4 ms·

My understanding is that insulin resistance leads to increase DNL in the liver, so you end up with a greater production rate of LDL particles, but each one cont

My understanding is that insulin resistance leads to increase DNL in the liver, so you end up with a greater production rate of LDL particles, but each one contains less cholesterol. I’m not woke on the mechanisms, but there’s a review paper here if you’re interested: https://www.sciencedirect.com/science/article/abs/pii/S1050173801000846?via%3Dihub https://www.sciencedirect.com/science/article/abs/pii/S10501... Re: the twitter conversation: the diet heart hypothesis is specifically about replacing saturated fat with polyunsaturated fat. If you just reduce overall fat, you may even be making that P:S ratio worse. In the case of the WHI it means that the study is essentially null by default on that issue. Dietary cholesterol is an interesting one - basically there is a significant effect of dietary cholesterol on serum cholesterol, but only when you go from very low to low levels. After that, the effect tails off dramatically. So in the general population you might not expect a 30% reduction to make a significant difference. Additionally, you have to consider the overall picture. Maybe the reduction in dietary cholesterol did have a small beneficial effect, but the fact that the intervention group ended up with lower PUFA consumption than the control group meant this reduction was overshadowed by that effect. There’s no evidence that oxidised fats in unsaturated fats are a cause for concern for health. Aside from that I don’t think stringing together a bunch of mechanisms and speculating about them is a particularly useful way to carry out science. What we care about is actual outcomes from actual interventions. So yes, I agree that in those with metabolic disease and insulin resistance, we should address this issue. The evidence seems to suggest this is best done by losing weight. If there’s a certain dietary pattern that helps someone do that, great. If it’s a GLP-1 agonist, go for it. Whatever works. But we also know that fat quality affects CVD risk too, and by a decent amount. So within whatever dietary pattern one settles on, replacing SFA with PUFA would also be a good idea. We can do both!

jodrellblank 2y ago
> "If you just reduce overall fat, you may even be making that P:S ratio worse." Ugh. > "There’s no evidence that oxidised fats in unsaturated fats are a cause for concern for health." https://openheart.bmj.com/content/5/2/e000898 https://openheart.bmj.com/content/5/2/e000898 says: "The low-density lipoprotein (LDL) oxidation hypothesis gained traction during the 1980s because it was noted that in general, native unoxidised LDL does not cause foam cell formation. In other words, LDL had to become oxidised first in order for atherosclerosis to develop [..] what causes LDL to become oxidised in the first place? It was later discovered that the oxidation of LDL was initiated by the oxidation of linoleic acid contained within the LDL particles [..] a more comprehensive theory, the ‘oxidised linoleic acid theory of coronary heart disease’, is as follows: dietary linoleic acid, especially when consumed from refined omega-6 vegetable oils, gets incorporated into all blood lipoproteins (such as LDL, VLDL and HDL) increasing the susceptibility of all lipoproteins to oxidise and hence increases cardiovascular risk [..] cholesterol was protected from oxidation if bound to saturated fat but susceptible to oxidation when bound to linoleic acid" That is condeming oxidised serum fats, not oxidised dietary fats, but it appears to be condemning "omega-6-rich vegetable oils" in the diet because they are more likely to oxidise in the body(?). I'm guessing if they are already oxidised when eaten that matters, because the only way it couldn't matter is if we deconstructed fats we eat and rebuilt them completely from scratch and if we did that completely then none of any of this would matter. The link's Box 1 has 29 points criticising those fats, Box 2 has 1 point in their favour "reduces total cholesterol and LDL". > "Aside from that I don’t think stringing