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[医学动态] 抑制免疫细胞内的脂肪酸能减少动脉粥样硬化的风险

[医学动态] 抑制免疫细胞内的脂肪酸能减少动脉粥样硬化的风险

Science News Inhibiting Fatty Acids in Immune Cells Decreases Atherosclerosis Risk

ScienceDaily (July 23, 2010) — Scientists at Washington University School of Medicine in St. Louis have found a way to significantly reduce atherosclerosis in mice that does not involve lowering cholesterol levels or eliminating other obesity-related problems.

They report their findings in the July 23 issue of the Journal of Biological Chemistry.

Atherosclerosis is the process through which fatty substances, such as cholesterol and cellular waste products accumulate in the lining of arteries. Those buildups, called plaques, reduce blood flow through the artery and can contribute to heart attack, stroke and even gangrene. It is common in individuals with obesity-related problems such as high blood pressure, high cholesterol and diabetes.

In this study, the research team inhibited atherosclerosis in mice by interfering with production of a substance called fatty acid synthase. This enzyme converts dietary sugars into fatty acids in the liver, where it plays an important role in energy metabolism. But fatty acids also are involved in atherosclerosis.

"The plaques that clog arteries contain large amounts of fatty acids," says senior investigator Clay F. Semenkovich, MD. "We engineered mice that are unable to make fatty acid synthase in one of the major cell types that contribute to plaque formation. On a standard Western diet high in fat, the mice had less atherosclerosis than their normal littermates."

Animals can't survive without fatty acid synthase, so mice in this study were able to make the substance in most of their tissues. They couldn't manufacture it, however, in macrophages, a type of white blood cell that surrounds and kills invading microorganisms, removes dead cells from the body and stimulates the action of other immune cells. Macrophages are dispatched in response to injury, infection and inflammation.

Atherosclerosis is the most common cause of heart disease, which is the leading cause of death in the United States. Semenkovich, the Herbert S. Gasser Professor and chief of the Division of Endocrinology, Metabolism and Lipid Research, says doctors tend to concentrate on treating the surrounding risk factors related to atherosclerosis, such as diabetes and high blood pressure, but he says the blockages themselves cause the most serious, life-threatening problems.

"With the current epidemic of obesity and diabetes, people sometimes forget that it's the blockages in the arteries that really kill people," he says. "We've made progress using statin drugs, for example, that lower cholesterol and fight plaque buildup, but a lot of people who take statins still die from cardiovascular disease. We need better therapies."

These mouse experiments suggest targeting fatty acid synthase in macrophages may provide a potential treatment strategy for humans. The researchers identified factors in the fatty acid pathway that seem to be capable of preventing plaques from blocking arteries in mice. He says those substances -- LXR-alpha and ABCA1 -- eventually may become drug targets.

"It may be possible, for example, to take macrophages out of humans, inhibit fatty acid synthase in those cells, and then infuse the macrophages back into the same person," he says. "From what we've observed in mice, we would hypothesize that approach might prevent or interfere with plaque buildup in people."

Inhibiting fatty acid synthase in macrophages may not keep blood vessels clean forever, according to Semenkovich, but he says it could lower the risk of heart attacks and strokes while people are making lifestyle changes in order to lose weight, gain control of blood sugar levels or lower triglycerides and cholesterol.

"This discovery allows us to separate atherosclerosis from associated conditions such as diabetes and high cholesterol," he says. "In fact, in the mice without fatty acid synthase in their macrophage cells, there were no effects on diabetes. Cholesterol in the blood remained the same. But there were fewer blockages in arteries. If a similar approach worked for humans, it could help prevent heart attacks and strokes and give people a chance to get healthier by losing weight and lowering cholesterol."

This work was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute of the National Institutes of Health, and by Fellowship Awards from the American Diabetes Association and the American Heart Association.


