#395 - 脑脂质学：理解 APOE、胆固醇稳态、阿尔茨海默病风险以及降脂疗法对脑健康的影响 | Tom Dayspring, M.D.

星形胶质细胞仍然大量生产胆固醇，但有一种细胞停止了合成，那就是神经元。

Astrocytes continue to produce it at a high form, but there's one cell that stops producing cholesterol, and it's the neurons.

当大脑长到成人大小时，神经元就说：不，不，不，我再也不自己合成了。

When the brain is full adult size, the neuron says, No, no, no, I'm not going to make any more.

我只想让星形胶质细胞生产，然后运给我就行。

I want the astrocytes to make it and send it to me.

这背后其实有个很简单的原因。

And there's a simple reason it does that.

我们以前的播客里还聊过胆固醇合成那套复杂的路径。

We even, in our earlier podcast, discussed the very complex cholesterol synthesis pathways.

整个过程一共有37个步骤。

It's actually 37 steps.

每一步都依赖不同的酶。

Every step is a different enzyme.

每一步都需要消耗ATP。

Every step requires ATP.

任何一个细胞合成一分子胆固醇，都要消耗三十多个ATP分子。

Any cell to synthesize one molecule of cholesterol consumes over 30 molecules of ATP.

神经元当然是大脑中最活跃的细胞，它整天都在不断发放动作电位，这些活动都需要大量ATP。

The neuron, of course, is the most active cell in the brain because it's firing off all these action potential in their synapses all day long, and that requires ATP.

所以神经元当然不想浪费ATP去合成胆固醇，如果能从别处获得，它就懒得自己做了。

So the neuron does not want to waste ATPs making cholesterol if it can get it elsewhere.

神经元把ATP都留着，用在自己的正常运作上。

The neuron starts using ATP for its functioning.

于是，这个负担就落到了星形胶质细胞身上。

And then it falls on the astrocyte.

这就是大脑里胆固醇合成的大致情况。

So that's a little bit about cholesterol production in the brain.

所有细胞都能合成胆固醇，但到了某个阶段，神经元就会说：我不干了。

All of the cells can do it, but at a certain point the neurons say, I don't want to do it anymore.

星形胶质细胞，你们能帮我合成胆固醇，再送过来吗？

Astrocytes, can you please make cholesterol and get it over to me?

这就涉及到大脑中的脂质运输系统了。

And this is where we get into the brain lipid transportation system.

因为在血液里，正如我们之前说过的，脂质是通过脂蛋白在血浆中运输的。

Because in the blood, as you we've enumerated, lipids travel within the lipoproteins in the plasma.

但在大脑里，细胞之间来回传递的胆固醇并不依赖血液。

Well, in the brain, the cholesterol that's going back and forth between cells doesn't use the blood.

它依靠的是大脑的细胞间质，也就是所谓的脑髓鞘液。

It uses the brain interstitial tissue, which is called the matrosome.

如果我们看大脑，它是一种结缔组织，里面充满了无数的细胞，比如胶质细胞和神经元。

So if we take the brain, it's this connective tissue, and there are zillions of these cells in them, the glial cells in the neurons.

这些细胞彼此靠得很近，但并不是连在一起的。

Now they're very close together, but they're not contiguous.

它们之间没有直接连接。

They're not binding to each other.

所以，如果一个星形胶质细胞生产了胆固醇，而那边的神经元说：‘我需要这个，快给我送过来’，那就必须有一个大脑内的胆固醇运输系统，或者叫脂质运输系统。

So if an astrocyte produces cholesterol molecules and the neurons over there saying, Hey, I need that, send it to me, we have to have a brain cholesterol transportation system or a brain lipid transportation system.

那星形胶质细胞具体做什么呢？

And so what do the astrocytes do?

和身体其他部位的情况一样。

Same thing that happens in the periphery.

它们会制造一种脂蛋白。

It makes a lipoprotein.

但这里有个很大的不同。

But there's gonna be a big difference here.

首先，星形胶质细胞得合成胆固醇。

So the first thing the astrocytes are gonna have to do is synthesize cholesterol.

这个过程我们就不细说了，以前的播客里讲过。

Very quickly, we won't elaborate in-depth, but we've had podcasts on this before.

胆固醇的合成路径之一会经过倒数第二个甾醇前体，在脑部的星形胶质细胞里，这个物质叫脱氢胆固醇。

One of the cholesterol synthesis pathways goes through the next to last sterile penultimate sterile, and in the brain astrocytes, it's called desmosterol.

然后脱氢胆固醇就会转化成胆固醇。

And then desmosterol becomes cholesterol.

所以我们可能会谈到一种方法，就是通过脑脊液来检测脱氢胆固醇的水平。

So we'll probably talk about this is one way where we can measure desmosterol in the cerebrospinal fluid.

不过这其实挺难实现的。

Nah, that's kind of hard to do.

但在血浆里，它的水平和大脑的胆固醇生成是有关联的。

But in the plasma, it correlates with brain cholesterol production.

所以星形胶质细胞会合成胆固醇。

So the astrocyte makes cholesterol.

接下来它得给胆固醇裹上一种载脂蛋白，这样它才能被释放到细胞外基质里，游过去送到神经元那里。

It's now gonna obviously have to wrap it with a protein, an apoprotein, so it could shoot it out into the mattressome where it can travel, swim over and get to the neuron.

这里的关键区别在于。

And here's the difference.

在身体其他部位，我们说过，主要的结构蛋白是载脂蛋白B和载脂蛋白A。

In the periphery, we said, Hey, the structural proteins are apoB and apoA.

而在大脑里，起作用的是著名的载脂蛋白E。

In the brain, it's the famous apolipoprotein E.

ApoE很多人都知道，它跟大脑有关，因为不同类型的ApoE和认知障碍、阿尔茨海默病有关。

And apoE, many people know, oh, that has something to do with the brain because we know there are types of apoE that are associated with cognitive disorders and Alzheimer's disease.

不过咱们先只聚焦在ApoE这个蛋白上。

But let's just stick to the apoE protein.

所以星形胶质细胞合成胆固醇后，把它结合在一起，形成一个小小的脂蛋白，分泌到脑脊液里。

So the astrocyte synthesizes, it binds to cholesterol, and it becomes a little lipoprotein, which it secretes into the mattressome.

但这种脂蛋白是含有ApoE的。

But it's an apoE containing lipoprotein.

如果我们把这些含ApoE的脂蛋白拿去离心，它们会直接沉到离心管底部。

Now if we could take out those apoE containing lipoproteins and put them in a centrifuge, they would sink right to the bottom of the centrifuge.

那还有什么也会沉到离心管底部呢？

But what else would be sinking to the bottom of the centrifuge?

血液里的高密度脂蛋白。

High density lipoproteins in the plasma.

所以脑内的脂蛋白被称为HDL，因为它们的浮力和密度跟血液里的HDL一样。

So the brain lipoproteins are referred to as HDLs because they have the buoyancy and density of a plasma HDL.

但它们很不一样，因为血浆里的HDL会有两三个甚至四个apoA-I分子。

But they're very different because the plasma HDL will have two, three, four copies of apoA-one.

而脑部的HDL只含有两三个apoE分子，这才是关键区别。

The brain HDL will have a couple of three copies of apoE, and that is the big difference.

一旦进入网状结构，这个颗粒还会继续成熟。

Now, once it's in the matrosome, this particle, it continues to mature.

胆固醇会转变成胆固醇酯，聚集到颗粒中心，变成一个更大的脂质颗粒。

Cholesterol becomes cholesterol ester, goes to the center of the particle, and it becomes a big fat particle.

但别忘了，它的任务是把胆固醇运送到神经元那里。

But remember, its mission is to deliver cholesterol to the neuron.

所以神经元得把含apoE的颗粒抓过来，吞进去，或者抓住它并脱去脂质。

So the neuron's going to have to grab that apoB containing particle and internalize it or grab it and delipidate it.

那你们猜猜，神经元会表达什么受体？

So guess what the neuron expresses?

低密度脂蛋白受体。

Low density lipoprotein receptors.

这就容易让人误解，因为如果有人说，我知道大脑里的神经元有LDL受体，那大脑里肯定就有LDL。

And that creates confusion because if somebody says, Oh, I know the brain, the neurons have LDL receptors, so there have to be LDLs in the brain.

不对。

No.

因为LDL受体只对几种载脂蛋白有亲和力。

Because the LDL receptor, has affinities of just a couple of apoproteins.

在身体外周，LDL受体找的是ApoB100。

In the periphery, the LDL receptor is looking for apoB 100.

但在外周，ApoE也能和LDL受体结合。

But in the periphery, even apoE can bind to an LDL receptor.

而在大脑里，LDL受体只识别含ApoE的脂蛋白，因为根本不存在含ApoB的脂蛋白。

But in the brain, the LDL receptor only binds to apoE containing lipoproteins because there are no apoB containing lipoproteins.

所以其实是同一个受体。

So it's the same darn receptor.

这就是为什么我觉得我们该别再叫它LDL受体了。

And this is why I think we should stop calling it the LDL receptor.

所以我们应该叫它apoB和apoE受体。

And we call it we should call it the apoB, apoE receptor.

这才是它真正识别的东西。

So That's what it recognizes.

所以，汤姆，我其实对这一点挺困惑的。

So, Tom, I'm I'm actually quite confused by this.

我有很多地方想回头再理一理。

So there's a lot I want to back up on.

我就先从这一点说起吧。

I'll just start with that point.

我们先回到肝脏来看一下。

So let's back up to the liver for a moment.

肝脏上有这个受体，我们还是继续叫它LDL受体。

The liver's got this receptor, which we will continue to refer to as an LDL receptor.

当一个含apoB的颗粒——也就是普通的LDL——到达肝脏时，它表面只包裹着一个apoB。

When an apoB particle, an LDL, a garden variety LDL makes its way to the liver, it has one and only one apoB around it.

