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š§µ Dec 9th anniversary thread
On this day in 2015 I received a lab result that would alter the course of my life.
Just two weeks earlier I had gotten my very first bloodwork after half a year on #keto that showed my total and #LDL #Cholesterol had nearly doubled (!)ā¦ /1
On this day in 2015 I received a lab result that would alter the course of my life.
Just two weeks earlier I had gotten my very first bloodwork after half a year on #keto that showed my total and #LDL #Cholesterol had nearly doubled (!)ā¦ /1
2/ With that first test I was overcome with shock and curiosity ā much more former than the latter.
I wanted to get a repeat test to confirm this wasnāt a lab error.
I wasnāt ready to give up #keto, but I was miserable enough that I ate considerably less.
I wanted to get a repeat test to confirm this wasnāt a lab error.
I wasnāt ready to give up #keto, but I was miserable enough that I ate considerably less.
3/ At the same time I learned as much as I could about Lipidology - which focuses on how the body moves lipids (like cholesterol) in the blood.
And to my surprise, this system is already very familiar to me as a software engineer given it is a distributed object network.
And to my surprise, this system is already very familiar to me as a software engineer given it is a distributed object network.
1/ Two weeks ago we released our paper on the #LipidEnergyModel (#LEM) along with our video abstract for it. I'm pleased to say it has led to many great connections and expanded discussion.
I'm going to recap on a lot of these in this thread. š§µ ...
I'm going to recap on a lot of these in this thread. š§µ ...
2/ First and foremost, thanks to everyone for their extraordinary support in retweeting our announcement, sharing our paper, and letting researchers know of this model.
3/ As we state many times (including within the video abstract), this model doesn't describe all possible influences on cholesterol levels. For example, other things can impact LDL-C such as M/PUFA-to-saturated fat composition, fiber, genetics, medication, etc. 
1/ A very busy time
But in this late moment of calm before the weekend, I'm finding myself truly humbled that our #LMHRpaper is finalized and has crossing so many interested eyes.
I hope many will agree with us this phenomenon is well worth researching.
cholesterolcode.com/our-paper-on-lā¦
But in this late moment of calm before the weekend, I'm finding myself truly humbled that our #LMHRpaper is finalized and has crossing so many interested eyes.
I hope many will agree with us this phenomenon is well worth researching.
cholesterolcode.com/our-paper-on-lā¦
2/ Via @nicknorwitz: "... this paper has stimulated vigorous discussion, risen to the top of its journal for all time reads, and is among the top 15 trending papers across all American Society of Nutrition associated journals for the year 2021." nutrition.org/15-trending-nuā¦
3/ There's quite a bit more work in the pipeline from the many great collaborators I have the honor to be working with. We're passionately working on a #LipidEnergyModel paper, the #LMHRstudy (currently underway), and a couple other projects I can't announce just yet...
1/ Yes -- if you're curious as to why @nicknorwitz and I are chatting so often about ANGPTLs, it's worth working our way backwards...
If you're powered by fat, your tissues are getting it from free fatty acids or triglycerides (which is really three FAs bundled together)...
If you're powered by fat, your tissues are getting it from free fatty acids or triglycerides (which is really three FAs bundled together)...
2/ Recently I was much more focused on fasting (see ) and lipoprotein lipase (LPL) dynamics (see )
3/ And indeed, the regulatory strings behind LPL up and down regulation is a much bigger part of the story with regard to VLDL turnover -- and thus potential resulting effects on LDL-C, HDL-C, and Triglycerides (TG).
1/ š "HDL Triglycerides"
or rather HDL-TG
-- As in, triglycerides onboard HDL particles
āļø Highly associated with: total TG, glycerol, fatty liver index. āļøOpposite w/ HDL-C/-P
And ofc š"Patients with carotid plaques also showed higher HDL-TG."...
pubmed.ncbi.nlm.nih.gov/31252694/
or rather HDL-TG
-- As in, triglycerides onboard HDL particles
āļø Highly associated with: total TG, glycerol, fatty liver index. āļøOpposite w/ HDL-C/-P
And ofc š"Patients with carotid plaques also showed higher HDL-TG."...
pubmed.ncbi.nlm.nih.gov/31252694/
2/ @josefagirona, @lluismasana et al conclude the abstract with:
"HDL-TG should be considered a biomarker of metabolic and cardiovascular risk and could be a marker of HDL dysfunction."
If I can offer a different hypothesis (again, consistent with the #LipidEnergyModel)...
"HDL-TG should be considered a biomarker of metabolic and cardiovascular risk and could be a marker of HDL dysfunction."
