合体亚基 6(INTS6)是脂肪细胞分化的必需物质。本研究旨在探讨 INTS6 的表达及其在肝脏脂肪变性过程中的作用。研究人员检测了INTS6和PPARγ在脂肪性肝炎小鼠模型肝脏中的表达情况,以及11名重度肥胖和组织学证实的代谢功能障碍相关性脂肪性肝炎(MASH)患者在减肥手术前和手术后一年的配对肝活检样本中的表达情况。为了在体外诱导肝细胞脂肪变性,用游离脂肪酸处理了永生化人肝细胞系 Hc3716。在脂肪性肝炎小鼠模型中,我们观察到肝脏诱导了 INTS6、PPARγ 和脂肪细胞特异性基因。相反,对 PPARγ 起负性调节作用的 β-catenin却减少了。活检的人体肝脏显示,INTS6 和 PPARγ mRNA 水平之间存在很强的正相关性(r2 = 0.8755)。减肥手术后,PPARγ、FABP4 和 CD36 的基因表达大多下调。在体外实验中,我们观察到游离脂肪酸处理后,Hc3716 细胞中的油红 O 染色呈浓度依赖性增加。随着这一变化,INTS6、PPARγ 和脂肪细胞特异性基因的表达也被诱导。使用 siRNA 敲除 INTS6 能显著抑制细胞脂质积累,同时还能诱导β-catenin 和 PPARγ 下调。总之,INTS6的表达与PPARγ密切相关。通过β-catenin-PPARγ轴抑制INTS6可明显减轻肝细胞脂肪变性,这表明INTS6可能是治疗MASH的一个新的治疗靶点。
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来源期刊
CiteScore
11.00
自引率
2.10%
发文量
109
审稿时长
53 days
期刊介绍: BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.
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