你能简单解释一下，这个LDL是怎么和LDL受体结合的吗？

Can you briefly explain confirmationally how that LDL interacts with the LDL receptor?

apoB蛋白的什么特性让它能像钥匙一样正好插进锁里？

What is it about the apoB protein that enables the key to fit into the lock?

apoB上有一个非常小的区域，叫做LDL受体结合域，抱歉，我说反了，是apoB上的结合域。

There's a very small segment of the apoB receptor that's called the LDL receptor binding domain, excuse me, on the apoB.

有一串特定的氨基酸排列成行，形成一定的表面电荷，而这边是LDL受体。

There are certain amino acids that line up, and they create they have a surface charge, And here's the LDL receptor.

LDL受体上也有一个特定区域，叫做apoB识别域。

Now the LDL receptor has a certain segment that is called the apoB recognition domain.

那里的一些氨基酸会产生特定的静电作用力。

There are certain amino acids there that create certain electrostatic forces.

apoB上那个结合域能否正确伸出，取决于它的空间构象，这就能解释为什么大颗粒LDL和小颗粒LDL的清除率不同——而那些结构正常的LDL，它们的apoB构象是标准的。

And if the domain on apoB and what determines is that sticking out properly is the confirmation of apoB, that explains the difference clearance rates between big LDLs and small LDLs, as opposed to normally constructed incised LDLs that have a normal apoB confirmation.

它们的清除速度要快得多。

They have much higher clearance.

小的LDL颗粒中，这个区域可能不容易暴露出来，而大的LDL颗粒呢，这个区域又不在该在的位置上。

The small LDL, where that domain may not be exposed as readily, or the big LDL, where it's not where it should be.

LDL受体很难轻易识别大的或小的LDL颗粒。

The LDL receptors don't as easily recognize big LDLs or small LDLs.

所以，那些拥有小LDL或大LDL的人，往往LDL颗粒数量很高，就是因为清除效率降低了。

And that's why people with small LDLs or even big LDLs often have very high LDL particle counts because clearances decrease.

LDL受体和apoB蛋白上其实只有几个很小的区域，只要它们能正确对齐，清除效率就会非常好。

So there are certain just small areas on the LDL receptor and the apoB that if they align properly, you have great clearance.

去年，我们从NIH的同行那里得到了一项新发现，刚刚发表：LDL受体是以二聚体形式发挥作用的。

New news is just discovered and published last year from our friends at the NIH is LDL receptors act as a dimer.

实际上，是两个受体同时表达、协同工作。

There's actually two of them that express at the same time.

就像两只龙虾钳子，能一次性夹住两个LDL颗粒。

It's like two lobster claws, and they grab two LDL particles at the same time.

不过，这对理解LDL受体的清除机制来说，影响其实不大。

So that's sort of irrelevant to just understanding the LDL receptor clearance process.

所以这解释了为什么LDL在血液中的滞留时间会更长。

So that explains part of the extended plasma resonance times of LDLs.

apoB的结构到底是怎样的？

How is the apoB conformed?

汤姆，既然LDL的大小在正常范围内变化都会影响清除效率，我真的很惊讶，同一个LDL受体居然能轻易地识别出大脑里那种极小的脂蛋白上apoE的某个部位，找到足够的构象匹配来完成清除。

So, Tom, given that the size of the LDL within a variation of normal can impact clearance, it really surprises me that that same LDL receptor can easily find somewhere on the apoE wrapping a very, very, very small lipoprotein in the brain enough of a conformational match to make that work.

这不仅让我大开眼界，而且简直让我这个满脑子胆固醇的大脑难以理解——我原以为，apoE脂蛋白比LDL小得多，更接近HDL，就算那段apoE和apoB序列完全同源，也不可能被受体识别出来，可事实偏偏就是这样。

So that is not only news to me, but very difficult to wrap my little cholesterol rich brain around, because I would think that the apoE lipoprotein being so much smaller than an LDL and being much closer to an HDL would never be able to find it even with complete homology between that section of apoE and apoB, which presumably must be the case or you wouldn't have the match.

是的。

Yeah.

apoE主要参与清除的是乳糜微粒和VLDL。

The primary reason where apoE gets involved with clearance of lipoproteins is on chylomicrons and VLDLs.

这些颗粒每个上面带有多个apoE分子，而apoB每个颗粒只有一个。

They carry several copies of apoE per particle, unlike the apoB, which is one copy per particle.

当它们完全充满甘油三酯时，体积会变得非常大。

So when they are fully full of triglycerides, they're very big.

apoB 的结构发生了某种改变。

The apoB is distorted in a certain way.

肝脏里负责清除 VLDL 和乳糜微粒的受体，叫做 LDL 相关受体一型。

Now the receptor in the liver that's gonna clear VLDLs and chylomicrons is called the LDL related receptor one.

所以它只对 apoE 有亲和力。

So it only has an affinity for apoE.

正是 LRP 清除了大部分含 apoE 的颗粒，比如千脂蛋白和 B 型 LDL。

So it's the LRP that clears most of the apoE containing particles, the kylos and the b LDLs.

这就是为什么它们在血液里的存留时间这么短。

And that's why they have such short plasma residence time.

我现在提一下这个点。

I'm gonna mention it now

因为汤姆，我刚才问的是另一个问题，可能我误解了你之前说的内容。

because it's gonna Tom, I was asking a different question, which maybe is maybe I misunderstood something you said.

我问的是神经元上的 LDL 受体。

I was asking about the neuron with its LDL receptor.

神经元上有LDL受体，它是怎么识别并把那个携带apoE的极小极小的脂蛋白从血液中拉出来的呢？

How does the neuron with an LDL receptor tag and pull a tiny, tiny, tiny lipoprotein with an apoE on it out of

真正的原因是，我之所以跟你们讲肝脏是怎么清除VLDL的，就是因为LRP只认apoE。

And the real reason, and this is why I'm explaining to you how the liver clears VLDLs and because the LRP only recognizes apoE.

大脑不仅表达LDL受体，还大量表达LDL受体相关蛋白。

And the brain not only expresses LDL receptors, but they express a lot of the LDL receptor related protein I see.

明白了。

Okay.

好的。

Okay.

这是一种针对apoE的清除机制。

Which is an apoE affinity clearing.

清楚了。

Understood.

明白。

Understood.

LDL受体可以清除一部分，不过主要还是靠LRP。

The LDL receptor can clear some of the Yep.

ApoE部分确实能被清除，但真正起主要作用的是LRP。

ApoE part, but it's the LRP that's doing most of it.

神经元表达的最后一个受体，我们之前提到过，叫清道夫受体B1。

The last receptor that the neuron expresses, and we've talked about this, is called the scavenger receptor b one.

它能结合HDL并去除其脂质，但这也是一个识别ApoE的清道夫受体。

That binds to the HDL and it delipidates it, but it's an apoE recognizing scavenger receptor also.

所以神经元里的所有受体基本上都在找ApoE，尤其是LRP，它只识别ApoE；而清道夫受体则识别ApoA1。

So everything in the neuron is basically looking for apoE and it gets it through, especially the LRP, which is only an apoE recognizing receptor, and the scavenger receptor recognizes apoA-one.

通常情况下大脑里不会有，但偶尔也会有，我们后面会讲到。

Typically not in the brain, but it can be, and we'll get to that also.

不过ApoE和清道夫受体的配合也很有效。

But apoE works well with the scavenger receptor too.

所以外周组织里的LDL其实很少。

So very few LDLs in the periphery.

我的意思是，大概只有2%的LDL携带了apoE，大部分其实都没有apoE。

I mean, maybe 2% of your LDLs have an apoE on and mostly there's no apoE.

虽然LDL受体能识别它，但这条清除途径其实很次要，就是LDL上带apoE的情况。

That although the LDL receptor can recognize it, it's it's a minor clearance pathway, apoE on an LDL.

我想回过头聊聊胆固醇的合成。

I wanna go back to the synthesis.

你刚才稍微提到了这一点。

You you alluded to this briefly.

我们有两种胆固醇合成途径。

We have two cholesterol synthetic pathways.

我的意思是，一条通路分叉成两条不同的路径。

I mean, one pathway that branches and bifurcates into two pathways.

这两条路径都能生成胆固醇，但中间的代谢物差别很大。

And in each of those pathways, they make cholesterol, but the intermediaries are quite different.

所以用的酶不一样，中间产物也不一样。

So different enzymes and different intermediaries.

我们通常根据它们倒数第二步的分子来称呼这两条通路。

And we often refer to them thinking of what their penultimate molecule is.

你已经提到过其中一条，就是从脱氢胆固醇转化成胆固醇的路径，另一条则是从粪甾醇转化成胆固醇的路径。

So you already referred to one, which is the path that turns desmosterol into cholesterol, and then the other one, of course, turns lathosterol into cholesterol.

在大脑中，这两条胆固醇合成通路的相对比例是多少？

What is the relative balance of cholesterol synthesis in the brain between those two pathways?

这个问题很有意思。

Very interesting.

在身体外周，绝大多数胆固醇是通过粪甾醇路径合成的。

In the periphery, the vast majority goes through the liposterol pathway.

通过脱氢胆固醇路径的量非常少。

Very little goes through the desmosterol pathway.

事实上，在外周组织中，主要使用脱氢胆固醇路径的是那些负责合成类固醇的细胞。

In fact, the primary cells that use the desmosterol pathway in the periphery are our steroidogenic tissues.

其他所有细胞，虽然也会有少量走脱氢胆固醇路径，但大部分还是走粪甾醇路径。

All of our other cells, I mean a little bit will go through the desmoster pathway, but most is lithostril.

所以如果你在血液里检测到类固醇水平升高，特别是岩藻固醇偏高，那说明外周细胞正在过量合成胆固醇。

So if you are measuring sterols in the blood, lithostril is up, you know, it's the peripheral cells that are overproducing cholesterol.

