Nov 2018: Dr. Peat Talks About Cholesterol Esters Causing Aging

[haidut]

Yes that’s how PUFA lowers serum LDL.

They also shuttle trigs and cholesteryl esters back to the liver resulting in NAFLD and rapid development of CVD. Whoever came up with the idea that lowering blood cholesterol treats/prevent CVD or liver disease should be in jail. Nobody can be that stupid...but they can certainly be that corrupt.
Fish oil increases atherosclerosis and hepatic steatosis, although decreases serum cholesterol in Wistar rat. - PubMed - NCBI

 

[haidut]

In addition to progesterone and lidocaine mentioned in the newsletter, pregnenolone may help as well. The study below suggests pregnenolone could be a competitor for the ACAT enzyme that creates cholesteryl esters and as such inhibit the formation of those esters, as pregnenolone had 50-100 fold higher affinity for ACAT than cholesterol does. So far there is no evidence that pregnenolone esters are harmful and at least one of them (pregnenolone sulfate) is known to serve as the long term storage form of pregnenolone.
Cellular Pregnenolone Esterification by Acyl-CoA:Cholesterol Acyltransferase
"...Pregnenolone (PREG) can be converted to PREG esters (PE) by the plasma enzyme lecithin: cholesterol acyltransferase (LCAT), and by other enzyme(s) with unknown identity. Acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2) convert various sterols to steryl esters; their activities are activated by cholesterol. PREG is a sterol-like molecule, with 3-β-hydroxy moiety at steroid ring A, but with much shorter side chain at steroid ring D. Here we show that without cholesterol, PREG is a poor ACAT substrate; with cholesterol, the Vmax for PREG esterification increases by 100-fold. The binding affinity of ACAT1 for PREG is 30–50-fold stronger than that for cholesterol; however, PREG is only a substrate but not an activator, while cholesterol is both a substrate and an activator. These results indicate that the sterol substrate site in ACAT1 does not involve significant sterol-phospholipid interaction, while the sterol activator site does. Studies utilizing small molecule ACAT inhibitors show that ACAT plays a key role in PREG esterification in various cell types examined. Mice lacking ACAT1 or ACAT2 do not have decreased PREG ester contents in adrenals, nor do they have altered levels of the three major secreted adrenal steroids in serum. Mice lacking LCAT have decreased levels of PREG esters in the adrenals. These results suggest LCAT along with ACAT1/ACAT2 contribute to control pregnenolone ester content in different cell types and tissues."

 

[GAF]

13 minutes of amateur research...There is an enzyme that converts C esters back to free C

See Wolman disease

Wolman Disease - NORD (National Organization for Rare Disorders)

Apparently big pharma has it for $375k per year or per dose blah blah

Maybe idealabs can conjure up this simple enzyme. Apparently knowledge of this enzyme is far from new.

 

[Mito]

“Because of the mechanism of synthesis (see below), plasma cholesterol esters tend to contain relatively high proportions of the polyunsaturated components typical of phosphatidylcholine (Table 1). Arachidonic and “adrenic” (20:4(n-6)) acids can be especially abundant in cholesterol esters from the adrenal gland.”

Cholesterol and Cholesterol Esters - structure, occurrence, biochemistry and function

 

[jb116]

@haidut curious about fatty acid esters like the SFA esters. How come they are beneficial vs. Cholesterol esters?

 

[Sourdoughbanana]

They also shuttle trigs and cholesteryl esters back to the liver resulting in NAFLD and rapid development of CVD. Whoever came up with the idea that lowering blood cholesterol treats/prevent CVD or liver disease should be in jail. Nobody can be that stupid...but they can certainly be that corrupt.
Fish oil increases atherosclerosis and hepatic steatosis, although decreases serum cholesterol in Wistar rat. - PubMed - NCBI

Lowering blood cholesterol VIA DRUGS or PUFAs. You make it sound like higher cholesterol is superior than normal cholesterol.

