PNAS:科学家发现可显著降低糖尿病症状的药物
生物通/王英 · 2015/01/14
最近在《PNAS》杂志发表的一项研究中,一种酶——称为可溶性环氧化物水解酶(sEH)的抑制剂,不仅能预防糖尿病的发作,还能逆转糖尿病在肥胖小鼠中的影响。


糖尿病能够预防甚至被逆转吗?根据加州大学戴维斯分校Bruce Hammock和巴塞罗那大学Joan Clària带领的一项最新研究称,这完全是有可能的,至少在遗传性肥胖小鼠中可以实现。这项研究涉及到Hammock实验室所发现的一种有效的酶抑制剂,这种抑制剂可大大降低炎症、炎性疼痛和神经病理性疼痛。

相关研究结果发表在最近的《PNAS》杂志,在这项研究中,一种酶——称为可溶性环氧化物水解酶(sEH)的抑制剂,不仅能预防糖尿病的发作,还能逆转糖尿病在肥胖小鼠中的影响。

Hammock说:“我们以前的研究表明,我们正在研究的这种药物本身能降低小鼠的糖尿病症状,但是Joan Clària的工作令人兴奋之处在于,如果小鼠通过转基因而具有增高水平的omega-3脂肪酸——这种药物在小鼠中就可以提供预防或治疗作用。”

据美国疾病控制和预防中心估计,约有2.91亿美国人,或9.3%的人口患有糖尿病,其特点是不正常的血糖水平。这其中包括810万例未确诊病例。

很显然,这种新药通过稳定一种omega-3脂肪酸(称为DHA)的代谢物而发挥作用。Hammock说,这些代谢产物被认为可以促进富含omega-3脂肪酸饮食的有益效果。之前加州大学戴维斯分校Hammock、Nipavan Chiamvimonvat、Robert Weiss、Anne Knowlton和Fawaz Haj实验室的研究表明,这种酶可减少或逆转糖尿病相关的医学问题,例如肾功能衰竭、高血压、糖尿病疼痛、动脉硬化和心脏衰竭。

加州大学戴维斯分校食品健康研究所食品科学和技术系主任J. Bruce German没有参与这项研究,但是他表示:“这一令人兴奋的研究,详细阐述了饮食中的omega-3脂肪酸如何发挥重要的健康效果。”

Clària是巴塞罗那大学医学院副教授、巴塞罗那医院生化和分子遗传学服务高级顾问。在这篇论文中,Clària将施用sHE抑制剂描述为“预防肥胖相关共患病的一种很有前途的策略”。

Clària称,这项研究也深入阐述了sHE和omega-3环氧化合物在胰岛素敏感组织(特别是肝脏)中的作用。

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  • Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: Role for omega-3 epoxides

    Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3–derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3–dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases.

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