If I can offer a different hypothesis (again, consistent with the #LipidEnergyModel)...
3/ Consider these HDL particles with higher levels of triglycerides aren't really that unique.
They more likely a downstream result of metabolic dysfunction as opposed to a distinct species of particle.
They more likely a downstream result of metabolic dysfunction as opposed to a distinct species of particle.
1/ New #LipidEnergyModel video on ANGPTL proteins via @nicknorwitz
And a few added thoughts...
ANGPTLs are *all* inhibitors. They are applying the breaks to the Lipoprotein Lipase (LPL) in particular.
So consider this analogy...
And a few added thoughts...
ANGPTLs are *all* inhibitors. They are applying the breaks to the Lipoprotein Lipase (LPL) in particular.
So consider this analogy...
2/ Imagine a room full of people at tables being served with trays of food regularly coming from the kitchen moved around the room by waiters.
No one is particularly famished, but they aren't especially full either, so they are absently taking food off the trays to maintain...
No one is particularly famished, but they aren't especially full either, so they are absently taking food off the trays to maintain...
3/ However, a few guests at one table leave to get some exercise and return quit hungry.
And here's the catch: You can't tell specific people to do specific things (including the waiters), but you can say things to the entire room. Is there a way to solve this puzzle?
And here's the catch: You can't tell specific people to do specific things (including the waiters), but you can say things to the entire room. Is there a way to solve this puzzle?
1/ Okay, finally getting around to this experiment video by @ScepticalDoctor
Naturally, this has many things I'm interested in -->
- N=1
- #Lipids (esp #Cholesterol)
- and not least of all, Anna and I have many respectful, kind debates (more of that plz, #NutritionTwitter)
Naturally, this has many things I'm interested in -->
- N=1
- #Lipids (esp #Cholesterol)
- and not least of all, Anna and I have many respectful, kind debates (more of that plz, #NutritionTwitter)
2/ "But this experiment is mainly for entertainment purposes. Self experiments like this are irrelevant from a scientific perspective."
Unsurprisingly, I do disagree on this wording. I think it's fair to say self-experiments have "limited" relevance (depending on design)...
Unsurprisingly, I do disagree on this wording. I think it's fair to say self-experiments have "limited" relevance (depending on design)...
3/ ... But a well designed N=1 can provide quite a lot of scientific value, even if primarily hypothesis-generating.
1/ Okay, let's talk ANGPTL3-4-8 model. Mega thx to @nicknorwitz for getting well ahead of me on the angptls and their influence on LPL.
Here's the central figure, which we'll be referencing.
(Don't worry if you get lost, I'll unpack this more below..)
royalsocietypublishing.org/doi/10.1098/rsā¦
Here's the central figure, which we'll be referencing.
(Don't worry if you get lost, I'll unpack this more below..)
royalsocietypublishing.org/doi/10.1098/rsā¦
2/ "Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues."
Translation: LPL is like a key cells use to open lipoprotein boats to offload their fat-fuel cargo (TG)
Translation: LPL is like a key cells use to open lipoprotein boats to offload their fat-fuel cargo (TG)
3/ "Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting"
Sure, post-meal we do more storing in fat via LPL, otherwise we do less.
Sure, post-meal we do more storing in fat via LPL, otherwise we do less.
1/ Heard enough Lipoprotein Lipase (LPL)?
The tl:dr -> There's more selective control with fatty acid exchange in tissues than we fully understand... but we have a lot more we've learned recently...
#LipidEnergyModel @nicknorwitz
sciencedirect.com/science/articlā¦
The tl:dr -> There's more selective control with fatty acid exchange in tissues than we fully understand... but we have a lot more we've learned recently...
#LipidEnergyModel @nicknorwitz
sciencedirect.com/science/articlā¦
2/ "Preferential uptake of FAs into high demand tissues such as the heart, muscle and brown adipose tissue cannot be achieved by non-specific uptake, which would acutely distribute FAs equally into all cells."
- Translation: there's some selective trafficking going on here.
- Translation: there's some selective trafficking going on here.
3/ "A second uptake process modulated by activity of capillary lipoprotein lipase (LpL) involves FAs derived from triglyceride (TG) rich lipoproteins (chylomicrons and very low density lipoproteins." (VLDL)
- Yes, lipoproteins + LPL = hydrolysis of TG to cells
- Yes, lipoproteins + LPL = hydrolysis of TG to cells
1/ #ListeningThread
Two fantastic intellectuals, @robbwolf and @lipoprotein, chatting about lipids, cardiovascular disease, and #LMHRs
Good podcast for my evening walk ā might add some thoughts hereā¦
Two fantastic intellectuals, @robbwolf and @lipoprotein, chatting about lipids, cardiovascular disease, and #LMHRs
Good podcast for my evening walk ā might add some thoughts hereā¦
2/ Wow, in the intro Rob mentions Bill having discussed LMHRs with me (and yes, weāve had many great chats on the topic). Where he agrees, and where he disagrees. To be sure, I have a bit of an advanced preview on what that will likely be. ;) but Iām excited to hear it in the ep.