 

[yerrag]

“Because of the mechanism of synthesis (see below), plasma cholesterol esters tend to contain relatively high proportions of the polyunsaturated components typical of phosphatidylcholine (Table 1). Arachidonic and “adrenic” (20:4(n-6)) acids can be especially abundant in cholesterol esters from the adrenal gland.”
View attachment 11448
View attachment 11449
Cholesterol and Cholesterol Esters - structure, occurrence, biochemistry and function

And I made liposomal C using high-PC lecithin in an attempt to improve delivery of vitamin C to the inner cell. After 1 day of use (I couldn't sleep the whole night - must have messed up my blood sugar regulation), I threw away the entire batch. Now, I'm even more happy I did because of how the PC could turn cholesterol into its ester.

On the fifth section, Cholesterol Esters, of the above link, it is stated that "Cholesterol esters are major constituents of the adrenal glands." If this is so, why is it so? It has to serve a function. Otherwise, it would be a cause of impairment for the adrenal glands. I'm wondering if the statement is a statement of the natural order of things, or that it reflects an observance of a state of pathology mistakenly assumed as a normal state.

 

[yerrag]

In addition to progesterone and lidocaine mentioned in the newsletter, pregnenolone may help as well. The study below suggests pregnenolone could be a competitor for the ACAT enzyme that creates cholesteryl esters and as such inhibit the formation of those esters, as pregnenolone had 50-100 fold higher affinity for ACAT than cholesterol does. So far there is no evidence that pregnenolone esters are harmful and at least one of them (pregnenolone sulfate) is known to serve as the long term storage form of pregnenolone.
Cellular Pregnenolone Esterification by Acyl-CoA:Cholesterol Acyltransferase
"...Pregnenolone (PREG) can be converted to PREG esters (PE) by the plasma enzyme lecithin: cholesterol acyltransferase (LCAT), and by other enzyme(s) with unknown identity. Acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2) convert various sterols to steryl esters; their activities are activated by cholesterol. PREG is a sterol-like molecule, with 3-β-hydroxy moiety at steroid ring A, but with much shorter side chain at steroid ring D. Here we show that without cholesterol, PREG is a poor ACAT substrate; with cholesterol, the Vmax for PREG esterification increases by 100-fold. The binding affinity of ACAT1 for PREG is 30–50-fold stronger than that for cholesterol; however, PREG is only a substrate but not an activator, while cholesterol is both a substrate and an activator. These results indicate that the sterol substrate site in ACAT1 does not involve significant sterol-phospholipid interaction, while the sterol activator site does. Studies utilizing small molecule ACAT inhibitors show that ACAT plays a key role in PREG esterification in various cell types examined. Mice lacking ACAT1 or ACAT2 do not have decreased PREG ester contents in adrenals, nor do they have altered levels of the three major secreted adrenal steroids in serum. Mice lacking LCAT have decreased levels of PREG esters in the adrenals. These results suggest LCAT along with ACAT1/ACAT2 contribute to control pregnenolone ester content in different cell types and tissues."

On the other front, increasing cholesterol production, Ray mentioned cyclodextrin.

But I'm puzzled when I came across this article, talking about cyclodextrin as a cholesterol-lowering drug: https://www.invasivecardiology.com/...ey-can-be-excreted-body-reduces-arterial-wall

I wonder if the writer was referring to cholesterol ester (or oxidized LDL) using the term "cholesterol crystals," once again being disingenuous so cholesterol stays framed as the bad guy.

I thought the subject of cholesterol esters to be new and helpful. I decided to send this message a la viber to my private groups:

Why is saturated fats superior to polyunsaturated fats (PUFAs)? Saturated fat- coconut oil, beef tallow, butter. PUFA- soya oil, corn oil, canola oil (American Heart Association "heart-healthy" oils), EPA and DHA from fish oils.