together a bunch of mechanisms and speculating about them is a particularly useful way to carry out science." Well I'm not gonna understand biology, chemistry, lipid science to the level of a PhD researcher, PhD statistician, medical doctor, or an interested smart amateur biologist/chemist, myself. If I also can't have a bro-science chain of layperson reasoning, then your position boils down to "Science is only for experts, and only the experts I choose, not those they believe the wrong things so they're quacks, trust me" which is .. disagreeable. > "What we care about is actual outcomes from actual interventions." We can't see those until people don't die of heart disease fourty years later. This is why I'm so on the side of Dr William Davis because the CAC score seems to be the only good non-invasive measure of plaque available, something which can show an almost direct outcome of intervention on plaque. Whereas "serum LDL went down" is easily measurable but doesn't show if plaque formation is slowed, stopped, reversed, or unchanged. I also think that if low-fat did avoid or reverse heart disease, the massive international push over the last 50 years for low-fat foods would have made it absolutely clear, and instead heart disease is up up up. Doubling down on "people simply didn't eat low-fat yoghurt hard enough, do that harder" is just so unconvincing. > "But we also know that fat quality affects CVD risk too" When you say fat quality, do you mean PUFA vs SFA? Or do you mean things like presense of Glyphosate, trans-fats, contaminations in the food chain, things ordinary people mean by quality? > "and by a decent amount. So within whatever dietary pattern one settles on, replacing SFA with PUFA would also be a good idea. We can do both!" You've made a strong case that reducing serum cholesterol would be a good idea. Not such a strong case that reducing dietary fat would be a good idea. And not much case at all that replacing SFA with PUFA is a good idea. Let's be clear that I'm lost in the details of SFA, PUFA, linoleics, Omegas, LDLs/HDLs, triglycerides, cholesterols, which ones are more important, which ones are a tiny effect but easier to study or more interesting to study. When someone is 150lbs overweight and insulin resistant and never does an exercise it can't possibly come down to wibbling over whether they ate two slices of bacon vs half an avocado, or whether they put butter or margarine on a scone that one time. On the other hand if someone is Mark Sisson[1] a lean former ironman runner and paleo/low-carb enthusiast who got famous for eating a "big-ass salad" everyday, who does intermittent fasting, eats salmon and leaves with avocado oil dressing for lunch, then a ribeye stake with asparagus and avocado for dinner, no snacks, no desert, who cares about health, is he at risk of heart disease because he put heavy cream in his one coffee of the day and has red meat on his plate instead of nutloaf? I guess you're suggesting to remove a daily Starbucks coffee with whipped dairy cream and sugar, right? No-brainer, I would agree. But telling Mark Sisson to replace that steak with tofu? He has solved or avoided so many other problems people have with food - no food cravings or hunger, he's not overweight, he's not fatigued or big swings of energy, he's unusually healthy for someone in a Western country at his age (50s IIRC) that he's gotta be doing a lot right, not a lot wrong. He's gotta be somewhere close to a good human diet even if that is too much meat to eat every day for other reasons. [1] https://www.youtube.com/watch?v=knbo9Tw2b9g https://www.youtube.com/watch?v=knbo9Tw2b9g
- KempyKolibri 2y ago
