From the Research Administration Team, Seoul National University Bundang Hospital, 13620 Gyeonggi, Republic of Korea.
the Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, 24341 Chunchon, Republic of Korea.
J Biol Chem. 2018 Mar 16;293(11):3981-3988. doi: 10.1074/jbc.RA117.000885. Epub 2018 Feb 5.
Maresin 1 (MAR1), which is derived from docosahexaenoic acid biosynthesized by macrophages, has been reported to improve insulin resistance. Recently, it has been documented that MAR1 could ameliorate inflammation and insulin resistance in obese mice. These findings led us to investigate the effects of MAR1 on hepatic lipid metabolism. We found that MAR1 could stimulate AMP-activated protein kinase (AMPK), thereby augmenting sarcoendoplasmic reticulum Ca-ATPase 2b (SERCA2b) expression. This stimulation suppressed lipid accumulation by attenuating the endoplasmic reticulum (ER) stress in hepatocytes under hyperlipidemic conditions. Attenuation was mitigated by knockdown of AMPK or thapsigargin, a SERCA2b inhibitor. We also demonstrated that MAR1 administration resulted in increased hepatic AMPK phosphorylation and mRNA expression, whereas hepatic ER stress was reduced in high-fat diet (HFD)-fed mice. Moreover, MAR1 treatment suppressed hepatic lipid synthesis, thereby attenuating hepatic steatosis in HFD-fed mice. In conclusion, our results suggest that MAR1 ameliorates hepatic steatosis via AMPK/SERCA2b-mediated suppression of ER stress. Therefore, MAR1 may be an effective therapeutic strategy for treating non-alcoholic fatty liver disease (NAFLD) via regulation of ER stress-induced hepatic lipogenesis.
马尿酸 1（MAR1）来源于巨噬细胞生物合成的二十二碳六烯酸，据报道可改善胰岛素抵抗。最近，有文献记载 MAR1 可改善肥胖小鼠的炎症和胰岛素抵抗。这些发现促使我们研究 MAR1 对肝脂质代谢的影响。我们发现 MAR1 可以刺激 AMP 激活的蛋白激酶（AMPK），从而增加肌浆内质网 Ca-ATP 酶 2b（SERCA2b）的表达。这种刺激通过减弱内质网（ER）应激来抑制肝细胞在高脂血症条件下的脂质积累。AMPK 或 thapsigargin（SERCA2b 抑制剂）的敲低减轻了这种抑制作用。我们还证明，MAR1 给药导致肝 AMPK 磷酸化和 mRNA 表达增加，而高脂肪饮食（HFD）喂养的小鼠肝 ER 应激减少。此外，MAR1 治疗抑制了肝脂质合成，从而减轻了 HFD 喂养小鼠的肝脂肪变性。总之，我们的结果表明，MAR1 通过 AMPK/SERCA2b 介导的 ER 应激抑制来改善肝脂肪变性。因此，MAR1 可能是通过调节 ER 应激诱导的肝脂肪生成来治疗非酒精性脂肪性肝病（NAFLD）的有效治疗策略。