Reasons: Youthful skin, Absence of fatty liver disease, avoidance of atherosclerosis, longevity and health.

Why?
-LDL does not get oxidized to form plaques (atherosclerosis).
-Cholesterol does not get converted to cholesterol esters, which accumulate in tissues (aged skin is accumulated cholesterol esters, fatty liver disease likewise)
-LDL is needed to produce protective hormones such as progesterone; elderly especially need to have higher cholesterol to provide for it, but LDL must be "unoxidized" - the good LDL. Take saturated fats, instead of PUFAs, to ensure good LDL.

Lastly, the reason PUFAs lower cholesterol (hence mischaracterized as healthful by the AHA) is because they cause cholesterol to be converted to cholesterol ester. Not healthful at all.

I threw it out there. Hope it connects with a soul.

 

[Sourdoughbanana]

Saturated fats aren’t superior. It’s more complicated than a black or white situation based from Petri dish studies.

https://www.sciencedirect.com/science/article/pii/S0952327897904208

The literature is abundant in both sides, what matters is what happens in truly healthy subjects ie. normolipemic ie. not the dudes with 2x normal LDL who think it’s fine to have the cholesterol metabolism of a centenarian

 

[yerrag]

Saturated fats aren’t superior. It’s more complicated than a black or white situation based from Petri dish studies.

https://www.sciencedirect.com/science/article/pii/S0952327897904208

The literature is abundant in both sides, what matters is what happens in truly healthy subjects ie. normolipemic ie. not the dudes with 2x normal LDL who think it’s fine to have the cholesterol metabolism of a centenarian

You're the one talking about petri dish studies. Is the literature abundant on both sides? Really? The unbiased side and the biased side you mean? Of course. When did we broach the subject of dudes with 2x LDL? And centenarians? What are you smoking?

Rather than link to an abstract where the authors don't know how to explain the subject in a straightforward manner, and make comments that are just as hard to understand, why not follow Ray Peat and explain things ordinary people can understand?

 

[jb116]

Lowering blood cholesterol VIA DRUGS or PUFAs. You make it sound like higher cholesterol is superior than normal cholesterol.

It is more superior, to not having that adaptive response. Most superior obviously is normal cholesterol due to conversion. Worse case is low cholesterol due to pufa or drugs.

 

[Mito]

On the fifth section, Cholesterol Esters, of the above link, it is stated that "Cholesterol esters are major constituents of the adrenal glands." If this is so, why is it so? It has to serve a function. Otherwise, it would be a cause of impairment for the adrenal glands. I'm wondering if the statement is a statement of the natural order of things, or that it reflects an observance of a state of pathology mistakenly assumed as a normal state.

“Adrenal cortical mitochondria contain a mixed function oxidase capable of converting cholesterol to pregnenolone; this enzyme requires NADPH, oxygen and cholesterol. This cholesterol side chain cleavage enzyme system contains a Flavoprotein, an iron sulphur protein and a specific cytochrome P450 termed cytochrome P450scc. ACTH stimulates the adrenal cortex by activating adenyl cyclase producing an elevated intracellular concentration of cAMP. This in turn increases the activity of a cytosolic cAMP dependent protein kinase. Adrenal cortical cytosol contains a cholesterol ester hydrolase which is activated by ATP and a protein kinase. This enzyme may be deactivated by a phosphoprotein phosphatase. The adrenal cortex contains lipid droplets that are rich in esterified cholesterol. Cholesterol ester hydrolase can release free cholesterol from the lipid droplets. The free cholesterol released may be used to supplement the mitochondrial cholesterol as a pregnenolone precursor. Steroid hormone production by the adrenal cortex exhibits a diurnal rhythm and correlates with the activity of the cytosolic cholesterol ester hydrolase. The acute steroidogenic response to ACTH may be in part attributed to the availability of free cholesterol to the mitochondrial cholesterol side chain cleavage enzyme complex. The intracellular movement of free cholesterol from lipid droplets to mitochondrial inner membranes may be impeded by protein synthesis inhibitors such as cycloheximide. The precise mechanism of this block in steroidogenesis remains to be elucidated. Various drugs and oestrogenic hormones suppress the plasma and adrenal cholesterol concentrations. If adrenal cells are deficient in cholesterol, these cells exhibit a diminished response to ACTH. The response to this hormone can be corrected by supplying cholesterol via exogenous plasma lipoproteins. The route that free cholesterol follows within the adrenal cortical cell and the physiological factors influencing free cholesterol movement in such cells are important issues to be explored in future.”
Cholesterol metabolism in the adrenal cortex. - PubMed - NCBI


