Chapter 31: Synthesis of Fatty Acids, Triacylglycerols, and the Major Membrane Lipids

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Okay, let's untack this.

When we talk about lipids, most of us immediately think of dietary fat, right?

But what if I told you these molecules are actually far more than just energy storage?

They're the silent architects of our cell membranes, powerful cellular messengers, and even play a critical role in our body's defense system.

Today, we're taking a deep dive into the fascinating world of lipid metabolism.

We'll be focusing specifically on how our bodies build, store, and utilize fatty acids, tricylglycerols, and the essential lipids that literally make up who we are.

And what's truly limiting here, I think, is that we'll trace the incredible journey of these molecules from their most basic building blocks all the way to their complex roles in maintaining health and sometimes driving disease.

You can see just how interconnected these biochemical pathways really are and why understanding them is crucial for everything from managing your weight to developing cutting edge medicines.

Think of this as your guide, helping you connect the dots through the intricate processes that keep your body functioning at a fundamental level.

So our mission for you today is to gain a crystal clear understanding of this intricate system, how we construct, stash away, and activate these vital lipids, and what happens when those finely tuned processes go a little off kilter.

Consider it your shortcut, maybe, to understanding the molecular machinery behind a very fat topic with plenty of genuine ah -ha moments along the way, hopefully.

So let's get into the needy gritty then.

Where does the body even begin when it needs to build fatty acids?

You might be surprised to learn that a major source of the raw material, the carbon for this process in humans,

actually comes from dietary carbohydrates.

Exactly.

Our bodies are incredibly efficient, perhaps too efficient sometimes, at converting excess calories from glucose into fatty acids.

This fat factory operates primarily in the liver, though your adipose or fat tissue also chips in.

If we connect this to the bigger picture, it explains why someone like Percy Vee from our case studies, you remember him, despite eating a low -fat diet, he could still gain weight from excessive carbohydrates.

It truly shows you can get fat without eating fat.

It's quite a concept.

Wow.

So how does that conversion actually happen?

How do carbs become fat?

Well, your body cleverly takes glucose, breaks it down via glycolysis into pyruvate, right there in the cytosol, then pyruvate moves into the mitochondria, gets converted to acetyl -CoA and another molecule, oxaloacetate.

These two condense to form citrate.

Now here's a trick.

Acetyl -CoA itself can't easily leave the mitochondria, but citrate can.

So citrate gets shuttled out into the cytosol and then an enzyme called citrate liase basically splits it back into acetyl -CoA and oxaloacetate.

It's a bit of a detour, but necessary.

Okay.

So that's how we get the basic building block acetyl -CoA out where it needs to be.

What's next?

Right.

Now we have our acetyl -CoA bricks in the cytosol.

The next key step involves a crucial control switch enzyme.

It's called acetyl -CoA carboxylase or ACC.

ACC adds another carbon group to acetyl -CoA forming malonyl -CoA.

This needs biotin and energy in the form of ATP.

Malonyl -CoA is actually the two -carbon unit that gets added repeatedly to build the fatty acid chain.

Okay.

So malonyl -CoA is the key intermediate.

Then how does the chain get built?

This is where a large multifunctional enzyme complex comes in.

It's called fatty acid synthase or FAS.

Think of it like a sophisticated assembly line in the cytosol.

FAS sequentially adds those two carbon units from malonyl -CoA, one after another, onto a growing fatty acid chain.

This whole process requires reducing power, which comes from NADPH, mostly from the pentose phosphate pathway.

Remember that?

And it keeps adding units until the chain is 16 carbons long.

That final product is palmitate.

Palmitate.

Got it.

16 carbons.

That's quite the process.

And I imagine the body doesn't want to be building fat and burning it at the exact same time, right?

That seems inefficient.

Precisely.

That would be a wasted effort.

What we call a futile cycle.

And the body has a brilliant built -in mechanism to prevent this.

That malonyl -CoA we just talked about.

The key intermediate for synthesis.

