Dave Feldman: Lipid Metabolism and Macrophages - The Hidden Connection | Low Carb Cruise 2023 - 02

Unfortunately, because of the way this presentation was done, we were not able to capture the slide-view to edit into this video. This is what we have. Captured at the 2023 Low Carb Cruise. Interested in Low-Carb/Keto events? Check out www.lowcarbevents.com/
Dysfunctional lipid metabolism can lead to impaired immune function. High glucose has been linked to increased LDL transcytosis, which can lead to decreased LDL cholesterol. This suggests that glucose may have a role in regulating immune function by affecting lipid metabolism. Various inflammatory cytokines induce transcytosis of LDL particles through endothelial cells. Hyperglycemia can likewise induce LDL transcytosis along with potentially inhibiting autophagy. Dysfunctional lipid metabolism of the immune response may play a significant role.

[@taniafuentez9588]

Learning so much from each speaker at this year's Low Carb cruise. Dave Feldman has been way ahead of the curve for years. I particularly appreciate his clarity on an often misunderstood subject vital to us all.

[@KetoChowYoutube]

He is tremendous!

[@1timbarrett]

An impressively organized speaker; it was a pleasure to learn from Dave Feldman. And a big thanks to all at Keto Chow - you know who you are - for making this year’s Keto Cruise lectures available to all of us online…! 🙏

[@KetoChowYoutube]

Many thanks for watching! I'm pleased to hear that it was valuable to you.

[@HollyGeee]

Thanks for recording, love Dave and his research

[@robyn3349]

Thank you, Dave Feldman!

[@sherylburt7863]

Excellent presentation! Thanks Dave, and Keto Chow !

[@chrissypearson5597]

Appreciate all Ur doing for us LMHR's Dave, Excellent talk, lets hear more!

[@yjsungmstw2]

Amazing speech. I have been thinking about the same question you raised: why would our body make a compound (LDL) that is aiming at bombarding our vascular endothelium? Some other things must have happened to these molecules (hence, the "modified" LDL) before they can strike on the endothelial cells. Your speech also pointed to two (out of many) factors that may "happen" to these LDL-C particles: high glucose and inflammation. Bravo!

[@KetoChowYoutube]

Appreciate your feedback, thanks for stopping by our channel to watch.

[@michaelbreitenbach4092]

Modified or oxidized LDL?

[@AI-vs7sm]

Finally! After two and half years on low carb and watching way TOO MANY VIDEOS in this space, vegan and low carb, to hear both sides of argument. I have stayed low carb, but, I started asking one question on several websites as to WHAT makes only some of the LDL small dense particles get trapped if they are all going through the wall? And here is an engineer explaining it all ! Not Carvello, not other vegan cardiologists , but also not the low carb sites either. Ivor Cummins had the best answer to date, but, this is SO CLEAR! Thank You! I'm am not close enough to LMHR stats to volunteer, or I would!

[@thefisherking78]

Great presentation! Big fan of his work.

[@KetoChowYoutube]

Glad you enjoyed it!

[@kayeszymanski6945]

Thanks for the thorough explanation Dave Feldman. Also thanks to Keto Chow for making this available! ❤

[@KetoChowYoutube]

Our pleasure!

[@kelliekresse5710]

Thank you Keto Chow!

[@KetoChowYoutube]

Your are welcome!

[@ogeoge6000]

Thanks. I wonder if Dave has read Dr Malcolm Kendrick's book The Clot Thickens, he has a very different take on this process that seems more plausible. I'd love to know what Dave thinks of Malcolm's theory.

[@baronvon609]

Dr Paul Mason is also onboard with Dr Kendrick.He's made a video on KZbin about the thrombogenic process.

[@wocket42]

@@baronvon609 The important part is: FH isn't just high LDL. It's only "just high LDL-C" if all you look at is LDL-C. Very smart people seem to miss this point. FH could be a myriad of things we don't know about. Yet: people measure LDL and say "we know this is the only thing that changed in FH people therefor LDL-C must always be bad in all people".

[@baronvon609]

@@wocket42 LDL cholesterol isn't one of the five markers of having good metabolic health which is far more important.Mason, Bikman and Diamond have just produced a paper about this.All metabolic markers optimal and LDL goes up in some cases after been on keto.

[@lindabirmingham603]

​@@wocket42Some people with FH also have abnormal clotting factors ( fibrinogen which causes clotting). Those with FH that do not have high fibrinogen the the same or longer lives than the rest of the population.