有意思的是，在大脑里，孩子十岁之前，所有细胞都在合成胆固醇，包括神经元。

Very interesting in the brain, when I told you up to the age of 10, all of the cells are producing cholesterol, including the neurons.

实际上，神经元合成胆固醇的途径是通过岩藻固醇的。

The neuron synthesis pathway actually does go through lithosterol.

但到了十岁左右，神经元决定不再合成胆固醇，这时候神经元就不再产生岩藻固醇了。

But at the age of 10, when the neuron decides I don't want to make cholesterol anymore, there's no lithosterol being produced by the neurons.

这时候，积累下来的全是脱氢胆固醇。

It's all desmosterol that's winding up.

如果神经元里出现了胆固醇分子，那一定是通过星形胶质细胞，走脱氢胆固醇这条通路输送进来的。

If there's cholesterol molecules winding up in the neurons, it's through the astrocyte, the block pathway going through desmosterol.

当然，如果大脑出现胆固醇短缺，神经元也能重新启动胆固醇合成，但在正常生理状态下，这种情况不会发生。

Now in a pinch, if there's a cholesterol deficiency in the brain, the neurons can start synthesizing cholesterol again, but in normal brain physiology, that doesn't happen.

所以岩藻固醇不能作为大脑胆固醇合成的标志物，主要原因在于，尽管大脑里确实有少量岩藻固醇途径在运作，但血液里检测到的岩藻固醇，95%都来自身体其他部位的细胞。

So, lithostril is not used as a marker of brain cholesterol synthesis for the big reason, even though there is some lithostril pathway going on in the brain, if you measured it in the blood, 95% of it is your other cells making it.

但如果你测量血液中的脱氢胆固醇，它的含量与脑脊液和脑组织中的脱氢胆固醇高度相关。

Whereas if you measure desmosterol in the blood, the majority of it reflects, correlates extremely high with cerebrospinal fluid, desmosterol and brain tissue, desmosterol.

所以这是一个非常有用的指标，我们可以通过血液检测来获取，因为血浆中的脱氢胆固醇与脑脊液和脑部胆固醇的水平高度一致。

So that becomes a very cool marker that we can actually measure in the bloodstream, because desmosterol in the plasma correlates very highly with cerebrospinal fluid and brain cholesterol.

这是为什么呢，汤姆？

And why is that, Tom?

这让我觉得反直觉，因为它们看起来完全是两条独立的通路。

That's counterintuitive to me because they seem like completely independent pathways.

为什么血液里测到的脱氢胆固醇能反映大脑的胆固醇合成情况？

Why should the desmosterol you measure in the blood tell us anything about the cholesterol synthesis of the brain?

我觉得，这方面你比我更擅长找出背后的演化逻辑，进化可能在关键部位只保留了一条通路。

I think, and you're better at figuring out these teleologic reasons than I, that evolution decided there's one pathway that we're gonna do in very critical areas.

大脑只靠自身合成胆固醇，并储存在脂肪组织里，我们希望它完全依赖这条通路。

The brain, which only makes its own cholesterol and stores it in the steatorrhogenic tissue, we want them to be dependent on that pathway.

为什么？

Why?

这个我没法给你确切答案，但这条通路确实反映了这一点。

I don't have an answer for you on that, but that's what that pathway, reflects.

明白了。

Alright.

我们回头再聊这个，因为我知道这背后有重要的临床意义，值得我们认真思考。

We'll come back to that because I know there's a there's a clinically relevant reason that we we might wanna think about that.

好的。

Okay.

我们已经知道，神经元一旦达到一定年龄，就会减少像包工头那样到处奔波、搞建设的高耗能模式，转而更倾向于做设计师，因为这样更节能。

So we've established that the neurons, once they reach a certain age, wanna start optimizing less around being general contractors and construction workers and more around being architects because of the energy cost.

同时我们也确认了，大脑里有一套不同的脂蛋白负责运输胆固醇，让神经元能从周围的少突胶质细胞，也可能包括星形胶质细胞那里，持续获得足够的胆固醇。

And we've also established that you have a different lipoprotein that is transporting cholesterol in the brain so that the neurons can still acquire plenty of it from their neighboring oligodendrocytes and presumably to some extent astrocytes.

我想为听众澄清一点，虽然我们之前没明说，但细心的听众应该已经注意到了——我们一直在谈载脂蛋白E，而你也提到过，它和阿尔茨海默病有关。

I do want to just make one point clear for the listener, which we haven't really explicitly stated, but the astute listener, of course, has already picked up on the fact that we've talked about apoE, and as you've said, apoE has a relationship to Alzheimer's disease.

我只想确保大家分得清APOE基因和载脂蛋白E蛋白的区别。到目前为止，我们讨论的始终是载脂蛋白E这个蛋白质，也就是小写a、小写p、小写o、大写E组成的apoE，我们说的一直都是这个蛋白。

I just want to make sure people understand the difference between apoE genes and apoE the protein, because to date, through this discussion, we have only spoken about apolipoprotein E, a protein, and this is denoted with a small a, small a, small p, small o, big E, and that's when we're talking about apoE, the protein.

但如果你写成全大写的APOE，那就是指基因型了。当然，你有两份，所以可能是3.3、3.4、4.4、2.3这样的组合。

But if you were to write all caps APOE, you'd be referring to the genotype, and of course you have two of these, so you could be a 3.3 or 3.444, 2.3, etcetera.

你能不能解释一下这六种基因型组合——从2.2到4.4——之间的区别？它们如何产生不同的蛋白质？然后我们再聊聊为什么这很重要。

You want to just explain the relationship between those different six combinations of genotypes, everything from a two two to a four four, and how the different genes make different proteins, and then we should talk about why that's relevant.

是的，这一点在我们的讨论中非常关键。

Yeah, and it's a big part of this discussion.

apoE蛋白有不同的形态。

So the apoE protein comes in different shapes.

这些叫异构体。

Called isoforms.

彼得已经讲过很多次了。

Peter has explained this many times.

其实这些异构体之间，差别就只有一个氨基酸。

It's really only one different amino acid in the darn protein that separates these.

但就是这一个氨基酸的替换，会彻底改变整个肽链的折叠方式，进而影响它能结合什么物质——而这正是载脂蛋白最关键的功能。

But just removing or replacing or putting the wrong amino acid in the entire peptide changes its ability to bend and shape, that will affect what it can bind to, which is the crucial function of apo proteins.

所以你从妈妈和爸爸那里各继承了一个基因，妈妈给一个，爸爸给一个。

So there are the you inherit the genes from mom and dad, and that means one gene from mom, one from dad.

也就是说，你从妈妈那里得到一个等位基因，从爸爸那里得到另一个。

So you get one allele in your gene and the other allele from each.

那你的妈妈是APOE2、APOE3还是APOE4？你爸爸呢？

So was your mom an apoE two, three or four, or likewise with dad?

而你可能会继承好几种不同的组合。

And you're going to inherit, there's several potentials.

你可能是E2/E2、E2/E3、E3/E4、E2/E4、E4/E4，或者纯合的E4/E4。

You can be an E2, E2, E2, E3, E4, E3, E2, E2, E4, E4 or E double, homozygote for E4.

取决于你具体继承了哪两种基因，你的APOE蛋白结构就会略有不同，这会影响它在结合脂蛋白时的功能表现。

So depending which of those genes you attack, your apoE protein is going to be constructed a little bit differently, which is going to affect its ability to function whatever apoE is doing when it's stuck to a lipoprotein.

它最主要的作用是作为配体，决定哪些分子能与它结合，或者除了脂蛋白之外，APOE还能和什么结合。

And the main thing it's doing, it's serving as a ligand to what things are going to bind to or even what the apoE will bind to other than the lipoprotein.

因此，你体内产生的APOE类型，对某些疾病的发病机制至关重要。

So the type of APOE you manufacture is critical to certain disease pathologies.

彼得可以告诉你具体的数值。

Peter can give you the exact indices.

普通人大多是 apoE3E3 基因型。

The average person has an apoE3E3 genotype.

我觉得大概三分之二的人都是这样。

I believe it's about two thirds of people that have that.

携带 apoE 基因的人本来就少，尤其是 E2 纯合子更少见。

Far less people carry the apoE gene, especially apoE two homozygosity.

彼得，你来说说有多少人是 E4 杂合子，又有多少是 E4 纯合子？你有这些数据吧。

Peter, why don't you tell how many carry the e four heterozygotes and the e four homozygotes, you have those percentages.

这要看具体的研究数据，但一般来说，大约百分之五十五的人是 E3E3，也就是所谓的野生型。

I mean, you know, again, it depends on the series you look at, but it seems about fifty five percent of the population are e three e three, the so called wild type.

百分之二十到二十五的人可能是 E3E4，而 E4E4 的人只占百分之一到二。

Twenty to twenty five percent might be e three e four, and one to 2% would be E4, E4.

正如你所说，E2E2 是最罕见的表型。

As you pointed out, E2, E2 is the most rare phenotype by far.

这远低于百分之零点五。

That's significantly less than half a percent.

我觉得E2E3大概在百分之二到三之间。

I think E2, E3 is probably on the order of two to three percent.

E2E4也很罕见。

E2E4 is also quite rare.

最常见的是E3E3和E3E4，两者远远领先。

The two most common by far are E3E3 and E3E4.

我们在这档播客里多次提到过，阿尔茨海默病的风险从E3E3——始终作为基准——到E3E4和E4E4，是呈非线性上升的。

As we've talked about many times on the podcast, the risk associated with Alzheimer's disease between three three, which is always the reference case, and three four and four four, those go up nonlinearly.

E3E4携带者，也就是有一份E3和一份E4的人，会产生一种不如野生型有效的载脂蛋白E，他们的阿尔茨海默病风险大约是E3E3携带者的两倍。

The three four individuals, the people that have one copy of three, one copy of four, they make a version of apoE, the protein that's not as good as the wild type, and their risk of Alzheimer's disease is about two times higher than someone who has a three, three.

