■代谢支持细胞增殖和生长。令人惊讶的是,miR-22是由胆汁酸等代谢刺激物诱导的。因此,这项研究检查了miR-22是否可能是一种代谢消音剂.
■在从患者和小鼠模型获得的细胞和脂肪肝中研究了miR-22与成纤维细胞生长因子21(FGF21)及其受体FGFR1表达之间的关系。我们评估了单独使用miR-22抑制剂以及与奥贝胆酸(OCA)联合治疗脂肪变性的效果。
■在人和小鼠脂肪肝中,miR-22的水平与FGF21,FGFR1和PGC1α的水平呈负相关,提示肝脏miR-22作为代谢消音剂。的确,miR-22通过直接靶向减少FGFR1,并通过减少PPARα和PGC1α对其结合基序的募集来减少FGF21。相比之下,miR-22抑制剂增加肝脏FGF21和FGFR1,导致AMPK和ERK1/2激活,在小鼠模型中有效治疗酒精性脂肪变性。法尼醇x受体激动剂OCA诱导FGF21和FGFR1,以及它们的抑制剂miR-22。miR-22抑制剂和OCA可有效治疗饮食诱导的脂肪变性,无论是单独还是组合。联合治疗在改善胰岛素敏感性方面最有效,在肥胖小鼠中释放胰高血糖素样肽1,并降低肝脏甘油三酯。
■代谢刺激物同时诱导miR-22,FGF21和FGFR1可能维持FGF21稳态并限制ERK1/2激活。减少miR-22增强肝脏FGF21并激活AMPK,这可能是治疗脂肪变性和胰岛素抵抗的新方法。
■这项研究检查了肿瘤抑制因子的代谢作用,miR-22,其可由代谢刺激物如胆汁酸诱导。我们的新数据显示,miR-22的代谢沉默效应是由于代谢刺激物的减少而发生的。这可能有助于脂肪肝的发展。与这一发现一致,miR-22抑制剂可有效逆转酒精和饮食诱导的脂肪肝;抑制miR-22是一种有前景的治疗选择,可与奥贝胆酸联合使用.
UNASSIGNED: Metabolism supports cell proliferation and growth. Surprisingly, the tumor suppressor miR-22 is induced by metabolic stimulators like bile acids. Thus, this study examines whether miR-22 could be a metabolic silencer.
UNASSIGNED: The relationship between miR-22 and the expression of fibroblast growth factor 21 (FGF21) and its receptor FGFR1 was studied in cells and fatty livers obtained from patients and mouse models. We evaluated the effect of an miR-22 inhibitor alone and in combination with obeticholic acid (OCA) for the treatment of steatosis.
UNASSIGNED: The levels of miR-22 were inversely correlated with those of FGF21, FGFR1, and PGC1α in human and mouse fatty livers, suggesting that hepatic miR-22 acts as a metabolic silencer. Indeed, miR-22 reduced FGFR1 by direct targeting and decreased FGF21 by reducing the recruitment of PPARα and PGC1α to their binding motifs. In contrast, an miR-22 inhibitor increases hepatic FGF21 and FGFR1, leading to AMPK and ERK1/2 activation, which was effective in treating alcoholic steatosis in mouse models. The farnesoid x receptor-agonist OCA induced FGF21 and FGFR1, as well as their inhibitor miR-22. An miR-22 inhibitor and OCA were effective in treating diet-induced steatosis, both alone and in combination. The combined treatment was the most effective at improving insulin sensitivity, releasing glucagon-like peptide 1, and reducing hepatic triglyceride in obese mice.
UNASSIGNED: The simultaneous induction of miR-22, FGF21 and FGFR1 by metabolic stimulators may maintain FGF21 homeostasis and restrict ERK1/2 activation. Reducing miR-22 enhances hepatic FGF21 and activates AMPK, which could be a novel approach to treat steatosis and insulin resistance.
UNASSIGNED: This study examines the metabolic role of a tumor suppressor, miR-22, that can be induced by metabolic stimulators such as bile acids. Our novel data revealed that the metabolic silencing effect of miR-22 occurs as a result of reductions in metabolic stimulators, which likely contribute to the development of fatty liver. Consistent with this finding, an miR-22 inhibitor effectively reversed both alcohol- and diet-induced fatty liver; miR-22 inhibition is a promising therapeutic option which could be used in combination with obeticholic acid.