[@realfoodcures]

At 24:14, The question is "What is causing LDL modification? Is it an inflammatory response or lack of capability to achieve its goals?" Everyone thinks it is inflammation but I think it is lack of ability to achieve it's goals. LDL is an opsonin which means it prepares unwanted organisms (virus, bacteria, parasites) to be consumed by macrophages. In my practice, I get parasites out of my patients en masses since 2007. Standard medicine sucks at parasites , mold, and chronic viruses. The more infections someone has, the worse their heart disease outcomes are. Medicine needs to start healing the body instead of treating LDL as the cause. There are so many reasons why heart disease occurs. Now we know the more plastic nanoparticles are in plaque, the worse heart disease outcomes are. This is just another example of the need to clean the body out instead of adding more poisonous phama pills.

[@dadesway]

It has been pointed out by many that the mutation that leads to dysfunctional LDL receptors is often *linked* with a mutation that compromises optimal working of the blood coagulation system. People who have the linked mutations typically die before they are 30. People who just have FH without the coagulation system mutation tend to leave longer than most (High Cholesterol is associated with lower risk from disease in older people) . . . (Ivor Cummins amongst others have raised these points) Another consideration . . . Macrophages have Scavenger receptors . . . these amongst other things can pick damaged and damaging (small) LDL particles which they to process; however, when overwhelmed they can become dysfunctional foam cells. Endothelial cells can also present scavenger receptors and are geared to remove damaged LDLs from the blood stream. It has been proposed that such a system evolved to remove a pathogenic body (oxidised LDL) from the blood stream. Whether the oxLDL passes through by transcytosis to be dealt with by macrophages on the other side is a possibility?

[@lisagayhart2482]

I always learn something when he talks

[@Clinto1984]

Great talk Dave. Your talk kind of touches on my issue with the thrifty gene / antagonistic pleiotropy hypothesis as applied to ASCVD i.e. that yes, ApoB is actively transported to the subendothelial space via transcytosis but it is for purposes conferring survival (and hence reproductive) benefit to the organism within the reproductive window (we selected for VLDL's TG transport ability, for example), but over time the process potentially becomes pathologic in ways that the physiology did not need to "anticipate" to ensure propagation (as it is now outside of the productive window and in the selection shadow re: LDL, the degradation product of VLDL, presents threats to vasculature over time i.e. cholesterol-years etc.). It is a compelling and elegant theory (thrifty gene selecting VLDL leading to antagonistic pleiotropy in selection shadow), but I have issues with it. One of them you talk about, that being the fact that the physiology actively transports ApoB containing lipoproteins into the subendothelial space (SRB1, ALK1 via caveolae). The other is that the physiology carries out this active process seemingly "aware" that it presents a potential threat to the vasculature, as we have evolved mechanisms that subsequently remove cholesterol from macrophages (macrophage cholesterol efflux). So the physiology expends energy to carry this particle across EC's, into the subendothelial space to be engulfed by macrophages, where it subsequently removes it. This appears to be a physiological process to me. Stary observed what appeared to be initiation, progression and regression of precursor lesions in fetuses through to adolescents on autopsy, leading him to hypothesize that the development of fatty streaks through to Type III lesions and their subsequent regression was perhaps a normal physiological process that may occur independent of plasma lipoprotein concentrations. It was only when a lesion progressed to Type IV and onwards that it appeared to be a pathological state leading to complicated lesions. This is corroborated somewhat by autopsies carried out on wild herbivores having arteriosclerotic (and some minor, but not complicated atherosclerotic) lesions within their vasculature despite very low plasma ApoB concentrations - incidentally at regions of high mechanical stress, such as in humans. In the case of the wild elephant studies carried out by McCullagh et al, it lead the researchers to conclude that it was a process of arterial remodeling in response to endothelial stress or damage that did not correlate to plasma lipid concentrations of the studied elephants. Adding more nuance to the story, it appears as though the fetal zone of the adrenals utilizes a significant amount of hepatically generated cholesterol carried on LDL particles as substrate for steroid synthesis. So the physiology is not "unaware" of LDL being the degradation product of VLDL, and it hasn't specifically selected for VLDL per the thrifty gene hypothesis, as it has been demonstrated that during fetal development LDL is specifically used as a cholesterol transport particle for the fetal zone. All of this tells me that the physiology has likely evolved to use LDL for various tasks (cholesterol transport in fetal stage, later transitioning to "chassis" for VLDL-TG transport among other things that you discuss in your talk); that it actively wishes to bring it through endothelial cells; that it actively remodels arteries in a way that increases the number of lipid rafts (caveolae) in regions of the vasculature subject to high mechanical stresses; and that it does all this despite being "aware" that there is a risk to this process - that being the deposition of cholesterol in the artery - that it must attenuate via macrophage cholesterol efflux. In my mind the pathology occurs when the efflux cannot be carried as per the above design. My speculation is that the ApoB particles undergo modifications in plasma that lead to increased likelihood of binding with proteoglycans and also decreased ability for the cholesterol to be subsequently freed from macrophages. Using FH as an example, these persons have issues with particle clearance (due to LDLR dysfunction) that lead to increased plasma residence time of ApoB particles that permit the particles to undergo atherogenic modifications (glycation, oxidation etc) that lead to them being more susceptible to the above (notwithstanding the other aspects of the mechanism at play in FH that you discuss in your talk). In someone with metabolic syndrome, insulin resistance or T2DM you have a preponderance of sdLDL (per Ron Krauss' work) that also lack conformity for LDLR recognition, leading to increased plasma residence time and the above cascade of events. To be fair to the current lipid hypothesis, an extremely high number of particles becoming trapped could completely overwhelm the RCT system as well, but selective retention is required for atherogenesis in the first place and I'm not sure at what point the endothelium just decides to start selectively retaining particles (per the concentration gradient hypothesis). In the LMHR, presumable you have LDL particles that meet the biology's "conformance specifications" i.e. they are readily recognized by the LDLR (there is no LDLR dysfunction per FH or metsyn, iR or T2DM), so the liver is taking these LDL in, but recirculating them so that they can quickly and easily be used as a "chassis" to build a conforming VLDL particle replete with TG for transport to peripheral tissue or whatever. If this is not a pathological state (caveat: hypothetical statement) then any cholesterol can readily be freed via macrophage cholesterol efflux should that process be required to occur (remembering that most particles freely transcytose all the way - they don't get retained in the endothelium at all). All of this is a long-winded way of sharing my hypothesis but also to say thanks for you work in this space Dave. I think the LMHR study and the work around it is incredibly important for progressing the field of understanding the mechanism of ASCVD and hopefully will improve risk stratification and targeted Tx options for pts in future.