当然，这还得看具体的数据集。

Again, it depends on the series.

有时候数据会显示高出三倍，但大致就是这个数量级。

Sometimes you'll see that at three times higher, but directionally, that's about the level.

相反，如果你有两个E4拷贝，风险会高得多。

Conversely, if you have two copies of the four, that risk is significantly higher.

十五年前，汤姆，当时的文献还说这个风险高出二十到二十五倍。

There was a day, Tom, fifteen years ago, the literature was calling that 20 to 25 times higher.

这个数字现在已经大幅下调了，我认为大多数研究都会认为是八到十二倍的增加。

That number has come down considerably, and I think most series would talk about that as being an eight to 12 fold increase.

拥有两个E4基因拷贝，风险确实会增加一个数量级，这意味着你产生的apoE蛋白效率低得多。

It's a full log increase in risk for sure to have two copies of the E4 gene, which means you're making an apoE protein that is far less effective.

是的，这会带来一系列影响。

Yes, and this is gonna have ramifications.

我们之前做过几期节目，彼得还请过丹·雷德来过。

We've done podcasts, and Peter has had Dan Rader on here.

外周HDL最重要的作用，其实不是它转运了多少胆固醇。

The most important thing about the peripheral HDLs is not the amount of cholesterol they traffic.

这个量其实挺小的，只是在体内来回传递而已。

It's kind of trivial and it gets transferred here and there.

如果你只是测量HDL胆固醇，几乎得不到任何有用的信息，因为HDL颗粒本身才是关键——它们占了你体内所有脂蛋白的90%。

And it almost tells us nothing if you're measuring HDL cholesterol, tells us nothing about what the HDL particles Remember, they're 90% of your lipoproteins out there.

所以显然，转运胆固醇并不是它们最主要的功能。

So clearly what they're doing to cholesterol is not their major function.

这意味着HDL还有其他作用。

So that means HDLs do other things.

随着研究深入，我们发现它们实际上参与了无数其他生理过程，调控着人体健康的方方面面。

And as we're learning, they do innumerable other things that regulate all aspects of human health.

它们其实是先天免疫系统的一部分，参与对抗炎症、感染、慢性病，甚至癌症。

They're actually a part of the innate immune system, so they're involved with fighting inflammatory diseases, infectious diseases, chronic diseases, cancer.

所以我们真正需要的，不是HDL胆固醇这种几乎没什么用的指标。

So what we wish we had is not HDL cholesterol, which tells us very little.

我们更希望有检测方法，能判断某个患者体内的HDL是否在正常发挥作用。

We wish we had tests that would tell us are the HDLs in a given patient's body doing what they're supposed to be doing?

它们到底有没有功能？

Are they functional or not?

但高密度脂蛋白所承担的功能实在太多了。

But there's so many different functions that HDLs perform.

关键不在于它们携带的胆固醇，而在于它们可能携带的蛋白质类型。

It has to do not with the cholesterol they're carrying, but yet the types of proteins they might be carrying.

目前已发现至少两百多种蛋白质存在于外周血的高密度脂蛋白颗粒上。

Well over 200 proteins have been described in the periphery as being found on HDL particles.

但这并不意味着一个高密度脂蛋白颗粒上会携带一百种肽段。

Now that doesn't mean there's an HDL particle carrying a 100 peptides on it.

这根本不可能。

Impossible.

它们太小了。

They're too small.

每个高密度脂蛋白可能只携带一两种肽段，而每种肽段都可能有某种功能，甚至我们还不清楚它们具体是什么。

But each HDL might carry one or two peptides, and each of those peptides might have some function that it's hard to even know what they are.

它们是在帮助免疫系统，还是参与凝血，又或是别的什么？

Are they helping the immune system, or are they involved with coagulation, or what?

所以我们实际上拥有大量不同类型的HDL颗粒，每一种都携带一两个这样的肽段，再加上apoA-1和apoA-2，以及一些与脂质代谢相关的载脂蛋白。

So, we have actually numerous armies of HDLs, each constructed with one or two of those peptides in addition to apoA-one and apoA-two, some of the lipolipid related apoproteins.

因此，我们根本没有办法准确测量这些HDL亚群。

And so there's no way to know for us to measure these HDL subpopulations.

所有携带这些蛋白质的HDL都不含胆固醇，它们属于非常小的HDL颗粒。

Now, all of the HDLs that are carrying these proteins, they're not carrying cholesterol, so they are the really small HDL particles.

它们的密度最高，因为在离心过程中，颗粒的密度主要由脂质含量决定。

They have the highest density because really what determines the density of a particle in the centrifuge is its lipid content.

脂质越多，颗粒就越轻，越容易上浮。

The more lipids, the more buoyant they flow.

HDL所含的脂质比apoB颗粒少得多。

The HTL carries the least amount of lipids compared to the apoB particles.

所以它在离心管里会下沉。

That's why it sinks in the centrifuge tube.

而最小的HDL，也就是盘状HDL，只由apoA-1构成，它们会沉到管底，因为根本没有任何浮力。

But the tiniest HTLs, the discoidal HTLs, apoA-one by itself, they're sitting right at the bottom because there's zero buoyancy to them.

所以，我们现在有一大群非常微小、高密度的HDL颗粒，里面可能装载着关键的蛋白质。

So, if we have this whole army of very tiny, high density HDL particles that are packing probably critical proteins.

天哪，你难道不希望我们能测出它们吗？

Geez, don't you wish we could measure them?

但这里才真正有意思。

But here's where it gets interesting.

我们之前在播客里提到过，有一种脂蛋白能穿过血脑屏障进入大脑，那就是这些极小的HDL颗粒，要么是游离的apoA-one，要么是apoA-one和另外几个蛋白质结合而成的。

We've hinted earlier in this podcast that there is a lipoprotein that can traverse that blood brain barrier and get into the brain, And it's these extremely small HDL particles, either free apoA-one or an apoA-one that's bound to a couple of these other proteins.

也许这些蛋白质里，有些具有很强的抗氧化和抗炎作用。

And maybe some of these proteins are very important, antioxidative proteins, anti inflammatory proteins.

如果这些我们根本测不到的微小HDL颗粒能穿过血脑屏障，进入大脑，

So if those tiny HDLs that we cannot measure jump into the blood brain barrier or through it and they're now in the mattress.

那它们到底去了哪儿？

So where do they go?

它们一进去，就会立刻结合上第一个遇到的含apoE的脑部HDL。

They immediately bind to the first apoE containing brain HDL that they bump into.

于是，这个由星形胶质细胞产生的、含apoE的脑部HDL颗粒，现在也携带了一两份原本来自血液的apoA-I。

So all of a sudden, this astrocyte apoE constructed brain HDL particle is also carrying a copy or two of h apoA-one that actually originated from the plasma.

脑细胞本身是无法合成apoA-I的。

The brains can't synthesize apoA-one, the brain cells.

所以如果它出现在脑内——而我们已经知道它确实能进去——那它一定是穿过了血脑屏障。

So if it's in the brain, and we know it is, they do pass the blood brain barrier.

人们普遍认为，这个过程是通过受体介导完成的，很可能就是血脑屏障上表达的那类清道夫受体，帮助apoA-I或携带辅助蛋白的极小致密HDL进入脑内。

It is believed that is receptor mediated and might be this good old scavenger receptor, again expressed at the blood brain barrier that facilitates entry of apoA-one or the really small dense HDL, APOA-1s carrying accessory proteins.

我们希望的是，第一，只要它们能进去，那就太好了。

And the hope is, hey, number one, if they get in, great.

这样一来，脑部的HDL就出现了不同的亚型。

So now the brain HDLs, you have different subpopulation of brain HDLs.

你可能有只含apoE的脑部HDL。

You might have only APOE containing brain HDLs.

也可能存在含apoA-I的脑部HDL，但大多数应该是apoE和apoA-I共同存在的那种。

You might even have, some apoA-one brain HDLs, but most of them are gonna be apoE plus apoA-one brain HDLs.

那些跟着载脂蛋白A-一一起进来的其他蛋白，或许能在大脑里发挥一些积极作用。

And those other proteins that came with the apoA-one maybe can do start doing some good things in the brain.

这一点可能特别重要。

And where this might be really good.

在身体外周，其实早就存在脑功能相关的机制了。

So in the periphery, we have brain functionality.

我还没细说，但你很容易就能推断出来。

I did not introduce it, but it's easily you can deduce that.

等一下。

Wait a minute.

如果外周有功能正常的HDL，那很可能也存在功能异常的HDL——它们要么缺少应有的蛋白，要么携带了不该有的蛋白，反而会对组织造成伤害。

If there are functional HDLs in the periphery, I'll bet there are circumstances where there are dysfunctional HDLs in the periphery that are not equipped with the proper protein or they're carrying proteins they shouldn't be carrying, proteins that can do harmful things to tissues.

那些就是功能异常的HDL。

They would be dysfunctional HDLs.

要是能有个血液检测方法来发现这个就好了。

Don't I wish we had a blood test for that?

但我们还没有。

And we do not.

所以在大脑里，现在这些apoE颗粒可能携带着apoA-one。

So, in the brain, now you have these apoE particles maybe carrying apoA-one.

但如果你是apoE4的生产者，当你的星形胶质细胞产生apoE时，它会是apoE4型的，就像在外周一样，这是一种功能异常的apoE。

But now if you're an apoE4 producer, when your astrocyte produces apoE, it's going to be an apoE4 type of, and that tends just like in the periphery, it's a dysfunctional type of apoE.

所以如果你携带apoE4基因型，而你的星形胶质细胞产生的正是apoE4肽，并且它们构成了HDL的一部分，那这种HDL在大脑中很可能就是功能异常的。

So if you have the apoE4 genotype and your astrocyte is producing apoE4 peptides and they're what's constructed on the HDL, that's likely to be a dysfunctional HDL in the brain.

那这会意味着什么？

And what would that mean?