  On no, not the DiNicolantonio paper. I really need a copy & paste thing on hand to go over all the wild logical leaps this paper makes but alas, I don't. I'm going to try to keep it brief by just focusing on what's relevant to the discussion. > That is condeming oxidised serum fats, not oxidised dietary fats, but it appears to be condemning "omega-6-rich vegetable oils" in the diet because they are more likely to oxidise in the body(?) We can just bypass that entire speculation, because to get there we've already made a logical leap, namely assuming that oxLDL is even something we should care about. All the evidence suggests that the oxidation of LDL almost entirely occurs within the arterial wall (https://pmc.ncbi.nlm.nih.gov/articles/PMC2924812/ https://pmc.ncbi.nlm.nih.gov/articles/PMC2924812/). When LDL is retained, oxidation is practically inevitable. The important thing is number of ApoB tagged particles. So what would we expect to see in the real world if this hypothesis (that oxLDL is not an independent risk factor) was the case? Well, presumably if we adjusted oxLDL for ApoB, we would see the risk association disappear, since all oxLDL would be doing is just proxying for "amount of LDL", and the oxidation itself is not driving the risk. What do we actually see when we do this? When we perform a mutual adjustment of oxLDL and ApoB, and the association of risk from oxLDL disappears: https://pubmed.ncbi.nlm.nih.gov/16949489/ https://pubmed.ncbi.nlm.nih.gov/16949489/ So even if the speculation that PUFAs increase oxLDL count were valid (and I'm not granting it is), it would appear to be irrelevant as far as risk of CVD goes. > your position boils down to "Science is only for experts, and only the experts I choose, not those they believe the wrong things so they're quacks, trust me" which is .. disagreeable. That's not my position at all. Please try to employ the principle of charity when interpreting my position, or this is going to be very slow going, and likely unproductive. My point is that when you look at mechanisms, you're peering at one tiny part of a process of thousands (or more) moving parts. Just stringing together a bunch of those mechanisms into a narrative doesn't provide any kind of sound basis for making an inference about human health outcomes because it ignores every other mechanism at play. For example: mechanistically, exercise induces oxidative stress. I could do as you did above and string it together into a theory about how exercise is bad for your health, but I hope you'd agree that I'd be making a false inference. My point is not that we then throw our hands up and say "I guess I'll leave science to the experts". I never said that. I said we have to base our inferences off the summation of all the mechanisms at play. How do we do that? By looking at human outcome data (prospective cohort studies, mendelian randomisation, RCTs). Why don't we think exercise is unhealthy, despite the oxidative stress mechanism? Because we have human outcome data that shows the benefits of exercise. That is, we look at the exposure we're interested in (exercise) and the outcome we actually care about (say, mortality, or cardiovascular disease). Do people who exercise more have lower mortality rates when potential confounders are accounted for? If so, we have good reason to believe exercise is beneficial. This is how we should look at replacing SFA with PUFA. When we do that, what happens to the things we actually care about (heart disease, mortality etc)? Overwhelmingly, we improve outcomes. Why should we prize mechanisms above human health outcomes? It doesn't make sense to me. > When you say fat quality, do you mean PUFA vs SFA? Yes. > Let's be clear that I'm lost in the details of SFA, PUFA, linoleics The position I take is: - There seems to be a point, around 10% total energy from saturated fats, where risk increases significantly. Either side of that, changes to SFA still make a difference, but not to the same degree. - When it comes to reducing SFA, replacement is important. Replacing SFA with PUFA seems to be the most beneficial approach. In prospective cohort studies, each 5%E from SFA replaced with PUFA resulted in a 13% lower risk of CVD events, and a 26% reduction in coronary deaths. In RCTs, we see a 21% reduction in CVD events when substituting PUFA in for SFA (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011737.pub3/full https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...). In general the reduction in risk seems to come out at about 20-30% depending on study characteristics. Considering CVD is one of the top killers in the Western world, I think that's something worth paying attention to.