3/ 28:30 Bill: I think Dave Feldman has probably helped more than any one person in giving disability and how radically our bodies can change [lipid levels] in just daysā¦ So yeah, you can actually influence these results quite a bit in a 3 to 5 day period of timeā¦
1/ Thank you for the invitation, @chadinabhan.
I've now listened to the episode and was a bit surprised at a few points, but also less so with others.
Cholesterol is a very emotionally charged topic, and understandably so...
I've now listened to the episode and was a bit surprised at a few points, but also less so with others.
Cholesterol is a very emotionally charged topic, and understandably so...
2/ For me, this journey started 6 years ago with alarmingly high total and LDL cholesterol following my going on a ketogenic diet. I became obsessed with trying to understand why and begin reading everything I could on lipidology...
3/ I found through a series of experiments there was quite a bit of change I could induce based on dietary patterns. As I developed and executed this "citizen science" research, I turned it around back to the community to hopefully help us in advancing this important topic.
1/ #Thread - Hypothesis on why leanness + low carb likely to lead to high cholesterol
I originally retweeted this with a simple "yep" given how it this relates to the #LipidEnergyModel.
Many have asked me to expand, so this thread will be my simple, layperson-friendly breakdown
I originally retweeted this with a simple "yep" given how it this relates to the #LipidEnergyModel.
Many have asked me to expand, so this thread will be my simple, layperson-friendly breakdown
2/ Let's have some fun and use a relatable analogy...
Imagine you had exactly two kinds of stores in the neighborhood: bakeries and butcher shops.
You normally get groceries from both, but recently the bakeries were closed down, so now you just get meat only for meals...
Imagine you had exactly two kinds of stores in the neighborhood: bakeries and butcher shops.
You normally get groceries from both, but recently the bakeries were closed down, so now you just get meat only for meals...
3/ Now that the bakeries are down, there's more demand on the butcher shops, so they are having more inventory sent to them.
But then, the neighborhood increased while the number of butcher shops actually decreased, and this required an even higher rate of shipments to restock.
But then, the neighborhood increased while the number of butcher shops actually decreased, and this required an even higher rate of shipments to restock.
1/ Interesting thread via @ck_eternity_
I'll add some thoughts in my own thread to follow, but consider reading his entirely first.
As always, this is in the spirit of discourse. Love keeping it respectful and productive on such challenging topic. :)
I'll add some thoughts in my own thread to follow, but consider reading his entirely first.
As always, this is in the spirit of discourse. Love keeping it respectful and productive on such challenging topic. :)
2/ Before getting started, note the coming #LMHRstudy will effectively be tackling much of these common considerations quite directly as we study #LMHRs who have considerably high #LDL from being fat-adapted with otherwise #CVD healthy metrics (See CitizenScienceFoundation.org)
3/ While not commonly known, another major carrier protein for chol is Albumin. It's typically considered in light of transporting NEFAs, but its binding sites can (and are) applied to many other lipids, including cholesterol.
ncbi.nlm.nih.gov/pmc/articles/Pā¦
ncbi.nlm.nih.gov/pmc/articles/Pā¦
1/ This new MR study by @mendel_random, @mvholmes, et al makes use of UK Biobank data and determines #ApoB increases risk of #AllCauseMortality, and even #T2Diabetes
This is actually relevant timing as we are rapidly approaching the #LMHRstudy. sciencedirect.com/science/articlā¦
This is actually relevant timing as we are rapidly approaching the #LMHRstudy. sciencedirect.com/science/articlā¦
2/ If you didn't already know, "Lean Mass Hyper-responders" (#LMHRs) would be considered hypercholesterolemic, with this resulting from being very low carb (typically #keto), and are often lean and/or athletic.
(You can read more on this phenotype at CholesterolCode.com/lmhr)
(You can read more on this phenotype at CholesterolCode.com/lmhr)
3/ Setting aside why this population exhibits this (see #LipidEnergyModel for more), the most important question is whether they are at risk.
This MR study builds on the existing conventional expectation that they are, and no less in a dose-dependent manner...
This MR study builds on the existing conventional expectation that they are, and no less in a dose-dependent manner...