When its levels are high, signaling active fatty acid synthesis, it also puts the brakes on a different enzyme.

This enzyme, carnitine palmitoyltransferase A, or CPT -1, is the gatekeeper for getting fatty acids into the mitochondria to be burned for energy.

So high malonyl -CoA essentially shouts, hold on, we're building here, don't break anything down.

Pretty clever, huh?

Very clever.

Okay, so we have palmitate, but surely the body needs other types of fatty acids too.

Absolutely.

Here's where it gets really interesting.

Once we have palmitate, our body doesn't stop there.

It can customize these fatty acids.

That's right.

Malmitate can be elongated, meaning more two -carbon units are added, usually in the endoplasmic reticulum.

So 16 carbons can become 18 carbons, like

If you want to be desaturated, which means adding double bonds, this requires oxygen and ADH and cytochrome B5.

For instance, palmitic acid can be converted to palmitoleic acid, which has one double bond.

Oh, okay.

But what about things like omega -3s and omega -6s?

Can we make those too?

Good question.

And the answer is no, not entirely.

Here's a crucial limitation.

Humans cannot synthesize certain polyunsaturated fatty acids.

Specifically, we can't introduce double bonds at the omega -3 and omega -6 positions, counting from the methyl end of the fatty acid.

These are called essential fatty acids, like linoleic acid in omega -6 and linoleic acid in omega -3.

They must come from our diet.

Think plant oils, nuts, seeds, fish oils.

And they're not just for structure.

These essential fatty acids are the starting material for some incredibly powerful signaling molecules.

You mean eicosanoids.

Exactly.

Which brings us nicely to our next topic.

Right.

Speaking of powerful messengers, let's talk about eicosanoids molecules that have a huge impact on almost every cell in your body.

Yet most people have probably never even heard of them.

Yeah, what's fascinating here is their incredible potency and their local action.

Eicosanoids are a family of 20 carbon biologically active lipids.

They include things like prostaglandins, thromboxenes, and leukotrienes.

They act mainly as local hormones, meaning they affect the cells that produce them or cells very nearby,

like tiny localized messengers.

And they regulate just a huge range of vital processes.

Inflammation, smooth muscle contraction, blood pressure, blood clotting, pain, fever, you name it.

Wow.

Okay.

So where do they come from?

Their story usually begins with arachidonic acid.

That's a 20 carbon polyunsaturated fatty acid, often derived from the essential omega -6 linoleic acid.

Arachidonic acid is typically stored, tucked away in our cell membranes, esterified to phospholipids.

When a cell in a cell is released to respond to a stimulus, maybe an injury or an infection or a hormone signal, an enzyme,

often phospholipase A2 gets activated and it snips that arachidonic acid free from the membrane.

Okay.

So arachidonic acid is released.

Then what?

Once released, arachidonic acid can go down a couple of major pathways.

Let's focus on probably the most well -known one, the cyclooxygenase pathway or COX pathway.

A key enzyme here, cyclooxygenase, converts arachidonic acid first into an unstable intermediate, PGG2, and then into PGH2.

Now PGH2 is like a crossroads.

What happens next depends entirely on the tissue.

Different products in different places.

Exactly.

For instance, in platelets, PGH2 is converted into thromboxane A2 or TXA2.

TXA2 is really potent.

It makes blood vessels constrict and causes platelets to clump together, which is crucial for forming blood clots.

But in the cells lining our blood vessels, the endothelium, PGH2 gets turned into prostaglandin I2 or PGI2, also called prostacyclin.

And PGI2 does the opposite of TXA2.

It dilates blood vessels and stops platelets from aggregating.

So we've got these two opposing forces thromboxane pushing for clots and prostacyclin trying to prevent them.

It sounds like a really delicate balancing act.

It absolutely is a very delicate balance.

And this is where it gets incredibly clinically relevant because that cyclooxygenase enzyme actually exists in two main forms or isoforms, COX1 and COX2.

COX1 is considered constitutive.

