Plaque is the stuff of coronary heart disease. It is CONTROLLABLE, it is STOPPABLE, it is REVERSIBLE.
But you must be equipped with the right information on diet, nutritional supplements, and hopefully the avoidance of medication.
This is the blog that accompanies the 
Small LDL particles are triggered by consumption of carbohydrates. Eat more “healthy whole grains,” for instance, and small LDL particles skyrocket.
Increased hemoglobin A1c, HbA1c, a reflection of the last 60-90 days’ blood sugars, is likewise a reflection of carbohydrate consumption. The greater the carbohydrate consumption and/or carbohydrate intolerance, the greater the HbA1c. Most regard a HbA1c of 6.5% or greater diabetes; values of 5.7-6.4% pre-diabetes. However, note that any value of 5.0% or more signifies that the process of glycation is occurring at a faster than normal rate. Recall that endogenous glycation, i.e., glucose modification of proteins, ensues whenever blood sugars increase over the normal range of 90 mg/dl (equivalent to HbA1c of 4.7-5.0%). Glycation is the fundamental process that leads to cataracts, arthritis, and atherosclerosis.
Put the two together–increased quantity of small LDL particles along with HbA1c of 5.0% or higher–and you have a powerful formula for heart disease and coronary plaque growth. This is because small LDL particles are not just smaller; they also have a unique conformation that exposes a (lysine residue-bearing) portion of the apoprotein B molecule contained within that makes small LDL particles uniquely glycation-prone. Compared to large LDL particles, small LDL particles are 8-fold more prone to glycation.
So glycated small LDL particles are present when HbA1c is increased above 5.0%. Small, glycated LDL particles are poorly recognized by the liver receptor that ordinarily picks up and disposes LDL particles, unlike large LDL particles, meaning small LDL particles “live” much longer in the bloodstream, providing more opportunityt to do its evil handiwork. Curiously, small LDL particles are avidly taken up by inflammatory white blood cells that can live in the walls of arteries, where they are oxidized–”glycoxidized”–and add to coronary atherosclerotic plaque.
The key is therefore to tackle both small LDL particles and HbA1c.
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Dear Doctor Davis,
I am wondering if you can clarify the “oxidized LDL Cholesterol” concept. Including, of course the Small LDL as well.
I began wondering if the oxidation is primarily in the package, the LDL wrap, the signaling protein, or the internal body of cholesterol itself. Of course, all of the above is also a possibility.
The nature of the oxidation could be a good clue as to how it is especially detrimental to health, and so far, I haven’t found much easily available on the mechanisms of the detrimental effects. While it is useful to know the harmful nature of oxidized small LDL, some insight into the mechanism of harmful effects would be welcome and minimize the nagging question of “Why” for me.
This might be of interest:
A large study called the STRRIDE trial looked at the effects of different intensities and volumes of exercise on LDL particle size in sedentary, overweight men and women over eight months [3]. Group A performed 176 minutes of low intensity exercise (walking) per week. Group B performed 117 minutes per week at a moderate to high intensity (jogging, cycling, or using an elliptical machine). Group C exercised about the same amount of weekly time as group A, but at the same intensity as group B.
As one would likely guess, group C showed the biggest improvement in changing LDLs from small and dense to large and buoyant. However, a more telling sign was that group B had a stronger effect than group A, despite exercising an hour less per week. In other words, intensity is more important for improving LDL particle size than volume of exercise.
A follow-up of the subjects in this study showed some discouraging and encouraging effects on the particle size changes [4]. The discouraging news was that five days of inactivity following the study almost completely attenuated the particle size benefits from the trial. However, before you start labeling exercise as futile, consider this: while five days of rest basically brought the exercise groups back to baseline LDL particle sizes, they were still much better off than the sedentary control group, who experienced significant digressions in particle size during the course of this study
Hi James Buch,
The enzyme hepatic lipase’s (HL) lipolytic hydrolysis of the phospho-lipids on the LDL surface changes it so that LDL’s load of cholesterol esters can get taken out; this reduces the molecule’s volume and thus is then small LDL (smLDL). Men have more HL than women, until they go through menopause, and this propensity toward smLDL ( that can get oxidized) may explain male’s earlier tendency of coronary artery disease. Visceral/central obesity trends to upregulate HL & it seems visceral obesity affects men more than women (of course central obesity in both women & men will raise both genders’ HL enzyme levels). What decreases HL levels are things like calorie restriction & aerobic exercise (sedentary life increases HL).
Doc harps on avoiding elevated triglycerides after meals that load triglycerides into VLDL molecules because the enzyme cholesterol ester transfer proetein (CETP) shunts triglycerides from VLDL (& chylomicrons) over to the standard circulating “big bouyant” (large & fluffy) LDL and fosters transfer of cholesterol out of that LDL; the triglyceride takes up less space and thus get smLDL.