I saw this paper linked by @BioLayne (hat tip!) in a twitter discussion and had to stop and read most of it. Basically SFA vs PUFA infused muffin RCT. There's quite a lot of interesting data within. And it's publicly available, btw (no firewall)...
ncbi.nlm.nih.gov/pmc/articles/Pā¦
ncbi.nlm.nih.gov/pmc/articles/Pā¦
... The lipid profile changes for the SFA group are unsurprising to me, ofc. But I was surprised they went with ALT as the proxy for "liver fat accumulation". Relative change 53%, but I didn't find the absolute values listed for ALT between groups? Maybe in the supplement...?
... They had a subgroup of 10 (5 of each) where the did PET-MRIs (need more of this in studies) to detect "change in hepatic palmitate uptake" -- which tends to be a stronger proxy for liver fat accumulation, but it showed no association.
1/ Whether in agreement or not, @DBelardoMD's statement does represent the existing position of mainstream medicine, particularly lipidology. (Tho she's adding a bit more "color" to it, ofc :) )
My retweets like these are to further generate cross exposure to other voices...
My retweets like these are to further generate cross exposure to other voices...
2/ ... Think of it as working toward breaking down some of the echo-chamber-ism.
If you follow me, you're going to get this on a regular basis because I feel hearing every side is important (I have many friends who are LDL skeptics who definitely don't agree with me on this!)
If you follow me, you're going to get this on a regular basis because I feel hearing every side is important (I have many friends who are LDL skeptics who definitely don't agree with me on this!)
3/ And while we're at it -- here's a list of people I've had excellent, cordial conversations with who are likewise concerned about high LDL whether LMHR or not:
@DrNadolsky
@ethanjweiss
@lansberg
@Lpa_Doc
@NutritionMadeS3
Listen to them as well -- I do...
@DrNadolsky
@ethanjweiss
@lansberg
@Lpa_Doc
@NutritionMadeS3
Listen to them as well -- I do...
1/ Still one of my favorite studies in relation to the #LipidEnergyModel. One might wonder what happens to animals who become fat adapted due to fasting for a long period.
Obvious example: Hibernation
#LDL #Cholesterol goes up... does #Atherosclerosis?
pubmed.ncbi.nlm.nih.gov/22686205/
Obvious example: Hibernation
#LDL #Cholesterol goes up... does #Atherosclerosis?
pubmed.ncbi.nlm.nih.gov/22686205/
2/ They were comparing bears in captivity and the wild. And in both, lipid levels during hibernation are "considerably higher than what is normally found in humans"
3/ In spite of the high lipid levels alongside other risk factors, they found no signs of atherosclerosis in brown bears.
1/ How much does "Dietary Cholesterol" impact blood cholesterol levels?
This has been making the rounds lately and I have an experiment from 2018 is key to this question š
Remember the "White Bread and Processed Meat" experiment? cholesterolcode.com/the-tandem-droā¦
This has been making the rounds lately and I have an experiment from 2018 is key to this question š
Remember the "White Bread and Processed Meat" experiment? cholesterolcode.com/the-tandem-droā¦
2/ If you've followed me a while, you know I believe it isn't the actual ingestion of cholesterol on #LowCarb that has a big impact on serum levels -- it's predominantly the trafficking of fat. (See CholesterolCode.com/model)
But this is actually a very testable distinction...
But this is actually a very testable distinction...
3/ All we need is an experiment where I consume a lot of (1) low fat food that still (2) has ample amounts of cholesterol.
Thus, the "processed meat" side of the experiment is key if it has a decent amount of cholesterol -- and it does.
For example 9/21/18 I ate the following..
Thus, the "processed meat" side of the experiment is key if it has a decent amount of cholesterol -- and it does.
For example 9/21/18 I ate the following..
1/ Long running thought exp'nt:
If a drug did many of the same things with one's lipid profile as a #LowCarb diet, particularly decreasing triglycerides while increasing #LDL #Cholesterol:
1) Would it reduce ASCVD risk?
2) And if so, would it be more acceptable than #LowCarb?
If a drug did many of the same things with one's lipid profile as a #LowCarb diet, particularly decreasing triglycerides while increasing #LDL #Cholesterol:
1) Would it reduce ASCVD risk?
2) And if so, would it be more acceptable than #LowCarb?
2/ If you haven't heard, SGLT2 Inhibitors have recently emerged and have been gaining a lot of popularity. Data thus far shows they typically:
1) Decrease TG levels
2) Increase #LDL #Cholesterol levels
... yet...
3) Reduce risk for cardiovascular disease
1) Decrease TG levels
2) Increase #LDL #Cholesterol levels
... yet...