It's like the body's housekeeping enzyme.

It's pretty much always there, involved in normal physiological functions like protecting your stomach lining and making that baseline platelet thromboxane for clotting when needed.

COX2, on the other hand, is generally inducible.

Its levels are usually low, but they increase dramatically in response to inflammation, injury, or infection.

It produces prostaglandins involved in pain and inflammation.

Ah, COX1 and COX2.

I've definitely heard of those, especially in relation to painkillers.

Precisely.

This distinction led to the development of incredibly important drugs.

Aspirin, for example.

Aspirin works by irreversibly inhibiting both COX1 and COX2.

It actually acetylates the enzymes.

Now, in platelets, because they don't have a nucleus, they can't make new COX1 enzyme.

So even a low dose of aspirin, like the 81 mg often recommended, permanently knocks out COX1 in circulating platelets for their entire lifespan.

This leads to prolonged inhibition of thromboxane production, reducing the tendency for blood clots to form.

That's why low -dose aspirin is so effective in preventing heart attacks and strokes, like for someone like Cora N, who has cardiovascular risks.

Right.

And other NSAIDs, like ibuprofen.

They also inhibit COX enzymes, but usually reversibly.

So their effect wears off as the drug clears.

Now, I remember hearing about some drugs designed to target just COX2, the inducible one, to try and reduce stomach side effects from blocking COX1.

What happened there?

That's a great point, and it highlights the complexity, doesn't it?

Selective COX2 inhibitors, like Celecoxib, were developed with exactly that goal, reduce inflammation pain, while hopefully sparing the protective COX1 in the stomach.

And for many people, they worked well.

However, some of them, most famously Vioxx, were withdrawn from the market.

The problem, it turned out, was that by selectively blocking COX2, they reduced the production of that anti -clotting prostacyclin, PGI2, made in blood vessels.

But they didn't block COX1 in platelets, which continued to churn out pro -clotting thromboxane, TXA2.

So they inadvertently shifted that delicate balance we talked about, tipping it towards a pro -thrombotic state, increasing cardiovascular risk in some patients.

A really important lesson in biochemistry and unintended consequences.

Wow, yeah.

That really drives home the balance point.

Absolutely.

And just quickly, other factors influence this, too.

Corticosteroids, like the triamcinolone astenide that Emma W uses for her asthma, work partly by inhibiting phospholipase A2, so less arachidonic acid gets released in the first place.

They also suppress the induction of COX2.

And diet plays a role.

Diets rich in omega -3 fatty acids, like EPA found in fish oils, can compete with arachidonic acid.

This leads to the formation of different icosanoids like thromboxane E3 instead of A2, which is much less potent at causing clotting.

This is thought to be one reason fish oil is linked to reduced heart disease risk.

Fascinating how a simple molecule can have such far -reaching effects, and how we can target these pathways with drugs and diet.

Okay, so we've made fatty acids and some become powerful messengers.

What about the bulk of them?

The ones destined for long -term energy storage or transport around the body?

Right.

This brings us to a key challenge.

How does the body safely and efficiently store and move these energy -rich but water -insoluble molecules?

The answer is primarily triacyl glycerols, or TAGs.

These are the major storage form of fuel in our bodies, sometimes called triglycerides.

They're essentially three fatty acids attached, or esterified, to a glycerol backbone.

Very nonpolar, very energy -dense.

Now, both the liver and adipose tissue are major sites of TAG synthesis, but there's a crucial difference in how they get that glycerol backbone.

A difference?

What's that?

Your liver is quite versatile.

It has an enzyme called glycerol kinase, so it can directly phosphorylate free glycerol to make glycerol -3 -phosphate the backbone starter molecule.

It can also make glycerol -3 -phosphate from DHAP, which comes from glucose during glycolysis.

Adipose tissue, however, generally lacks glycerol kinase, so it can only make glycerol -3 -phosphate from glucose via DHAP.