这意味着它结合神经元受体的能力不如E3或E2那么好，因此胆固醇运输到神经元的过程就被打乱了。

It means that it doesn't bind to the neuron receptors as well as an E3 or an E2 might to those receptors, and therefore you have disrupted cholesterol transport into the neuron.

突然间，神经元得不到它所需的胆固醇，而这会造成严重问题，因为神经元会把胆固醇直接用在细胞膜上。

Now all of sudden a the neuron is not getting the cholesterol it needs, and that will create havoc because the neuron puts it right in the cell membranes.

如果你的细胞膜胆固醇含量不足，这里就会出问题，因为淀粉样前体蛋白就坐落在这个地方。

If you don't have the proper amount of cell membrane cholesterol, this is where something called amyloid precursor protein sits.

如果胆固醇平衡失调，就会被一种叫分泌酶的酶作用。

And if you don't have the right cholesterol balance, it's acted upon by certain enzyme called secretases.

这就是为什么你会开始产生β-淀粉样蛋白甚至tau蛋白，因为神经元细胞膜里的胆固醇不够。

That's where you start producing beta amyloid and even tau because you don't have the right amount of cholesterol in your neuron cell membranes.

这就是载脂蛋白E4与阿尔茨海默病有关的原因之一。

And this is how e four, one of the many reasons why it's associated with Alzheimer's.

我先说到这里，让你有机会插话，免得我接着讲E4的脑部HDL做不到、而E3或E2的HDL能做到的其他事情。

I'll stop there perhaps for you to jump in before I just maybe describe some of the other things that apoE four brain HDLs don't do that an apoE three or an apoE two HDL would.

实际上，我想先倒回去说一点，汤姆。我们之前一直绕着一个话题没明说，那就是：脑内胆固醇的移动，跟大家在听这个播客时很熟悉的淀粉样蛋白，到底有什么关系？

Well, I actually wanna take us backwards for a second, Tom, because one thing that we've danced around, but I don't think we've explicitly addressed is what is the relationship between brain cholesterol movement and something that people are very familiar with if they've listened to this podcast, which is amyloid.

大家当然都知道脑内β-淀粉样蛋白和磷酸化tau的堆积，现在也越来越清楚，我们已经有很好的生物标志物可以追踪这些物质了。

People are obviously familiar with the accumulation of beta amyloid and p tau in the brain, and people are now really starting to understand that we actually have great biomarkers where we can start to track those things.

这两者之间有联系吗？

Is there any relationship between those?

换句话说，当你谈到脑内胆固醇运输功能紊乱，我们知道这和载脂蛋白E基因型高度相关，而载脂蛋白E基因型又和阿尔茨海默病密切相关。

Other words, as you talk about all of this dysfunctional movement of cholesterol in the brain, and we know that that is highly associated with your apoE genotype, and we also know that your apoE genotype is highly associated with Alzheimer's disease.

所以我们还没把这三者联系起来：淀粉样蛋白、tau蛋白和胆固醇之间到底有什么关系？

So the one thing we haven't put together is what's the relationship between amyloid tau and cholesterol?

肯定是有联系的。

There must be a link.

对吧？

Right?

当然有。

Definitely.

这可是老话题了。

We go way back.

你可以看看阿尔茨海默病患者的尸检研究，发现他们的脑组织，尤其是神经元，胆固醇含量严重超标。

You can read the studies of autopsies patients with Alzheimer's disease, and they're really cholesterol overloaded tissues, especially the neurons.

记住，神经元的功能主要取决于细胞膜的完整性。

So remember, the neuron, the main thing determining its function is its cell membrane integrity.

如果细胞膜结构正常，信号传递才会顺畅，突触也能正常放电。

And if you have the proper cell main construction, signaling occurs properly, the synapses fire properly or so.

如果神经元的细胞膜里胆固醇过多，就会像我刚才提到的阿尔茨海默病患者那样，细胞膜上还有一种叫淀粉样前体蛋白的东西。

Now what will happen if you have too much cholesterol in that cell membrane, and this is what happens in the Alzheimer's patients, what I just alluded to a few seconds ago, also located in the cell membrane is amyloid precursor protein.

这种蛋白会进一步转化成β-淀粉样蛋白。

That's a protein that is gonna evolve into the production of beta amyloid.

淀粉样蛋白有两种类型，40型和42型，其中42型毒性更强，40型相对没那么有害。

So, and whether it produces there's two types of that amyloid, forty and forty two, with 40, two being the more injurious type of amyloid beta and the 40 being a less toxic type of amyloid beta.

当神经元细胞膜胆固醇含量过高时，就会激活一种叫β-分泌酶和γ-分泌酶的酶。

So when there's too much cholesterol in the cell membrane of a neuron, there's something called beta and gamma secretase.

这些酶会让淀粉样前体蛋白裂解，生成更多的淀粉样蛋白42。

They're enzymes that make the amyloid precursor protein cleave into the production of amyloid 42.

如果细胞膜里的胆固醇水平正常，就会由α-分泌酶主导，减缓前体蛋白的裂解，转而产生更多毒性较低的淀粉样蛋白40。

If there is the proper amount of cholesterol in the neuron cell membrane, it's a secretase alpha secretase that sort of slows the cleavage of amyloid precursor protein into apoB, and you wind up producing more of the beta amyloid 40, which is the less toxic form.

所以，细胞膜中的胆固醇含量，是影响这一过程的关键因素。

So, obviously, it's the cholesterol content in your cell membrane that is a major, major factor.

关于胆固醇的稳态，还有另一个方面，我们现在也可以提一下。

There's one other aspect of cholesterol homeostasis that we might as well introduce now.

细胞膜里胆固醇过多对神经元有害，因为膜的功能会受影响，而神经元是大脑中唯一能排出胆固醇的细胞。

Because too much cholesterol in the cell membranes is a danger to the neuron because the membrane isn't going to function, the neuron is the one cell in the brain that has the ability to get rid of cholesterol.

我们之前花了很长时间说，大脑会合成胆固醇并把它保留下来。

We've spent a lot of time saying the brain makes cholesterol and it retains it.

事实上，大脑中胆固醇的半衰期长达五年，而身体其他部位只有几天。

In fact, the half life of cholesterol in the brain is five years as opposed to a few days in the periphery.

这说明大脑是在储存胆固醇。

So that tells you the brain is reserving cholesterol.

但我早先就说过，任何细胞里胆固醇过多都是有毒的。

But early, early, I told you too much cholesterol in any cell is toxic.

神经元不仅会因此膜功能紊乱，胆固醇还会在细胞质里结晶，直接杀死神经元。

And the neurons not only will it disrupt membrane function, but it crystallizes in the cytosol of the neuron and it kills neurons.

我们当然不希望神经元死亡。

You don't want to kill neurons.

如果这种情况长期持续，就会引发某种慢性脑部疾病。

You're going to have some sort of chronic brain disease if that happens over time.

所以进化赋予了神经元一种能力，能把胆固醇转化成一种叫氧固醇的物质，具体来说就是24S-羟基胆固醇。

So evolution has given the neurons the ability to change cholesterol into something called an oxysterol, and the one it produces is called 24S hydroxycholesterol.

了解胆固醇生化结构的人知道，它在第一个环的第三位上有一个氧原子。

People who know what cholesterol looks like biochemistry wise, it has one oxygen molecule at the third position of the first ring.

24S-羟基胆固醇不仅保留了胆固醇原有的那个氧原子，还在第24位碳上加了第二个羟基。

24S hydroxycholesterol not only has that one cholesterol molecule, it has a second one at carbon 24.

这样一来，胆固醇分子的两端各有一个羟基。

So now you have a hydroxy group on both ends of the cholesterol molecule.

这使得它的水溶性稍微提高了一些。

That makes it a little bit more water soluble.

当神经元需要排出多余的胆固醇时，它会启动一种叫24S-羟基胆固醇合成酶的酶，把胆固醇转化成24S-羟基胆固醇——这种物质能溶于水。

So when the neuron says, I've got to get rid of cholesterol, it has an enzyme, 24S-hydroxycholesterol, will make cholesterol change into 24S-hydroxycholesterol, which is water soluble.

然后它就会离开神经元。

It comes out of the neuron.

它能轻松穿过星形胶质细胞层，到达血脑屏障，因为两端都有羟基，它是一种亲水性的脂质，可以顺利通过。

It floats right through the mattressome to the blood brain barrier where it can pass right through it because it's sort of a hydrophilic lipid with an oxygen hydroxy group on each end.

当它碰到血脑屏障时，脂肪酸和磷脂都很排斥羟基，于是它们就分开，形成一个小通道，让24S-羟基胆固醇跳进血浆。

When it hits the, blood brain barrier, the fatty acids and the phospholipids hate the hydroxy groups, so they separate and it just creates a little tunnel through which the 24S hydroxycholesterol can jump into plasma.

等等，它毕竟是个脂质。

Now, a minute, it's a lipid.

它不可能直接游进血浆，那血浆里有什么能迅速结合这种排出的24S-羟基胆固醇呢？

It can't jump into free plasma, but what's floating in the plasma that rapidly binds to the excreted 24S hydroxycholesterol?

要么是白蛋白，要么是路过的任何脑源性脂蛋白。

Either albumin or any brain lipoprotein that floats by.

现在它就变成蛋白质的一部分了。

Now it's part of a protein.

它要么结合在白蛋白上，要么结合在脂蛋白上。

It's on albumin or it's on a lipoprotein.

这些蛋白会把它运回肝脏。

They bring it back to the liver.

最妙的是这一点。

Now here's the cool thing.

除了大脑，身体里还有哪个组织能产生氧固醇？

What's the only other tissue in the body beside the brain that can produce an oxysterol?

就是肝脏。

It's the liver.

那肝脏对氧固醇会做什么处理呢？

And what does the liver do with oxysterols?

肝脏里可是有胆固醇的。

Well, the liver has cholesterol.

