Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway
Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway
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DOI：
10.1007/s00535-012-0546-7
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发表时间：
2012-07-01
影响因子：
6.3
通讯作者：
Suzuki, Kazuyuki
中科院分区：
文献类型：
--
作者：
Wang, Ting;Takikawa, Yasuhiro;Suzuki, Kazuyuki
背景据报道，在迷迭香中发现的鼠尾草酸（CA）具有抗氧化和抗脂肪形成的特性。我们最近证明，CA防止脂肪变性的ob/ob小鼠。在本报告中，我们调查的分子机制，其中CA抑制脂质积累在体内和体外invivor.Methods在体内研究中，ob/ob小鼠喂养标准的饲料与CA或无5周，然后他们的肝细胞脂质积累的测定。还评价了血清细胞因子浓度、脂质调节介质水平以及肝脏代谢和信号分子。在体外实验中，以HepG 2细胞为研究对象，进一步阐明了CA对细胞脂质蓄积的影响，并进一步证实了这些影响所涉及的信号通路。该效应与肝脏PPAR γ水平受抑制、炎性细胞因子（如IL-1 β、IL-12、IL-17、IFN-γ、MCP-1和MIP-1 β）表达减少以及ATP、乙酰辅酶A、NAD（P）（+）和NAD（P）H增加相关。其他信号分子，如EGFR，MAPK，AMPK和ACC，调节脂质代谢，在喂食CA饮食的小鼠中被激活。CA抑制棕榈酸诱导的细胞脂质积聚，并刺激EGFR和MAPK的磷酸化。用EGFR抑制剂AG 1478或MEK特异性抑制剂U 0126预处理可阻断CA对细胞脂质蓄积的影响，并降低PPAR γ的蛋白表达和活性。结论EGFR/MAPK信号通路在CA抑制肝细胞脂质蓄积中起重要作用。
Background Carnosic acid (CA), found in rosemary, has been reported to have antioxidant and anti-adipogenic properties. We recently demonstrated that CA protects against steatosis in ob/ob mice. In the present report, we investigated the molecular mechanism by which CA inhibits lipids accumulation both in vivo and in vitro.Methods In the in vivo study, ob/ob mice were fed a standard chow diet with or without CA for 5 weeks, then their hepatocyte lipid accumulation was determined. The serum concentrations of cytokines, the levels of lipid regulatory mediators, and the hepatic metabolic and signaling molecules were also evaluated. In the in vitro study, HepG2 cells were used to further clarify the effects of CA on cellular lipid accumulation and to confirm the signaling pathways involved in these effects.Results CA significantly reduced hepatocyte lipid accumulation. This effect was associated with repressed levels of hepatic PPAR gamma, reduced expression of inflammatory cytokines such as IL-1 beta, IL-12, IL-17, IFN-gamma, MCP-1, and MIP-1 beta, and increased ATP, acetyl CoA, NAD(P)(+), and NAD(P) H. Other signaling molecules, such as EGFR, MAPK, AMPK, and ACC, which regulate lipid metabolism, were activated in mice fed the CA diet. CA inhibited palmitate-induced cellular lipid accumulation and stimulated the phosphorylation of both EGFR and MAPK. Pretreatment with either the EGFR inhibitor AG1478 or the MEK-specific inhibitor U0126 abolished the effects of CA on cellular lipid accumulation and decreased both the protein expression and activity of PPAR gamma.Conclusions EGFR/MAPK signaling plays an important role in the inhibitory effect of CA on hepatocyte lipid accumulation.