jodrellblank 2y ago

> "If you just reduce overall fat, you may even be making that P:S ratio worse." Ugh. > "There’s no evidence that oxidised fats in unsaturated fats are a cause for concern for health." https://openheart.bmj.com/content/5/2/e000898 https://openheart.bmj.com/content/5/2/e000898 says: "The low-density lipoprotein (LDL) oxidation hypothesis gained traction during the 1980s because it was noted that in general, native unoxidised LDL does not cause foam cell formation. In other words, LDL had to become oxidised first in order for atherosclerosis to develop [..] what causes LDL to become oxidised in the first place? It was later discovered that the oxidation of LDL was initiated by the oxidation of linoleic acid contained within the LDL particles [..] a more comprehensive theory, the ‘oxidised linoleic acid theory of coronary heart disease’, is as follows: dietary linoleic acid, especially when consumed from refined omega-6 vegetable oils, gets incorporated into all blood lipoproteins (such as LDL, VLDL and HDL) increasing the susceptibility of all lipoproteins to oxidise and hence increases cardiovascular risk [..] cholesterol was protected from oxidation if bound to saturated fat but susceptible to oxidation when bound to linoleic acid" That is condeming oxidised serum fats, not oxidised dietary fats, but it appears to be condemning "omega-6-rich vegetable oils" in the diet because they are more likely to oxidise in the body(?). I'm guessing if they are already oxidised when eaten that matters, because the only way it couldn't matter is if we deconstructed fats we eat and rebuilt them completely from scratch and if we did that completely then none of any of this would matter. The link's Box 1 has 29 points criticising those fats, Box 2 has 1 point in their favour "reduces total cholesterol and LDL". > "Aside from that I don’t think stringing together a bunch of mechanisms and speculating about them is a particularly useful way to carry out science." Well I'm not gonna understand biology, chemistry, lipid science to the level of a PhD researcher, PhD statistician, medical doctor, or an interested smart amateur biologist/chemist, myself. If I also can't have a bro-science chain of layperson reasoning, then your position boils down to "Science is only for experts, and only the experts I choose, not those they believe the wrong things so they're quacks, trust me" which is .. disagreeable. > "What we care about is actual outcomes from actual interventions." We can't see those until people don't die of heart disease fourty years later. This is why I'm so on the side of Dr William Davis because the CAC score seems to be the only good non-invasive measure of plaque available, something which can show an almost direct outcome of intervention on plaque. Whereas "serum LDL went down" is easily measurable but doesn't show if plaque formation is slowed, stopped, reversed, or unchanged. I also think that if low-fat did avoid or reverse heart disease, the massive international push over the last 50 years for low-fat foods would have made it absolutely clear, and instead heart disease is up up up. Doubling down on "people simply didn't eat low-fat yoghurt hard enough, do that harder" is just so unconvincing. > "But we also know that fat quality affects CVD risk too" When you say fat quality, do you mean PUFA vs SFA? Or do you mean things like presense of Glyphosate, trans-fats, contaminations in the food chain, things ordinary people mean by quality? > "and by a decent amount. So within whatever dietary pattern one settles on, replacing SFA with PUFA would also be a good idea. We can do both!" You've made a strong case that reducing serum cholesterol would be a good idea. Not such a strong case that reducing dietary fat would be a good idea. And not much case at all that replacing SFA with PUFA is a good idea. Let's be clear that I'm lost in the details of SFA, PUFA, linoleics, Omegas, LDLs/HDLs, triglycerides, cholesterols, which ones are more important, which ones are a tiny effect but easier to study or more interesting to study. When someone is 150lbs overweight and insulin resistant and never does an exercise it can't possibly come down to wibbling over whether they ate two slices of bacon vs half an avocado, or whether they put butter or margarine on a scone that one time. On the other hand if someone is Mark Sisson[1] a lean former ironman runner and paleo/low-carb enthusiast who got famous for eating a "big-ass salad" everyday, who does intermittent fasting, eats salmon and leaves with avocado oil dressing for lunch, then a ribeye stake with asparagus and avocado for dinner, no snacks, no desert, who cares about health, is he at risk of heart disease because he put heavy cream in his one coffee of the day and has red meat on his plate instead of nutloaf? I guess you're suggesting to remove a daily Starbucks coffee with whipped dairy cream and sugar, right? No-brainer, I would agree. But telling Mark Sisson to replace that steak with tofu? He has solved or avoided so many other problems people have with food - no food cravings or hunger, he's not overweight, he's not fatigued or big swings of energy, he's unusually healthy for someone in a Western country at his age (50s IIRC) that he's gotta be doing a lot right, not a lot wrong. He's gotta be somewhere close to a good human diet even if that is too much meat to eat every day for other reasons. [1] https://www.youtube.com/watch?v=knbo9Tw2b9g https://www.youtube.com/watch?v=knbo9Tw2b9g