This means your fat cells can only effectively synthesize and store TAGs when glucose metabolism is active, essentially, when you're in a fed state and have plenty of glucose coming in to provide that glycerol backbone.

Ah, okay.

So adipose tissue needs glucose to store fat.

Makes sense.

So if I'm understanding this, the liver is essentially a lipid -packaging plant, taking fatty acids, maybe ones it just made from carbs or ones coming back from elsewhere and sending them out.

Precisely.

That's a great analogy.

In the liver, newly synthesized TAGs, often made

dietary carbohydrates, as Percivy's case starkly illustrates, are not just stored locally long term.

They get packaged up together with cholesterol, phospholipids, and special address label proteins called apolipoproteins, specifically one called APOB100 for this package.

This entire particle forms a very low -density lipoprotein, or VLDL.

Think of VLDL as a delivery truck packed full of triglycerides, manufactured in the liver and sent out into your bloodstream.

A protein called MTP, Microsomal Triglyceride Transfer Protein, is essential for loading the truck, basically.

Okay, so VLDL is the liver's fat delivery truck.

Where does it deliver to?

It cruises through your capillaries, heading for tissues that need energy or want to store it, especially adipose tissue and muscle.

In the capillary walls of these tissues, there's an enzyme called lipoprotein lipase, or LPL.

LPL acts like the unloading crew.

It gets activated by another apolipoprotein, apo -CII, which VLDL picks up from HDL in the blood.

Activated LPL then digests the tags inside the VLDL, breaking them down into free fatty acids and glycerol.

These fatty acids are then readily taken up by the nearby cell's muscle cells for energy, or adipose cells.

In fat tissue, those fatty acids are quickly reesterified with glycerol -3 -phosphate, made from glucose, remember, to be stored again as tags within the fat cell.

The leftover glycerol goes back to the liver.

So it's quite a dynamic system of packaging, transport, and unloading.

And if something goes wrong with this system, I guess it could lead to problems like too much fat in the blood.

Absolutely.

Take Cora N's case again.

She has familial combined hyperlipidemia.

This is a common genetic disorder, often complex, but it frequently involves the liver overproducing VLDL, possibly due to increased APOB100 production.

So too many delivery trucks are hitting the

high triglycerides and potentially high LDL cholesterol later on.

Treatment often involves dietary fat restriction, but also drugs like statins, which lower cholesterol synthesis, and sometimes niacin, which can help lower VLDL production in tags.

Another classic example is alcoholism.

High alcohol consumption generates a lot of NADH in the liver.

This high NADH inhibits fatty acid oxidation, the burning of fat.

So fatty acids build up and get reesterified into tags, packaged into VLDL, and shipped out.

This often leads to elevated VLDL levels in the blood, and eventually, if it continues, fat accumulation in the liver itself, fatty liver disease.

Okay, that covers storage and transport pretty well.

But lipids aren't just fuel or signals, right?

They're also the fundamental structure of our cells.

Let's explore glycerophospholipids and sphingolipids.

Yes, exactly.

Beyond fuel and signals, lipids are the very fabric of our cells.

This is where we see them as crucial structural components.

They are essential for building and maintaining cell membranes, providing barriers, and also contributing to specialized functions, like insulating our nerves.

Let's start with the

glycerophospholipids.

What are they?

Okay, so as the name suggests, their backbone is glycerol.

Like tags, they start with glycerol 3 -phosphate, which links up with two fatty acids to form phosphatidic acid.

This is a key intermediate.

But instead of adding a third fatty acid, like in tags, a polar head group containing phosphate is added.

This head group gives phospholipid its specific identity and function.

There are a couple of main ways this happens.

Either the diacylglycerol part reacts with an activated head group, like CDP -choline, to make phosphatidylcholine.

Or the phosphic acid itself gets activated with CDP to form CDP

diacylglycerol, which then reacts with the head group, like inositol, to make phosphatidyl inositol.

So you get molecules like phosphatidylcholine, also known as lecithin, a major component of most cell membranes.