你知道的，皮特，肝脏是我们制造胆汁酸的主要——甚至是唯一——的工厂，而胆汁酸属于氧化固醇。

You know, Pete, that the liver is our major our only manufacturer of bile acids, which are oxysterols.

所以胆固醇在肝脏里被转化成氧化固醇，用的酶和神经元表达的是同一种。这些氧化固醇经过几步转化，最终变成胆汁酸，一路排到肠道里。

So cholesterol gets transformed into an oxysterol in the liver, same enzyme that the neurons express, and the oxysterols, they go through several steps, but they become your bile acids down to your gut.

然后就跟着粪便一起排出去了。

Goodbye fecal y.

所以，大脑其实有个很巧妙的办法，就是通过这种转化来清除多余的胆固醇。

So the brain actually has this cool way of getting rid of excess cholesterol by that transformation.

它会被送到肝脏，然后通过粪便排出体外。

You send it to the liver where it could be fecal excluded or so.

所以这种24S羟基胆固醇变得非常重要。

So this 24S hydroxycholesterol gets very important.

但如果你的神经元细胞膜里胆固醇积聚得太多，现在它就在细胞膜上。

But if, again, you start to build up too much cholesterol in your neuron cell membrane, it's in the cell membrane now.

因此，神经元胞质里的胆固醇就变少了。

So there's less cholesterol in the cytosol of the neuron.

神经元就会停止生成24S羟基胆固醇。

The neuron stops making 24 s hydroxycholesterol.

大脑不再向血液中释放胆固醇了。

Brain is not escaping into the plasma anymore.

所以研究人员才把血浆中的24S羟基胆固醇当作评估大脑健康的生物标志物。

This is why researchers use 24 s hydroxycholesterol in the plasma as a biomarker of brain health.

它本来不该出现在血液里，因为大脑已经把所有胆固醇都留住了。

It shouldn't be there because the brain is retaining all its cholesterol.

神经元不再试图排出胆固醇了。

The neuron's not trying to excrete any cholesterol.

但如果真的排出了，血液里的浓度就会升高。

But if it does, the concentration of that in the plasma goes up.

肝脏不会把它的氧固醇分泌到血液里，但大脑会。

The liver doesn't secrete its oxysterols into the plasma, but the brain does.

所以它是反映大脑健康状况的绝佳指标。

So it's a great biomarker on brain health.

浓度过高就意味着大脑正在面临危险。

So too much tells you the brain is in danger.

因此，那些研发脑部药物、试图预防痴呆的科研人员，都会监测24S羟基胆固醇的水平——他们认为，如果药物有效，能帮助大脑预防阿尔茨海默病，血液里就该检测不到这种物质了。

This is why people who are developing drugs for the brain to try and prevent dementia, they monitor 24S hydroxycholesterol, because they think if their drug is helping the brain prevent Alzheimer's disease, you won't find 24S hydroxycholesterol in the bloodstream.

这属于一种无菌生物标志物，就像我们之前提到的脱氢胆固醇。

And that's one of the sterile biomarkers, as is the desmosterol that we alluded.

所以我们实际上有两个可以测量的指标。

So we actually have two things that we can measure.

问题是这样：

Here's the bad thing.

在现实中，测量脱氢胆固醇其实挺容易的。

In the real world, we can get desmosterol measurements fairly easily.

目前还没有任何商业实验室能提供24S羟基胆固醇的检测服务，它还只限于科研用途。

There's no commercial laboratory that twenty four s hydroxycholesterol has become available outside of research studies.

真希望我们能给病人做这项检测，因为这将是越来越多脑健康生物标志物中的又一个重要指标。

I wish we could measure that in our patients because it would just be another of the many biomarkers that are starting to emerge on brain health.

所以，回到重点，正是这种异常的ApoE4蛋白，它本该去结合那些负责将ApoE-HDL从脑部运进神经元溶酶体的受体，从而释放胆固醇供神经元使用。

So finally, back up, it's this disruptive, this apoE4 that is going to the receptors that should be internalizing the apoE HDL in the brain into the lysosomes in the neuron, which will generate cholesterol for the neuron to use.

但因为E4型脑部HDL的清除效率大幅下降，当它刚接触到细胞膜时，胆固醇虽然能进入神经元的膜结构，却无法进入细胞质。

But since there is markedly decreased clearance of the E4 brain HDL, just when it touches the membrane, the cholesterol can jump into the cell membrane of the neuron, but it doesn't get to the cytosol.

所以，E4患者体内的脂质代谢机制复杂得惊人。

So it's very complex, these lipid mechanics that are going on in the e four patient.

在我们继续讨论ApoE4在大脑中其他可能失效的功能之前，你们可以先就这一点提问。

And I'll let you ask about that before we get into other attributes of what apoE four might not be doing well in the brain.

我想提个问题，把话题进一步拉到临床层面。我们刚才聊了这么多，却一直没怎么谈药物的影响，现在我想把这一点补上。

Well, I kind of want to ask a question that brings it even further to something clinical, which is we've we've come this far in the discussion without really talking about the impact of pharmacology, so I want to I want to sort of make that bridge now.

我们当然不会细究所有为什么要用药物降低apoB的原因。

Obviously, we're not going to get into all the reasons why one would lower apoB pharmacologically.

这些在之前讨论外周机制时已经隐含了，但说到降低血脂的药物，大多数人第一反应根本不是贝特类、依折麦布、PCSK9抑制剂、胆汁酸螯合剂、CETP抑制剂这些，而是——

It's implied in so much of what we already discussed in the periphery, and when you talk about that, the thing that comes to most people's minds, I mean, most people aren't thinking of bempedoic acid and ezetimibe and PCSK9 inhibitors or bile acid sequestrants or CPET inhibitors or CTEP inhibitors rather.

一提到降脂药，大家默认想到的只有一类药，那就是他汀。

When you say lipid lowering therapy, everybody defaults into one class of drug, and that class of drug is called the statin.

那我们不妨聊聊他汀在大脑里到底起不起作用。我可以把讨论限定在两类他汀上：亲脂性的和亲水性的。

So let's talk for a moment about what statins do, if anything, in the brain, and I'll bracket the discussion by saying maybe we can formulate it through the lens of the two types of statins, those that tend to be more hydrophobic and those that tend to be more hydrophilic.

稍微说说这一类药的基本情况。

Maybe talk a little bit about that class of drugs.

我们没时间细讲它们的全部历史，所以就聚焦在现代常用的那些品种上，不往前追溯了。

I don't think we have the time to go into the entire history of them, so we even do it through the lens of the modern versions of those drugs as opposed to going back in time.

你能不能讲讲，这类药具体是怎么影响大脑的？

But talk a little bit about how those drugs work in the brain specifically.

他汀类药物确实是降低外周 apoB 的首选药物，这一点毫无疑问，因为它能有效减少动脉粥样硬化性心脏病。

Of course, statins are the number one drug to lower apoB in the periphery because that, no doubt about it, reduces atherosclerotic heart disease.

在目前常用的那些降低 apoB 的药物中，只有他汀类能够穿过血脑屏障，进入大脑。

But of all, and people rattled off, the classes of apoB lowering drugs that are primarily used nowadays, of all of those, there's only one that can penetrate the blood brain barrier and get into the brain, and it is the statin class.

其他提到的那些药物，要么只在肝脏起作用，要么根本不可能穿过血脑屏障。

All of those other drugs mentioned either work solely in the liver or no way they could penetrate the blood brain barrier.

它们对大脑中的胆固醇稳态没有任何影响。

It didn't do anything to brain cholesterol homeostasis.

所以，如果他汀类药物能进入大脑，彼得刚才提到了亲水性和亲脂性他汀，也就是脂溶性和水溶性他汀。

So if a statin gets into the brain now a little bit, Peter mentioned what we call hydrophilic, hydrophobic statins, lipophilic, lipophobic.

亲水性喜欢水，亲脂性喜欢脂质，讨厌水。

You know, a hydrophilic loves water, lipophilic, loves lipids, hates water.

早期有很多数据显示，单是穿过细胞膜，亲脂性他汀就更容易通过，因为细胞膜本身富含脂质，所以它们能轻松进入。

And, early on there was lots of data showing just traversing a cell membrane border, the, lipophilic statins get through easier because the border itself has got a lot of lipids in, so they all right, come right in.

相比之下，亲水性他汀要穿过屏障就困难得多。

So it's a little for the hydrophilic statins to penetrate a barrier.

实际上，肝脏里有受体能把它们拉进去。

Pretty much there are receptors that, pull them into even the liver.

亲水性他汀有专门的受体把它们快速运送到肝脏。

The hydrophilic statins, there are receptors that pull them into the liver and they get in quickly.

所以从策略上讲，亲脂性他汀应该更容易进入大脑。

So tactically, the, lipophilic statins should get into the brain a little easier than the hydrophilic statins.

但更近的研究表明，这其实没那么重要，一旦身体达到稳态——也就是你长期服用他汀，血液里保持稳定浓度时，所有他汀最终都会进入大脑。

But more modern studies have shown that really doesn't matter as much because once you're in a steady state, meaning you're on a statin, you have your blood level of the statin, ultimately, they're all in the brain.

是的。

Yes.

亲脂性的可能更容易进去，但亲水性的也能进去。

The lipophilic ones may get in a little easier, but they're the hydrophilic ones get in also.

因此，它们都能以不同程度抑制大脑中的胆固醇合成。

And they all have the ability therefore to various degrees inhibit cholesterol synthesis in the brain.

所以，我觉得没必要因为担心大脑影响而特意根据他汀的亲脂性或亲水性来选药。

So I don't think you necessarily have to pick a statin based on its lipophilicity or hydrophilicity worrying about the brain.

我觉得在实际临床中，瑞舒伐他汀这种亲水性他汀用得更多，它进入大脑的速度可能比阿托伐他汀这种亲脂性他汀慢一点，但只要达到稳态，所有药物最终都会进入大脑。

I think because in real world practice, rosuvastatin, a hydrophilic statin, is used more commonly, it certainly can get into the brain maybe a little less slowly than lipitor lipophilic statin, Tim, but if you're in a steady state, they're all in.