Central obesity usually correlates with elevated triglycerides and increased HL levels. However, if triglyceride genetics (or epigentics from Doc’s diet ,etc.) in the obese without that usual accompanying high triglycerides then that upregulated HL doesn’t cause a lot of that individual’s standard “big bouyant” LDL to become smLDL. HL also hydrolysizes triglycerides (and phospho-lipids) of chylomicrons, BetaVLDL, IDL, LDL & HDL. Both CETP & HL enzymes being elevated alone, or together, can provoke smLDL – genetic polymorphisms exist for both enzymes.
sm LDL has less antioxidants left yet it’s surface has higher ratio of poly-unsaturated acids which make it’s phospho-lipids more at risk of oxidation. And smLDL has less sialic acid left on it’s surface which fosters more poly-anion proteoglycan binding that increases the smLDL molecule’s transportability across the endothelial lining into the artery wall .
Doc harps on need for Magnesium because in real time magnesium is what interrupts the oxidation of smLDL from locking into an altered state & then salvaged plain old smLDL doesn’t get to go on to be so damaging.
Continued for J. Buch,
Oxidized small LDL (oxLDL) has fragments from it’s oxidized PUFA (poly-unsaturated fatty acid) that are reactive aldehydes (ex: malon-di-aldehyde & 4-hydroxynoneal-lysine) which then fragment that smLDL’s lipoprotein ApoB. That peroxidation of a PUFA acyl chain of the smLDL phospholipid leaves a type of carboxyl portion that the beta-2-glyco-protein I (Apo H) binds to using a “reactive” ketone as ligand link. Thus it is the position of the “reactive” ketone (keto-cholesteryl-9-carboxy-nonanoate) on the involved cholesterol molecule’s spine that determines the % of glyco-protein bonding that occurs (genetics influences ketone placement on a human cholesterol molecule).
Magnesium (Mg++) in the very early stage of glycated protein (Doc warns against advanced glycation end products) hooking up with LDL reverses the glyco-protein link to the “reactive” ketone. But if deficient Mg allows time to consolidate that contact then only a physiologiclly abnormally high pH will let Mg re-break that bonding.
Immunological T cells respond (with age & gender differences) to try to get oxLDL off the artery wall; and, if there is too much to handle there is the risk of developing a so-called oxidized LDL-containing Immune Complex (oxLDL-IC). And this oxLDL-IC provokes cytokines that perpetuate the inflammation response. Over time and older age there is less output of a malon-di-aldehyde oxLDL immune response; which is possibly what leads to long established plaque having less lipid component and more involvement of collagen. It is relatively younger plaque that is unstable and more likely to rupture; the collagen draws in more Calcium and unfortunately provokes artery hardening problems.
Now the lipid part from this oxLDL-IC gets into an immunological monocyte cell’s endosome and the ApoB gets into that same monocytes lysosome – sub-compartments inside the cytosol (cell interior). Then the lipid part in the endosome triggers heat shock protein (HSP 70/70B) which wrenches things so that the lysosome can’t get to work on the lipid and ApoB prevents the lysosome from doing proper interactions at the inside of that cell’s membrane to expel the burdens. Once oxLDL cholesterol esters bulk up a macrophage (monocyte) due to increasingly futile lysosome activity it becomes the notorious “foam” cell. Eventually that macrophage cell dies and the whole load get’s polymerized into plaque.
Hi Dr. Davis – with your indulgence:
Back to platelets( see above Nov. 7): vascular remodeling with age &/or ROS exposes a bit of phosphatidyl serine that platelets can “snag” onto as platelets flow along. Key to accomplish platelet snagging is signaling by the promoter P2gamma12 and normally insulin signaling down inhibits P2gamma12. But, notably for Type II diabetics (and assumedly proportional to an individual’s insulin resistance) their insulin doesn’t inhibit that snag signal. Type II diabetics also have P2gamma12 upregulated in their platelets. And if anyone is of P2gamma12 haplo-type H2 those individuals will have even more of the receptors for it and therefore an increased risk of peripheral artery disease. Irregardless of haplo-type, the Type II diabetic’s propensity for peripheral artery problems are compounded by their basal level of excess P2gamma12 .
Adhesion to the artery then physically involves the platelet surface Glyco-protein Ib & vonWillebrand factor hitched to collagen provoking Integrin 2beta1 (GPVI) so the platelet/collagen sets in place. If the level of promoter P2gamma12 in that challenged site is fortuitously low then the rate of adhesion to the blood vessel is poor. So, predictably, for Type II diabetics the adhesion rate (like platelet secretion & aggregation) is higher than normal. GPVI insult also signals a release of ADP & this ADP (like collagen itself) independently induces aggregation of platelets; the plaque recruits to build itself up to be more fibrous. The plaque matrix serves as nesting for oxLDL & dying macrophage foam cells to polymerize with.