Or phosphatidyl inositol, which is super important because it can be related to PIP2, a key player in intracellular signaling pathways.

There's also cardiolipin, crucial for mitochondrial membranes.

We also have some unique ones called ethercholesterolypids, like plasmologens and platelet activating factor, or PAF.

PAF has an ether link instead of an ester link at one position.

And it's a potent molecule involved in platelet aggregation and allergic responses.

Now, I know there's a really important clinical connection here, especially for premature babies.

Can you tell us about that respiratory distress syndrome?

Yes, absolutely.

A critical example.

This brings us to respiratory distress syndrome, or RDS, which tragically affects many premature infants, like Christy L.

in our case study.

RDS is linked to insufficient production of lung surfactant by the immature lungs.

Surfactant is a complex mixture, but its key components are specific glycerophospholipids, particularly dipalmatolylphosphatidylcholine, a type of lecithin, and also phosphatidylglycerol.

These lipids are amazing.

They reduce the surface tension inside the tiny air sacs of the lungs, the alveoli.

This prevents the alveoli from collapsing completely when the baby exhales.

It's absolutely essential for breathing.

In fact, measuring the ratio of lecithin to another lipid, sphingomyelin, the LS ratio, in the amniotic fluid before birth is a key way doctors assess fetal lung maturity and predict the risk of RDS.

Low LS ratio means higher risk.

That's incredible.

Such a specific lipid for such a vital function.

Okay, what about the other main structural type sphingolipids?

How are they different?

Alright, sphingolipids.

Key difference.

Their backbone isn't glycerol.

It's an amino alcohol called sphingosine, which is derived from the amino acid serine and palmitoyl CoA.

The basic unit is formed when a fatty acid is attached to sphingosine, creating ceramide.

Ceramide is the precursor for all other sphingolipids.

From ceramide, you can get sphingomyelin by adding a phosphocoline head group.

Shingomyelin is the only phospholipid not based on glycerol, and it's a major component of the myelin sheath that insulates nerve fibers, allowing rapid signal transmission.

Or you can add sugars to ceramide to create glycolipids.

Simple ones are serbocides, one sugar.

More complex ones are globosides and gangliosides, which have branched oligosaccharide chains, often containing sialic acid.

These glycolipids are really important on cell surfaces for cell -to -cell recognition, acting as antigenic determinants like our ABO blood groups, and even as receptors for certain viruses and bacterial toxins.

And if the breakdown of these goes wrong?

Ah yes, sphingolipids are normally broken down by specific enzymes and lysosomes.

If one of these enzymes is deficient due to a genetic mutation,

the corresponding sphingolipid accumulates within the lysosome, leading to a lysosomal storage disease.

These are collectively

sphingolipidoses or gangliosidoses like Tay -Sachs disease or Goucher disease, and they often have severe neurological consequences because of the importance of these lipids in the nervous system.

Okay, a lot of vital roles there.

Now finally, let's circle back to where we store a lot of fat adipose tissue.

You mentioned earlier it's not just passive storage, it's actually an endocrine organ.

That really challenges the old view of fat, doesn't it?

Indeed, it completely revolutionizes our understanding.

For a long time, fat was just seen as, you know, inert blubber.

But we now know that adipocytes, the fat cells themselves, are incredibly active.

They secrete a whole variety of hormones and signaling factors, collectively called adipokines.

And these adipokines actively regulate glycosin fat metabolism throughout your entire body.

So the crucial question becomes, how does your adipose tissue, the amount and health of it, influence your overall metabolic health?

So what are some key adipokines?

Well, probably the most famous one is leptin.

Leptin is released from adipocytes primarily in proportion to how much triglyceride they're storing.

So bigger fat cells, more leptin.

Leptin travels through the blood to your brain, specifically binding to receptors in the hypothalamus.

Its main job there is to signal satiety to tell your brain, okay, we're full, energy stores are sufficient, stop eating.

It also increases energy expenditure.

However, a major problem in many individuals with obesity is leptin resistance.