“Cholesterol serves as the precursor for adrenocortical steroidogenesis (for a review, 1). Although the adrenal cortex is capable of synthesizing cholesterol, cholesterol for steroidogenesis is primarily derived from plasma lipoproteins. Excess cholesterol is esterified with a variety of fatty acids and stored in cytosolic lipid droplets. Depending upon the conditions of stimulation, the stored cholesteryl esters may be hydrolyzed, and unesterified cholesterol is transferred into the mitochondrial inner membrane where the cholesterol side-chain cleavage reaction takes place.”
http://www.jlr.org/content/35/6/1115.full.pdf

 

[tankasnowgod]

Lowering blood cholesterol VIA DRUGS or PUFAs. You make it sound like higher cholesterol is superior than normal cholesterol.

That's because it is.

 

[tankasnowgod]

Saturated fats aren’t superior. It’s more complicated than a black or white situation based from Petri dish studies.

https://www.sciencedirect.com/science/article/pii/S0952327897904208

The literature is abundant in both sides, what matters is what happens in truly healthy subjects ie. normolipemic ie. not the dudes with 2x normal LDL who think it’s fine to have the cholesterol metabolism of a centenarian

OH! So would you like to talk about RCTs done in a human population that replaced Saturated Animal Fat with PUFA and compared the results? Excellent. Let's start with Sydney Diet Heart Study in 1978 that showed a far greater mortality among the PUFA group than the normal SFA group. Or there's trial conducted by Rose and associates, which had far higher CHD and total mortality in the PUFA group.

Of the 14 Controlled Trials that have put this idea to the test, only 3 (Morrison in 1955, Hood in 1965, and the Finnish Mental Hospital Study in 1972) showed any significant reduction in all cause and CHD mortality in the PUFA group. And none of those three were randomized, or blinded. There is no advantage for PUFA in any of the randomized trials, and as I pointed out above, sometimes the PUFA groups had far, far worse outcomes.

 

[GAF]

I made an error. The price for treatment of lysosomal acid lipase is about 500,000 Pounds per year. I apologize for my mistake.
NICE rejects Alexion’s rare disease therapy Kanuma - PharmaTimes
But, maybe they lowered it a bit by now....
Obviously, for whatever reason, mis-regulation of LAL in humans is an extremely common problem and if someone could conjure up this enzyme for widespread use that might be a good thing for people, but not so good for wall street. haidut wan kenobi is our only hope.

 

[GAF]

Structure and catalytic mechanism
Although a diverse array of genetically distinct lipase enzymes are found in nature; and, they represent several types of protein folds and catalytic mechanisms, most of them are built on an alpha/beta hydrolase fold[8][9][10][11] and employ a chymotrypsin-like hydrolysis mechanism using a catalytic triad consisting of a serine nucleophile, a histidine base, and an acid residue (usually aspartic acid).[12][13]

Lipase - Wikipedia

It seems clear to me that some citizen scientist with a lab, using the above information, could conjure up some LAL for us to try.