所有他汀类药物都能抑制大脑中的胆固醇合成。

They all have the ability to reduce cholesterol synthesis in the brain.

所以这是由分子大小决定的吗，汤姆？

So is that size driven, Tom?

是不是因为他汀的分子足够小，能穿过血脑屏障，而其他类药物不行？

Is it just that the size of a statin is such that it can get across the blood brain barrier, whereas the other classes can't?

这主要取决于他汀药物的分子结构，也就是什么因素让它具有亲水性或亲脂性。

It's just the construction of the, the statin drug on how, you know, what converts a hydrophilic or a lipophilic property to that given statin.

你看我们刚才展示的那张图，列出了所有不同的他汀类药物，它们各自都有点不一样。

You know, if you look at we put up a slide here showing all the different statins, they're all a little bit different.

它们的分子结构中，有些部分决定了亲水性，另一些部分则决定了亲脂性，或者说是疏脂性。

And there are certain aspects of that construction that gives them, hydrophilicity and other aspects of that alignment or construction of their molecules gives them the lipophilicity or or lipophobicity.

所以，回到我们之前说的，其实……

So, anyway, since we earlier, we just said, hey.

阿尔茨海默病是因为大脑和神经元里胆固醇太多了。

Alzheimer's disease is too much cholesterol in the brain, too much cholesterol in the neurons.

你可以假设，他汀类药物确实能进入大脑，而且所有种类都能，只要达到稳态，它们都有能力影响大脑中的胆固醇合成。

You could hypothesize that if statins did get into the brain, which they do and all of them do, and in a steady state, they all have the potential to affect cholesterol synthesis in the brain.

对很多人来说，稍微降低一点大脑中的胆固醇合成反而是好事，因为胆固醇过多会导致神经元和组织出现病变。

It might actually be good in a lot of people to slow down a little bit of the cholesterol synthesis in the brain because too much cholesterol results in, pathology of the the neurons and tissues.

这就是原因，不过我们这里就不详细展开了。

And this is why and we're not gonna review them here.

如果你看所有他汀类药物的临床试验和荟萃分析，大多数都显示他汀对大脑没有伤害，但有少数研究发现，他汀似乎能降低阿尔茨海默病或认知障碍的发生率。

If you look at all the statin trials, the meta analyses, most of them show statins really have no harm to the brain, but there are a few that do show statins seem to reduce the incidence of Alzheimer's disease or cognitive impairment in the brain.

没有任何研究显示他汀会损伤大脑。

None have shown that statins injured the brain.

是的。

Yeah.

为了方便听众，我们会在节目笔记里附上相关资料。

Well, just just for the listeners, we'll link to that in the show notes.

几年前我们做过一次AMA，我详细梳理了所有这些荟萃分析，简而言之，我们看过的每一项关于轻度认知障碍、阿尔茨海默病或未明确说明的痴呆的研究，结果都是中性或有所改善。

We did an AMA on this a few years ago where I went through all of the meta analyses, and, yeah, the the TLDR is that every study we looked at for either MCI or Alzheimer's disease or dementia, otherwise not specified, showed either neutrality or improvement.

这些都是随机对照试验，不过它们并没有把痴呆作为主要研究终点。

These are all RCTs, of course, though these are not studies that used dementia as a primary outcome.

这些研究都是把痴呆当作次要终点来考察的。

These are studies that are using dementia as a secondary outcome.

我总觉得这点特别有意思，汤姆，因为它既符合直觉，又有点反直觉，对吧？

I always find this to be interesting, Tom, because it's both intuitive and counterintuitive, right?

符合直觉的地方在于，你刚才说得很清楚：如果胆固醇在神经元里堆积是有毒的，那能降低大脑胆固醇合成的药，理论上应该有益。

It's intuitive in the sense that you just laid it out, which is, look, if cholesterol accumulation is highly toxic to the neurons, then a drug that reduces cholesterol synthesis in the brain should be beneficial.

但与此同时，胆固醇对大脑又是必不可少的，所以如果我们过度抑制胆固醇合成，会不会也带来问题呢？

But at the same time, cholesterol is essential to the brain, so if we overcook it and we reduce cholesterol synthesis too much in the brain, could that also be problematic?

确实，不过目前这还只是理论推测，因为没人会专门做研究去证实这一点。

Yes, and this is more in the hypothetical range right now because nobody's gonna do these studies to prove it one way or the other.

但正如彼得说的，胆固醇对大脑太重要了，我们绝不能过度抑制大脑里的胆固醇合成。

But because, as Peter just says, cholesterol is so important, you would never wanna over suppress cholesterol synthesis in the brain.

那可不太妙。

That would not be good.

那这种情况会发生吗？

So can that happen?

直觉上我们都明白，给不少人开他汀类药物的人，都见过几个出现脑雾的。

I think intuitively, we know anybody who's prescribed a bunch of statins to people have known a few of them get brain fog.

哎。

Hey.

我正在吃他汀。

I'm on the statin.

我感觉脑子不太灵光。

I'm not thinking right.

啥感觉都没有。

Nothing.

我的注意力没以前好了。

You know, my addition isn't as good as it used to be.

一旦停掉他汀，这些症状很快就会消失。

And we stop the statin and rather quickly that goes away.

所以有一种假设是，他汀可能过度且迅速地抑制了胆固醇的合成。

So one hypothesis would be that is the person that the statin is over suppressing cholesterol synthesis rather rapidly and severely.

正因如此，患者才会出现神经方面的症状，而停药后就好了。

And that's why they got neurologic symptoms and they stop it.

很明显，你已经停用了他汀。

Obviously, you've stopped the statin.

你正在恢复大脑里原本进行的那些合成过程。

You're restoring whatever synthesis was going on in the brain or so.

这样一来，这个假设就说得通了。

So, that becomes a plausible hypothesis.

我说过，根本不会有人去做研究来证实或推翻这个说法。

And I said nobody's ever going to do a study to prove that or disprove it.

但你也可以认为，阿尔茨海默病的形成需要几十年时间。

But you could also say Alzheimer's disease takes decades to develop.

所以，如果你吃了他汀类药物但没有出现急性脑雾，那可能意味着长期轻微抑制胆固醇对你来说是安全的。

So again, if you're I give you a statin and you don't get that acute brain fog, it's probably safe to over suppress cholesterol a little bit over time.

尤其是如果你携带ApoE4基因，或者家族中有阿尔茨海默病史，风险更高的话。

And maybe especially so if you're an e four or you have a family history putting you at risk for Alzheimer's disease.

这仍然是个假说，但结合你刚才提到的那些临床试验结果——显示他汀类药物整体获益有限——这个解释就显得挺合理了。

Again, a theory, but it would be supported by the trials you just said that then to show you're not much going on or benefit, and that could be the plausible reason.

现在我们回到你之前提到的脱氢胆固醇和磷酸化通路。

Now we go back to you've went through the desmosterol and the phosphoryl pathways.

大约十年前有一项研究做得很好，他们用质谱法同时检测了脑脊液和血液中的脱氢胆固醇水平，发现两者高度相关，说明血液里的脱氢胆固醇水平能很好地反映中枢神经系统中的情况。

There's a nice study published almost a decade ago where they were doing cerebrospinal fluid desmosterol levels and plasma desmosterol levels and measuring it by mass spec, and there was high correlation between the CSF desmosterol and the plasma desmosterol, saying that, wow, desmosterol in the plasma, it reflects desmosterol in the central nervous system.

更有趣的是，这项研究还发现，脱氢胆固醇水平低的人，患阿尔茨海默病相关认知障碍的风险更高。

And even more interesting, that study showed that the people with low desmosterol have the higher incidence of cognitive impairment in Alzheimer's disease.

这一点你也在播客里多次提到过。

So if and we you've talked about this many times on the podcast too.

如果我们给患者，尤其是ApoE4携带者，开他汀类药物是为了降低阿尔茨海默病风险，那监测血液中的脱氢胆固醇水平，似乎确实有道理。

If we are administering statins to our patients, even the e four patients on the hope that we are gonna help lessen their incidence of Alzheimer's disease, maybe keeping an eye on plasma desmosterol sort of makes sense.

如果你因为他汀类药物而过度降低了胆固醇，可以调整药物剂量，或者干脆停用他汀，改用其他几种你刚才提到的药物来降低载脂蛋白B，从而减少心脏病发作的风险。

And if you do over suppress it with your statin therapy, maybe you can change the dose of that statin therapy, or maybe you can just abandon statin therapy and lower apoB to reduce heart attacks with the several other drugs that you ran through very quickly there.

这变得非常有意思。

It gets very interesting.

最后再联系一下24S-羟基胆固醇。

And last thing to tie it into that 24S-hydroxycholesterol.

记住，如果你正在走向阿尔茨海默病，血液里的这种物质会升高。

Remember, if you're on the way to Alzheimer's disease, that's increased in the plasma.

有研究显示，一旦开始服用他汀，24S-羟基胆固醇就会下降。

There are studies showing that if you prescribe a statin, the 24S-hydroxycholesterol disappears.

这再次证明，他汀确实抑制了大脑内的胆固醇合成，而且可能降到了一个理想水平——因为你不希望看到它过高。

That would again be proof that the statins are lessening cholesterol synthesis in the brain and maybe to a level that's really desirable because you don't wanna see that.

但你还要结合脱氢胆固醇来看，如果它偏低，那可能就压得太狠了。

But then you would back it up with desmosterol because if that was low, oh, I've maybe suppressed it a little bit too much.

这些都是非常棒的假说。

All wonderful hypothesis.

这方面的研究数据非常多，我随便就能列出二十篇关于脑内脱氢胆固醇及其重要性的文献。

It has a lot a lot of data, I can easily provide 20 references on desmosterol in the brain, how critical it is.