Even though their leptin levels are high, the brain doesn't respond properly to the signal.

It's like the smoke detectors going off, but nobody's calling the fire department.

This contributes to ongoing appetite and difficulty losing weight.

Okay, so leptin signals fullness, but it can become ineffective.

What else?

Another incredibly important one, which works somewhat differently, is adiponectin.

In contrast to leptin, adiponectin secretion tends to be reduced as adipocytes get larger and more inflamed, which is common in obesity.

So less adiponectin in obesity.

And adiponectin is generally considered a good guy metabolically.

It acts on muscle and liver, partly by activating an enzyme called AMP -activated protein kinase, AMPK.

This activation enhances fatty acid oxidation, fat burning, and improves glucose uptake and insulin sensitivity in those tissues.

So lower adiponectin in obesity is actually a bad thing.

Yes, exactly.

The reduced adiponectin levels, often seen in obesity, are thought to contribute significantly to the development of insulin resistance.

When tissues become resistant to insulin, they struggle to take up and use circulating fatty acids and glucose effectively.

This leads to elevated blood glucose levels and often high triglyceride levels, two key features of what we now call the metabolic syndrome.

Right, the metabolic syndrome.

So it's really this cluster of problems all interconnected and influenced by how our lipid metabolism and adipose tissue are functioning.

Precisely.

Metabolic syndrome isn't one disease, but a cluster of risk factors.

Increased waist circumference, abdominal obesity, elevated triglycerides, low levels of the good HDL cholesterol, elevated blood pressure, and elevated fasting blood glucose.

Having this cluster dramatically increases your risk of developing type 2 diabetes and cardiovascular disease.

You can see how someone like Percy V through prolonged excess carbohydrate intake leading to obesity is heading straight down this path, partly because his expanding adipose tissue is sending out dysfunctional signals, maybe too little adiponectin, maybe leptin resistance.

And at a more fundamental level, we know that high levels of circulating free fatty acids, or non -esterified fatty acids, NIFA, which often occur in obesity and insulin resistance, can directly worsen the situation.

They can impair glucose uptake by muscle, and even interfere with the pancreas's ability to secrete insulin properly, creating a vicious cycle.

Wow.

It really all ties together.

So, reflecting on everything we've covered, what's the big takeaway here?

Well, we've journeyed from how we make simple fatty acids from dietary carbs to how they're customized, stored, transported as tags in VLDL, used to build complex membranes like phospholipids and sphingolipids, and act as potent signals like eicosanoids.

And crucially, how adipose tissue itself communicates via adipokines like leptin and adiponectin.

The lipid life cycle is truly one of the most dynamic and critical processes in our biology.

Yeah, absolutely.

And if we connect this to the bigger picture, I think understanding these pathways really reveals why things like diet, lifestyle, and even our individual genetic predispositions have such profound impacts on our metabolic health.

It provides the biochemical foundation for comprehending widespread diseases like obesity, type 2 diabetes, fatty liver disease, and heart disease.

And importantly, it also highlights the targets for therapeutic interventions, whether it's managing heart attack risk with a simple centriole drug like aspirin that targets COX enzymes, or developing sophisticated surfactant therapy to save premature infants based on understanding phosphatidylcholine, or even looking towards future drugs that might modulate adipokine signaling.

It's a powerful reminder, isn't it, that every bite of food we eat sets off this incredibly complex cascade of biochemical events that literally shape our body and our health moment by moment.

Okay, so the provocative thought we want to leave you with today is this.

As our understanding of these intricate lipid signals, especially adipokines, continues to grow,

how might this knowledge lead to truly personalized nutrition and medicine approaches in the future?

Could we move beyond one -size -fits -all health advice and tailor recommendations based on an individual's unique lipid metabolism and adipokine profile?

Something to think about.

Thank you so much for joining us on this deep dive into the fascinating and absolutely vital world of lipid metabolism.

We hope you're leaving feeling a little more well -informed and maybe a lot more curious.