 

[yerrag]

“Adrenal cortical mitochondria contain a mixed function oxidase capable of converting cholesterol to pregnenolone; this enzyme requires NADPH, oxygen and cholesterol. This cholesterol side chain cleavage enzyme system contains a Flavoprotein, an iron sulphur protein and a specific cytochrome P450 termed cytochrome P450scc. ACTH stimulates the adrenal cortex by activating adenyl cyclase producing an elevated intracellular concentration of cAMP. This in turn increases the activity of a cytosolic cAMP dependent protein kinase. Adrenal cortical cytosol contains a cholesterol ester hydrolase which is activated by ATP and a protein kinase. This enzyme may be deactivated by a phosphoprotein phosphatase. The adrenal cortex contains lipid droplets that are rich in esterified cholesterol. Cholesterol ester hydrolase can release free cholesterol from the lipid droplets. The free cholesterol released may be used to supplement the mitochondrial cholesterol as a pregnenolone precursor. Steroid hormone production by the adrenal cortex exhibits a diurnal rhythm and correlates with the activity of the cytosolic cholesterol ester hydrolase. The acute steroidogenic response to ACTH may be in part attributed to the availability of free cholesterol to the mitochondrial cholesterol side chain cleavage enzyme complex. The intracellular movement of free cholesterol from lipid droplets to mitochondrial inner membranes may be impeded by protein synthesis inhibitors such as cycloheximide. The precise mechanism of this block in steroidogenesis remains to be elucidated. Various drugs and oestrogenic hormones suppress the plasma and adrenal cholesterol concentrations. If adrenal cells are deficient in cholesterol, these cells exhibit a diminished response to ACTH. The response to this hormone can be corrected by supplying cholesterol via exogenous plasma lipoproteins. The route that free cholesterol follows within the adrenal cortical cell and the physiological factors influencing free cholesterol movement in such cells are important issues to be explored in future.”
Cholesterol metabolism in the adrenal cortex. - PubMed - NCBI


“Cholesterol serves as the precursor for adrenocortical steroidogenesis (for a review, 1). Although the adrenal cortex is capable of synthesizing cholesterol, cholesterol for steroidogenesis is primarily derived from plasma lipoproteins. Excess cholesterol is esterified with a variety of fatty acids and stored in cytosolic lipid droplets. Depending upon the conditions of stimulation, the stored cholesteryl esters may be hydrolyzed, and unesterified cholesterol is transferred into the mitochondrial inner membrane where the cholesterol side-chain cleavage reaction takes place.”
http://www.jlr.org/content/35/6/1115.full.pdf

Thanks. So, if I'm reading it correctly, cholesteryl esters occur naturally in the adrenal gland as a stored form on cholesterol. It is converted to free cholesterol by a cholesterol ester hydrolase, and this makes the cholesterol available for conversion to pregnenolone, of which cortisol is a downstream product. If this were the case, then would it be correct to assume that the body has a mechanism to convert cholesterol esters to free cholesterol, thru activation by enzymes? So it is a matter of enabling enzymatic processes, and hindering it would be a matter of having deficiencies that block the enzymes from being synthesized?

 

[Sourdoughbanana]

It is more superior, to not having that adaptive response. Most superior obviously is normal cholesterol due to conversion. Worse case is low cholesterol due to pufa or drugs.

That’s a good reminder for people

 

[Sourdoughbanana]

That's because it is.

No, but I’m not surprised someone who believes in megadoses of vitamin A+D oh and huh DHT is beneficial for hair, thinks that more saturated fats for more cholesterol is a desirable outcome.

Thank god you’re not a health professional

 

[tankasnowgod]

No, but I’m not surprised someone who believes in megadoses of vitamin A+D oh and huh DHT is beneficial for hair, thinks that more saturated fats for more cholesterol is a desirable outcome.

Thank god you’re not a health professional

How do you know what I do for a living?

Still waiting for you to post any studies that DHT is at all responsible for hairloss (you said you could post so many, and yet...... crickets).

I also don't know what you mean by "believes in megadoses of Vitamin A+D."