所以目前这个理论是非常合理的，但别指望现在就有临床试验来证实或推翻这个假说。

So this is a very plausible theory right now, and don't expect a clinical trial to prove or disprove this hypothesis right now.

我们会在节目笔记里附上这些参考资料，汤姆。

We'll link to those sources, Tom, in the show notes.

我还想快速提一下另一种药，依泽替米贝。

One other drug I just want to talk about really quickly is ezetimibe.

依泽替米贝嘛，你知道，它主要是在身体外部起作用，这么说吧？

Again, ezetimibe is a, you know, a drug that really works outside the body, so to speak, right?

它作用于肠道。

It works in the gut.

它能阻断类似尼曼-匹克C1型1号的转运蛋白。

It blocks the Niemann Pick C1 like one transporter.

对于不是高吸收型的人群，它的效果其实并不明显。

And in people who are not hyperabsorbers, it's not even a particularly effective drug.

但有一种说法认为，它可能对大脑有某种益处，而大脑恰恰是我们最想不到它起作用的地方。

Yet there is a kind of a suggestion that it might have some benefits in the brain, which is the furthest place from where we think of it working.

对此你有什么看法？

What what can you say about that?

说实话，这真的很惊人。

You know, it's kind of amazing.

就像你说的，谁会想到，一种只在肠道起作用的药，居然可能对大脑有好处呢？

Like you said, who would ever even hypothesize that that this drug that acts in the intestine might have beneficial effects in the brain or so.

我们有几位神经科的同事，比如理查德·艾萨克森和凯莉·恩诺蒂斯，他们一直深入研究这些疾病。

And I think, you know, we have a couple of neurologic colleagues, Richard Isaacson and Kelly Eniotis, who are very involved with these diseases.

据他们反映，除了帮助患者控制载脂蛋白B之外，这些病人似乎在认知功能上也有改善。

And is there anecdotal belief that addition to helping them control their apoB in their patients, there seems to be some cognitive benefit in the people they deal with or so.

所以现在，这背后有了更合理的解释。

So now there's actual plausible reason.

而依泽替米贝这种药，根本无法穿过血脑屏障。

Now, zetimibe is one of those drugs that just cannot cross the blood brain barrier.

那它到底是怎么帮助痴呆症的呢？

So how in aural could it be helping dementia or so?

但它有一个代谢物叫依折麦布葡萄糖醛酸苷，虽然量很少，却真的能穿过血脑屏障，而依折麦布本身做不到。

But it has a metabolite called ezetimibe glucuronide that actually can pass through the blood brain barrier in small amounts, but unlike ezetimibe, it gets in.

动物研究显示，这种代谢物会干扰己糖激酶，影响大脑蛋白质的糖基化。

And there are animal studies showing that it interferes with hexokinase and the glycosylation of brain proteins.

如果能降低这种作用，大脑的炎症可能会减轻一些。

If you reduce that, there's some benefit, less inflammation in the brain or so.

所以有这个机制，而且我待会儿一定把相关研究的文献发给你，大家都可以去看看，这确实有道理。

So there is that and again, it's a study I will definitely give you the reference to that people can read, that there's some plausibility to it.

而且，在神经科领域深耕的医生们，也都有这样的经验：它确实有辅助作用。

And there's an anecdotal belief among neurologists who live in this field that it's a helper.

这难道不让人觉得很有意思吗？

So wouldn't that be cool?

彼得，当我们对你的患者 aggressively 控制 apoB 时，我们经常用依折麦布，因为我们更倾向于用低剂量的他汀。

You know, Peter, as we control apoB aggressively in your patients, We use a lot of ezetimibe because we prefer to use low dose statins.

如果我们没达到apoB的目标，就会加用依泽替米贝。

And if we don't get to the apoB goal, we're adding ezetimibe.

我们从第一天起就会检查胆固醇的合成和吸收情况。

We also, day one, check synthesis and absorption.

有些患者从第一天就开始用依泽替米贝，因为他们属于吸收过强型，这种情况下降apoB的效果最明显。

So there are patients where we use ezetimibe day one because they're hyperabsorbers, and that's where you get the most efficacious apoB lowering.

未来，对于携带apoE4基因且apoB水平异常的人群，

So in the future, as we have people who carry the apoE4 alleles and they have apoB issues.

我们可能会先选他汀，也可能选依泽替米贝，但我认为，这类患者可能需要两者合用，直到有人能证实这一点。

We might pick a statin first, we might pick a zetimibe, but I think they might be a patient where you need a little bit of a statin and a little bit of ezetimibe until somebody proves this.

别指望会有随机对照试验去研究依泽替米贝对阿尔茨海默病血液生物标志物的影响，目前只有新药才刚开始做这类研究。

And I would not hold your breath waiting for a randomized controlled trial that ezetimibe, what it's doing to even some of the Alzheimer's biomarkers in the blood, because only emerging drugs are they starting to do those type of studies on.

没人会回头去查依泽替米贝对磷酸化tau蛋白或淀粉样蛋白比值这些指标有什么影响。

Nobody's gonna go back and look what ezetimibe does to p tau or the amyloid ratios or so.

真希望有人能去研究一下。

I wish somebody should.

其实只需要一个小规模的研究就够了。

You'd only need maybe a small study.

我倒是没想到，你或许能从现有的生物样本库中，找到之前做过依折麦布研究的数据。

Well, I'm surprised you could probably pull it out of a biobank for an existing study that was already done on ezetimibe.

至少我们可以从这类研究里获得一些线索，毕竟我们已经有他汀单用和他汀加依折麦布的对比试验了。

We could at least get the suggestion of that from such a study, because we do have at least one Well, know we have statin versus statin plus ezetimibe trials.

我们不是还有一个依折麦布单药试验吗？

Don't we also have a monotherapy Zetia trial?

只有在日本的老年人中做过，而且当时根本没考虑认知功能这个指标。

Only in Japanese elderly people, and I don't think cognition was one of the things.

那个研究只是开放式的，也没设盲。

Was just and it was not a a blinded trial, so it was an open

是开放标签试验。

label Open label trial.

对。

Yeah.

只是为了证明它在一级预防中能有效降低载脂蛋白B。

Just to show it was efficacious in lowering apoB in a primary prevention setting.

但那项研究根本没关注认知功能或生物标志物。

But they certainly didn't look at cognition or biomarkers in that study.

但如果他们的血清样本还保存着，至少可以看看磷酸化tau蛋白治疗前后的变化。

But if they still have serum banked, you could at least look at pre and post levels of p tau.

这确实可以做。

You definitely could.

对。

Yeah.

Aβ4240。

AB four thousand two forty.

这会是个很棒的研究课题，适合年轻博士或刚起步的脂质学家。

Be a great research project for some young PhD or a budding lipidologist.

希望现在有人正在听。

Hopefully listening right now.

我们来聊聊另一个常被提及、介于药物和补充剂之间的物质，那就是EPA和DHA对大脑健康的作用。

Let's talk about something else that is half drug, half supplement that gets talked about a lot for brain health, which is the role of EPA and DHA.

它们作为补充剂在市面上很容易买到，确实也有一些品牌是靠谱的，也就是说，你买到的东西和标签上写的是一致的，而且没有污染物。

Again, they're readily available as supplements over the counter, and there are certainly some brands out there that are legitimate, which is to say you're getting what the label says you're getting, and they're free of contaminants.

但它们也生产了这两种脂肪酸的药物版本。

But they also make pharmacologic variants of both of these fatty acids.

你可以随便怎么理解这一点，但我们现在到底知道多少关于EPA和DHA对大脑健康的影响呢？

So take that in whichever way you'd like, but let's what what do we know about EPA and DHA in brain health?

先不谈具体产品，我们来讨论一下EPA和DHA对大脑是否都重要。

Without talking about specific products, let's talk about if an EPA and DHA are both important to the brain.

大脑里DHA的含量要高得多，但我们现在发现，EPA对大脑也同样重要。

There's far more DHA, but we're finding out that even EPA is important for the brain now also.

因为我们身体无法自行合成Omega-3脂肪酸，必须通过饮食摄入。

So, since we can't produce omega-three fatty acids, we have to eat them.

当你吃下这些脂肪酸时，它们大多是以甘油三酯或磷脂的形式存在的。

And we're eating when you eat them, they're mostly in the form of a triglyceride carrier or a phospholipid carrier.

补充剂正是以这种方式将Omega-3输送给我们的。

And that's exactly how the supplements deliver omega-3s to us.

它们通常以甘油三酯的形式封装。

They're packaged in as a triglyceride.

在合成的甘油三酯中，通常有一个脂肪酸是Omega-3。

Typically, of the fatty acids on a synthesized triglyceride would be an omega-three.

有一种产品通过磷虾油以磷脂形式输送Omega-3。

And there is a product that delivers omega-3s as a phospholipid, from krill oil.

当你摄入甘油三酯或磷脂后，记住，真正能被吸收的只有游离脂肪酸。

So now once you ingest a triglyceride or a phospholipid, remember, the only thing that can really be absorbed is free fatty acids.

胰腺分泌的酶，也就是脂酶，会把脂肪酸从甘油三酯或磷脂载体上拆解下来，然后游离的EPA或DHA会与其他脂质结合，进入胆汁微胶粒，再通过脂肪酸转运蛋白CD36被吸收。

So pancreatic enzymes, lipases, leave off the fatty acids from the triglyceride or phospholipid vehicle, and then the free EPA or free DHA, which joins with other lipids in the biliary micelles, gets absorbed by a fatty acid absorber CD 36.

有趣的是，不仅游离脂肪酸可以被吸收，溶血磷脂也可以被吸收。

Interestingly, not only can a free fatty acid be absorbed, but a lyso phospholipid can be absorbed.

磷脂由一个磷酸基团、一个亲水头部和两个连接的脂肪酸组成。

A phospholipid has a phosphorus moiety and a head group and two fatty acids attached to it.