Dexmedetomidine ameliorates high-fat diet-induced nonalcoholic fatty liver disease by targeting SCD1 in obesity mice.
Dexmedetomidine ameliorates high-fat diet-induced nonalcoholic fatty liver disease by targeting SCD1 in obesity mice.
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右美托咪定通过靶向 SCD1 改善肥胖小鼠高脂饮食诱导的非酒精性脂肪肝
DOI：
10.1002/prp2.700
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发表时间：
2021-03
影响因子：
2.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Tao L;Guo X;Xu M;Wang Y;Xie W;Chen H;Ma M;Li X
脂肪肝是与肥胖相关的主要肝脏并发症之一。到目前为止，还没有批准用于这种病理学的治疗药物。胰岛素抵抗（IR）与非酒精性脂肪性肝病（NAFLD）的发病机制以及从脂肪变性到非酒精性脂肪性肝炎的疾病进展有关。在本研究中，我们对α2肾上腺素受体激动剂右美托咪定（DEX）的作用进行了表征，DEX可缓解高脂饮食（HFD）诱导的NAFLD小鼠肝细胞中的IR。每天腹腔注射DEX（100 μg·kg-1）16 d后，NAFLD小鼠体重减轻，肝脏脂肪滴变小变少，血浆甘油三酯水平明显降低，肝损伤改善。这种对肥胖小鼠脂质蓄积活性的抑制与脂肪生成酶硬脂酰辅酶A去饱和酶1（SCD 1）的mRNA和蛋白表达的稳健降低相关，这可能是通过负反馈抑制α 2A-肾上腺素受体（α 2A-AR），抑制C/EBP β、PPAR γ和C/EBP α介导的。此外，DEX还可通过抑制体内丝裂原活化蛋白激酶（MAPK）和核因子κ β（NFκB）信号通路改善IR和炎症。我们的研究结果表明，DEX可能作为一种潜在的抗脂肪变性药物，其可能通过抑制SCD 1的表达和MAPK/NFκB通路的抑制来改善肥胖相关的脂肪肝，并改善IR和炎症，并建议用于治疗NAFLD的潜在辅助用途。DEX改善HFD诱导的NAFLD，抑制脂质蓄积与肝脏中SCD 1的下调相关。其调节脂代谢、胰岛素敏感性和炎症的机制可能是通过抑制C/EBP β、PPAR γ和C/EBP α的表达，并通过MAPK和NFκB信号通路形成负反馈环，抑制α 2 A-AR和胰岛素水平。
Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no therapeutic drugs approved for this pathology. Insulin resistance (IR) is implicated both in pathogenesis of nonalcoholic fatty liver disease (NAFLD) and in disease progression from steatosis to nonalcoholic steatohepatitis. In this study, we have characterized effects of an α2‐adrenoceptor agonist, dexmedetomidine (DEX), which can alleviate IR in hepatocytes in high‐fat diet (HFD)‐induced NAFLD mice. The NAFLD mice received a daily intraperitoneal administration of DEX (100 μg·kg‐1) after 16 days exhibited lower body weight, fewer and smaller fat droplets in the liver, markedly reduced the plasma triglyceride levels, accompanied by improvement of liver damage. This inhibition of lipid accumulation activity in obese mice was associated with a robust reduction in the mRNA and protein expression of the lipogenic enzyme stearyl‐coenzyme A desaturase 1 (SCD1), which was probably mediated by the inhibition of C/EBP β, PPAR γ and C/EBP α through suppressing α 2A ‐adrenoceptor (α 2A ‐AR) via negative feedback. Additionally, DEX can also improve IR and inflammation by inhibiting the mitogen‐activated protein kinases (MAPK) and nuclear factor kappa beta (NFκB) signaling pathway in vivo. Our findings implicate that DEX may act as a potential anti‐steatotic drug which ameliorates obesity‐associated fatty liver and improves IR and inflammation, probably by suppressing the expression of SCD1 and the inhibition of MAPK/NFκB pathway and suggest the potential adjuvant use for the treatment of NAFLD. DEX improves HFD‐induced NAFLD, the suppression of lipid accumulation was associated with down regulation of SCD1 in liver. The mechanism in regulating lipid metabolism, insulin sensitivity and inflammation may due to suppressing the expression of C/EBP β, PPAR γ and C/EBP α and a negative feedback loop to inhibit α2A‐AR and the level of insulin in plasma through MAPK and NFκB singling pathway.
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