3) Reduce risk for cardiovascular disease
3/ Naturally, that has the attention for those of us interested in how triglyceride trafficking and turnover could be relevant to #LDL increasing for what may turn out to be non-pathogenic reasons (kinda my focus ;) )
CholesterolCode.com/model
But wait -- it get's better...
CholesterolCode.com/model
But wait -- it get's better...
1/ #ReadingThread
This paper by @zinocker, @kariannesve, @simondankel is proving an interesting read. Before I get too much further, I'm going to turn it into a "reading thread" and post some of these quotes as I go...
(Big hat tip to @bigfatsurprise) academic.oup.com/ajcn/advance-aā¦
This paper by @zinocker, @kariannesve, @simondankel is proving an interesting read. Before I get too much further, I'm going to turn it into a "reading thread" and post some of these quotes as I go...
(Big hat tip to @bigfatsurprise) academic.oup.com/ajcn/advance-aā¦
2/ "In this paper we propose a novel model, the homeoviscous adaptation to dietary lipids (HADL) model, which explains changes in lipoprotein cholesterol as adaptive homeostatic adjustments that serve to maintain cell membrane fluidity and hence optimal cell function."
3/ Later in the abstract: "Hence, circulating levels of LDL cholesterol may change for nonpathological reasons. Accordingly, an SFA-induced raise in LDL cholesterol in healthy individuals could represent a normal rather than a pathologic response."
1/ šThread -- About Me -- 5 year updateš
It's been a busy 24 hours since @joerogan's podcast dropped where @CarnivoreMD discussed our work (mega thx, Paul!). There's been a surge of new followers, so I figured it was high time to do an update for those just tuning in...
It's been a busy 24 hours since @joerogan's podcast dropped where @CarnivoreMD discussed our work (mega thx, Paul!). There's been a surge of new followers, so I figured it was high time to do an update for those just tuning in...
2/ I'm a senior software engineer and systems architect having developed a variety of platforms over my career.
Five years ago next month I saw my cholesterol levels skyrocket on a ketogenic diet and was extremely interested as to the mechanisms behind it...
Five years ago next month I saw my cholesterol levels skyrocket on a ketogenic diet and was extremely interested as to the mechanisms behind it...
3/ I began learning everything I could about Lipidology and the system that moves #cholesterol around in our body. To my surprise, it has many structural things in common with a network (a very advanced one, mind you), but soon I was manipulating my own lipid levels easily.
1/ RTing for balance, and because I agree with my colleague, @DrNadolsky.
But interestingly, the mechanism by which SGLT2i results in higher LDL and reduce TG could be relevant to the #LipidEnergyModel and how this may relate to the question of risk in this context...
But interestingly, the mechanism by which SGLT2i results in higher LDL and reduce TG could be relevant to the #LipidEnergyModel and how this may relate to the question of risk in this context...
2/ There's an interesting study from last year on this that caught my attention. Fair warning it is a transgenic mouse study, but at least it is mechanistic and thus decent for hypothesis-forming.
Let's unpack some key findings..
ncbi.nlm.nih.gov/pmc/articles/Pā¦
Let's unpack some key findings..
ncbi.nlm.nih.gov/pmc/articles/Pā¦
3/ Per @DrNadolsky above, it opens with:
"Sodium glucose cotransporter 2 (SGLT2) inhibition in humans leads to increased levels of LDL cholesterol and decreased levels of plasma triglyceride. Recent studies however, have shown this therapy to lower cardiovascular mortality."
"Sodium glucose cotransporter 2 (SGLT2) inhibition in humans leads to increased levels of LDL cholesterol and decreased levels of plasma triglyceride. Recent studies however, have shown this therapy to lower cardiovascular mortality."
1/Incredible exchange with @PeterAttiaMD and @ChrisMasterjohn! This latest episode is highly relevant to the podcast @PeterAttiaMD and I had last year re #LipidEnergyModel
----> It starts at 1:03:24 here: peterattiamd.com/chrismasterjohā¦ (All emphasis in this transcript image mine.)
----> It starts at 1:03:24 here: peterattiamd.com/chrismasterjohā¦ (All emphasis in this transcript image mine.)
2/ Attia: "This is a problem of flux.. Because you canāt understand flux with a snapshot, you have to have the goddamn video. I mean, thatās the analogy, I mean you take a picture of something and you donāt know the flux. Whatās in, whatās out, where itās being disposed of." Yes!
3/ @ChrisMasterjohnās gives a great car accident analogy and explains how looking at only one piece in isolation is so probematic, āBut if youāre looking at one element in the snapshot you can never even so much as build a story about what probably happened.ā