[@wocket42]

tl;dr, but I always suggest to look at our life style/diet patterns vs that of people 15k years ago and millions of years back. We are mostly missing the cycle of the seasons. We eat, sleep and work the same way all year around. This was not the case back then. So one can image that some physiological changes or damage is not a problem when it occurs or happens for a few weeks a year and a repair process can take place either the rest of the year or other special weeks in the year. So it's very difficult to make sense of something in the body when you have people who lived all their live say in the "fruit season", and never once in the "starving/fasting winter time", while the body expect certain periods to last only a few weeks and is missing others completely.

[@steve6034]

I hope you can succeed in arriving at the truth without trying to please invested industries. I think I am a typical mid 60's white male, 20 years on Statins, 20 years on blood pressure, active athletic youth consuming massive amounts of carbs and sugar, then a career in an office job, became obese, finally developed glucose resistance over the last 3 years, last year slowly take up Keto, lifestyle then lose 40kg, become very fit, Triglycerides' and cholesterol and blood pressure are then the lowest, stop medications, triglycerides' remain low but LDL goes right up. I don't want to start Statins again. Find a reason for me not to?

[@kathya1956]

How could you say cholesterol at your lowest when LDL went up. I assume HDL also went up.

[@steve6034]

@@kathya1956 Sorry, hard to tell the full story but with Keto and statins the levels were the lowest ever, stopped statins and triglyceride's stayed low, HDL slightly up, LDL quadrupled, but as I have stents 13 years ago, it further complicates the question if I have to go back on statins, but then taking statins for 10 years before I had the stents makes me believe it was inflammation, obesity, consumption of seed oils etc were the cause, not the cholestrol levels?

[@alwynpereira7363]

You are tough! and you'll find a way. Your journey is incredible.

[@mikemccarthy1638]

Everyone is conducting an experiment until the science clarifies (possibly in ~5 yrs or so w/ a boost from AI). Until then, you’re experimenting by default. Dr Robt Lustig saw that hi sugar in the American diet - added sugars, simple sugars (juice w/ its fruit fiber stripped out), fruit bred over time to increase its sugar content & hi-glycemic refined carbohydrates in general - was the leading cause of metabolic disease. See, eg, “Sugar is Poison.” Many yrs of study has led him to question the standard pharma method of treating diabetes & CVD. Among others, he now advocates that ~75% of LDL has no impact on CVD, that the remaining 25% very small particle LDL is the culprit - I’d be interested to see what would result from a consultation between these two scientists. (Another researcher asks a simple question about the role of cholesterol in arterial plaque - “Is cholesterol the arsonist or the fireman?”) Your comment does not address exercise. Since you’re trapped in this experiment anyway, you could experiment w/ exercise & other variables that can make a difference. - - high intensity interval training (several approaches, I do 90 secs at a jogging pace, followed by 30 secs of max intensity, continuously thru 7 repetitions, on a treadmill. Do it outside - dogs love it.) - static stretching to maintain range of motion & mild-moderate resistance training (weights, isometrics) to maintain muscle mass. - intermittent fasting, where you eat each day within a narrow window. I’m trying to get to a consistent 4-hr window, ending 3-4 hrs before bedtime, which matches my best circadian rhythm (diet is hi-protein, hi-good fat - salmon, mackerel, sardines, pasture-raised meat, eggs, dairy, selected veggies, no sugar or hi-glycemic carbs). - Reduce negative stress, stay on the parasympathetic side. Big deal but each of us has to find their own way… I’m 78 & still learning…