KempyKolibri 2y ago
On no, not the DiNicolantonio paper. I really need a copy & paste thing on hand to go over all the wild logical leaps this paper makes but alas, I don't. I'm going to try to keep it brief by just focusing on what's relevant to the discussion. > That is condeming oxidised serum fats, not oxidised dietary fats, but it appears to be condemning "omega-6-rich vegetable oils" in the diet because they are more likely to oxidise in the body(?) We can just bypass that entire speculation, because to get there we've already made a logical leap, namely assuming that oxLDL is even something we should care about. All the evidence suggests that the oxidation of LDL almost entirely occurs within the arterial wall (https://pmc.ncbi.nlm.nih.gov/articles/PMC2924812/ https://pmc.ncbi.nlm.nih.gov/articles/PMC2924812/). When LDL is retained, oxidation is practically inevitable. The important thing is number of ApoB tagged particles. So what would we expect to see in the real world if this hypothesis (that oxLDL is not an independent risk factor) was the case? Well, presumably if we adjusted oxLDL for ApoB, we would see the risk association disappear, since all oxLDL would be doing is just proxying for "amount of LDL", and the oxidation itself is not driving the risk. What do we actually see when we do this? When we perform a mutual adjustment of oxLDL and ApoB, and the association of risk from oxLDL disappears: https://pubmed.ncbi.nlm.nih.gov/16949489/ https://pubmed.ncbi.nlm.nih.gov/16949489/ So even if the speculation that PUFAs increase oxLDL count were valid (and I'm not granting it is), it would appear to be irrelevant as far as risk of CVD goes. > your position boils down to "Science is only for experts, and only the experts I choose, not those they believe the wrong things so they're quacks, trust me" which is .. disagreeable. That's not my position at all. Please try to employ the principle of charity when interpreting my position, or this is going to be very slow going, and likely unproductive. My point is that when you look at mechanisms, you're peering at one tiny part of a process of thousands (or more) moving parts. Just stringing together a bunch of those mechanisms into a narrative doesn't provide any kind of sound basis for making an inference about human health outcomes because it ignores every other mechanism at play. For example: mechanistically, exercise induces oxidative stress. I could do as you did above and string it together into a theory about how exercise is bad for your health, but I hope you'd agree that I'd be making a false inference. My point is not that we then throw our hands up and say "I guess I'll leave science to the experts". I never said that. I said we have to base our inferences off the summation of all the mechanisms at play. How do we do that? By looking at human outcome data (prospective cohort studies, mendelian randomisation, RCTs). Why don't we think exercise is unhealthy, despite the oxidative stress mechanism? Because we have human outcome data that shows the benefits of exercise. That is, we look at the exposure we're interested in (exercise) and the outcome we actually care about (say, mortality, or cardiovascular disease). Do people who exercise more have lower mortality rates when potential confounders are accounted for? If so, we have good reason to believe exercise is beneficial. This is how we should look at replacing SFA with PUFA. When we do that, what happens to the things we actually care about (heart disease, mortality etc)? Overwhelmingly, we improve outcomes. Why should we prize mechanisms above human health outcomes? It doesn't make sense to me. > When you say fat quality, do you mean PUFA vs SFA? Yes. > Let's be clear that I'm lost in the details of SFA, PUFA, linoleics The position I take is: - There seems to be a point, around 10% total energy from saturated fats, where risk increases significantly. Either side of that, changes to SFA still make a difference, but not to the same degree. - When it comes to reducing SFA, replacement is important. Replacing SFA with PUFA seems to be the most beneficial approach. In prospective cohort studies, each 5%E from SFA replaced with PUFA resulted in a 13% lower risk of CVD events, and a 26% reduction in coronary deaths. In RCTs, we see a 21% reduction in CVD events when substituting PUFA in for SFA (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011737.pub3/full https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...). In general the reduction in risk seems to come out at about 20-30% depending on study characteristics. Considering CVD is one of the top killers in the Western world, I think that's something worth paying attention to.