抑制免疫细胞中的脂肪酸可降低动脉粥样硬化风险
在圣路易斯的华盛顿大学医学院的科学家发现一种能够显著降低小鼠动脉粥样硬化疾病的方法,该方法不用降低胆固醇水平或者消除其它肥胖相关问题。

他们的发现刊登在JBC(生物化学杂志)的7月23期。

动脉粥样硬化是一个脂肪物质在动脉内壁的积累过程,如胆固醇和细胞产生的废物。这些增生物,称为斑块,使通过动脉的血流量减少并且可引起心脏病发作,中风甚至坏疽。带有与肥胖相关的问题,如高血压,高胆固醇和糖尿病,这些个体很常见。

在这项研究中,研究团队干扰一种叫做脂肪酸合成酶物质的产物,抑制了小鼠的动脉粥样硬化。这种酶将饮食中的糖在肝脏中转变成脂肪酸,肝脏在能量代谢中起着重要的作用。但是胆固醇也卷入了动脉粥样硬化的问题中。

“这些包含了大量脂肪酸的斑块阻塞了动脉,” Clay F. Semenkovich, MD高级研究员说“我们设计了一种小鼠,该小鼠产生斑块样物质的一种主要细胞不能产生脂肪酸合成酶。在西方饮食高脂肪的标准下,这些小鼠比同窝其它小鼠较少的发生动脉粥样硬化。”

动物没有脂肪酸合成酶不能生存,所以在此研究中的老鼠能够在绝大多数的组织中产生替代物质。然而,巨噬细胞不能制造它(脂肪酸合成酶),这是一种巡逻且杀死入侵微生物的白细胞,它能从身体中移除死细胞,激活其它免疫细胞。巨噬细胞在受伤,感染和炎症反应中被派遣出来。

动脉粥样硬化是一种最常见的心脏疾病,在美国是造成死亡的头号杀手。内分泌,代谢及脂质研究部首席Semenkovich, the Herbert S. Gasser 教授说,医生倾向于集中精力治疗与动脉粥样硬化相关的风险因素,例如糖尿病和高血压,但是他说阻塞本身造成了最严重的威胁生命的问题。

“随着肥胖和糖尿病的流行,人们经常会忘记是动脉的阻塞真正造成死亡,”他说。“我们在应用抑制素方面取得进步,例如,它能降低胆固醇和对抗斑块堆积,但是很多人服用了抑制素后仍然死于动脉粥样硬化。我们需要更好的治疗方法。”

这些老鼠实验暗示锁定巨噬细胞中的脂肪酸合成酶可能为人类提供潜在治疗策略。研究人员鉴定了脂肪酸通路的细胞因子,似乎能够预防小鼠动脉中斑块的堆积。他说这些物质——LXR-alpha and ABCA1——最终可能成为药物的靶标。

“也许有可能,例如说,将人类的巨噬细胞提取出来,抑制这些细胞中的脂肪酸合成酶,然后再将这些细胞注入同一个人的身体中,”他说。“从老鼠的实验可以观察到,我们将假设这种方法也许能防止或者干扰斑块在人体的堆积。”

抑制巨噬细胞中的脂肪酸合成酶不仅能够保持血管永久清洁,根据Semenkovich的理论,他说当人们在改变生活方式以达到减肥,保持血糖水平或者降低甘油三酯和胆固醇水平时,这能够降低心脏病发作和中风的风险。

“这项发现允许我们将动脉粥样硬化和相关的状况如糖尿病和高胆固醇分开,”他说。“事实上,在小鼠体内,没有脂肪酸合成酶的巨噬细胞,对糖尿病没有影响。血液中的胆固醇也维持在同一水平。但是动脉的阻塞更少了。如果在人类身上实行一个相似的方法,这可能帮助预防心脏病和中风发作,并且为人们提供一个通过减肥和降低胆固醇来达到健康的机会。”

这项工作由国立糖尿病,消化道和肾脏疾病和国家心脏,肺和血液的国立卫生研究院研究所和美国糖尿病协会和美国心脏协会的奖学金奖支持。


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