[@DanEngell]

I am in a very similar situation. I lost 40 lbs on keto and have kept it off for six years now. My trigs are way lower and HDL is way higher. Dave doesn't' mention it in this video but what I have heard on several other low carb channels is that the total LDL number is not critical. The important thing is the particle size of the LDL. High HDL and low trigs correlate with larger particle size of LDL. It is the small particles of LDL that get stuck in the artery wall. This is just what I have heard on KZbin dozens of times now. I'm definitely a happier camper doing low carb and almost completely off my blood pressure meds.

[@dr.proteomix1257]

He mentions patients with familial hypercholesterolemia have impaired lipid metabolism among their high LDL levels and as a result impaired macrophages as well. Is there any genetic or blood test that can be used to see if these are present? And if so what would be the solution?

[@trentonharris7676]

He skips one very important step in the process of atherosclerosis. That is, how does the vascular endothelial lining become so damaged as to allow LDL particles in, in the first instance?

[@lindabirmingham603]

Agreed, Malcolm Kendrick covers this is depth in " The Clot Thickens".

[@RichardFeuille]

My concern as well

[@ervisbudo8031]

What's high ldl? Ldl does not cause heart disease, maybe smoking, alcohol, seed oils, and processed sugars.

[@luchiayoung]

Excellent

[@KetoChowYoutube]

Thank you so much 😀

[@user-df2ei2bx1e]

see Paul Mason Dr. Paul Mason - 'The truth about high cholesterol'

[@KetoChowYoutube]

Thanks for the recommendation.

[@xiantaojiao]

Dave just cannot possible be an execellent software engineer😊

[@JD-rc6lq]

Wow I'd forgotten about "Fourth phase water" since I read "The fourth phase of water" by Gerald Pollack. At the time I wasnt sure if it was real or not!

[@RichardFeuille]

I too have wondered if the real problem here is with the vasa vasora and, is the mechanism here due to inflammation of those tiny vessels.

[@Bungifun]

I hope he realizes that this flies against his assumption that there is a high turnover of VLDL in his model. In addition, he doesn't get into why macrophages are not processing the lipids. This is important as it is part of creating the thickness of the occlusion. Macrophages fail to transition from their M1 phenotype to M2 and this is related to insulin and a number of other conditions. He also doesn't make the connection that the lipids may get attracted to feed the macrophages to prepare them for the transition to M2.

[@B-Mike]

Very bad placement of screen or location of the speaker. Cannot see the slides properly. Please, if possible, upload these slides.

[@KetoChowYoutube]

As noted in the description of the video, this is all we have access to.

[@gprivat812_my_selection6]

👍👍!!

[@Straightdeal]

Very geeky; quite difficult to follow. Have they made any progress? I don't really know. In 2023 there is so much difference of opinion in lipidology and insulin sensitivity/resistance, that maybe one should take extreme values of LDL-C a little more seriously.

[@eileenfb1948]

I would have benefitted from being able to see the board which had lots of important stuff hidden behind you. Can't be seen so why is it there.

[@KetoChowYoutube]

This is addressed in the description of the video, please read.

[@eileenfb1948]

@@KetoChowKZbin I didn't know that or I would have kept stopping the video and reading below. Thank you

[@susanbonner16]

😊

[@fR_eN]

12:50

[@250txc]

I'm with Dave ~100% but all this is going into corner cases even he was not expecting ... I'm also with the human body doing the correct thing about ~98% of the time no matter what most of these fancy white boys say...

[@kiemtruong6903]

If the girl with FH & had a heart attack at age 6 is still alive, check her for hyper-coagulation disorder

[@davidzip8841]

Anyone that listens to an engineer with untested theories, and somehow decides I am going to risk my cardiovascular health on this is making a huge mistake.

[@KetoChowYoutube]

As opposed to listening to doctors blindly repeating theories that were proven wrong decades ago and prescribing statins also proven to increase your risk of all- cause mortality. I'll stick with the engineer.

[@davidzip8841]

Statins have been shown in every study to reduce mace and all cause mortality. I think you and the engineer deserve each other.

[@napua5217]

@@davidzip8841check out Dr. Ali nadir Cardiologist and he explains why the science on statins is corrupt. Also when they say 50% reduction, they don’t tell you it’s from 1% to .50% even if that is a true statement it’s so minimal for the side effects of statins.

[@realfoodcures]

@@davidzip8841 the attempt is to get to the CAUSE, a concept the statin pushers are missing. Infections are causal to oxidized LDL.