ROS remodeling agents of the vasculature come from mitochondrial activity and it appears certain (overlooked) relevant gene pheno-types (and their respective polymorphisms) can be pro-plaque (or preventative) – speaking here in the sense of a primal influence on plaque risk as well as tendency of the actual amount of plaque. Sirtuin 5 (Sirt5), a mitochondrial Sirt (there are nuclear Sirt too) binds to Uncoupling Protein 5 (UCP5) and governs that (& other) UCP. Sirt (there are 6 types) remodels chromatin (DNA spooled around a histone ) via histone de-acetylase enzyme; while our UCP (there are 5 types) work in the inner mitochondrial membrane governing the proton electro-chemical gradient that is integral to the chain of oxidative phosphorylation (a way to generate ATP, among other functions).
Sirt action on DNA includes (among other dynamics) the cellular level encoding of how individual fatty acid metabolism fine tunes – lipid fatty acids included.Sirt action on DNA includes (among other dynamics) the cellular level encoding of how individual fatty acid metabolism fine tunes – lipid fatty acids included. Doc’s diet/protocol may ( I suggest) sometimes tweak out favorable health response(s) via induced epigenetics, because of remodeling that is induced in the chromation DNA unit packaging . Sirt’s histone de-acetylase working depends on NAD- to drive Sirt and Doc’s diet/protocol theoretically seems to be capable of altering NAD flow patterns from his weaning of cells’ mitochondria off of glucose.
UCP5 rules the inner mitochondrial membrane potential & the rate of oxygen use, which can become relevant to ROS levels. Both UCP5 and Sirt5 are upregulated in hypertension and Type II diabetics; the confluence of having geneticly more UCP5 along with Sirt5 are implicated in increased carotid artery plaque. (Of course nothing is linear in humans so haplo-type T- carrier UCP5 polymorphism rs5977238 benefit with less plaque risk and reduced plaque numbers.) Note: I am skipping over other Sirt & UCP; but will add that lots of pheno-typic UCP1 spins out extra amounts of reactive super oxide to drive down nitric oxide and implicated in accelerated aging of the vasculature.
Mito….:
I have viewed your comments at the Hyperlipid and always appreciate your detailed biochemical/physiological explanations per topic. Your grasp of details and mechanisms is amazing! What is your background? Are you a biochemist by trade?
HI STG,
My hope here is that I never hijack Dr. Davis’ blog ( I never personally posted on Hyperlipid blog). I trust Doc’s readers know he is not responsible for any errors I make. Being semi-retired from consulting on agro-industrial projects in developing countries I feed my mind by keeping up with health science & commenting here about correlations to Doc’s work.
Mito..
Excuse my error about you posting on the Hyperlipid. I guess I have read your posts elsewhere. In any case, your posts are very educational and explain precisely the biochemistry Thanks for sharing your knowledge!
Hi J. Kronk,
Saw your 11 Nov. query & feel diet advice here is for Doc to offer (not me). Doc discusses ApoE pheno-types he restricts dietary fat for. You “tagged” me where I was elaborating on platelets’ interaction with insulin & how insulin resistance is a game changer (not sure what confusing).
If one is insulin resistant then the signaling to build-up (anabolism) from insulin is selectively diminished and consequently break-down (catabolism) signals get into play. Proteo-lysis is protein cleaving and HDL’s protein component can be more rapidly subject to proteo-lysis; which I presume (?) is why/how some people degrade their HDL so quickly. Genetic quirks (& gender) also hit HDL levels notably; yet if quick enough turnover the “stale” HDL might be being replaced by more functional HDL. According to the “HATS” study HDL alone is not a predictor of coronary artery disease mortality.
Niacin usually decreases rate of catabolism of HDL, it helps secrete more ApoA1 to make into HDL & decreases amount of smLDL. Niacin isn’t perfect since it alters the extent to which HL (hepatic lipase enzyme) can work on a HDL molecule to morph it into the kind of HDL that has the maximum reverse cholesterol transport capability. HL is what hydrolyses the triglycerides in HDL – so, basicly if HDL loaded with trigs it has sparser room for scavenging cholesterol.
One’s genetic response to increased levels of circulating palmitate free fatty acid can interfere with insulin signalling in the liver. Whether clinically insulin resistant or due to a genetic quirk (you?), palmitate can phosphorylate liver insulin receptors in a manner unlike “normal” individuals do in the Akt process (insulin normally should get Akt going to stop liver gluco-neo-genesis – since insulin has glucose to drive into cells ). Essentially “excess” palmitate, in this example, is causing only a partial phosphorylation of Akt & is how researchers can use very high fat diets to induce experimental diabetes .
I don’t hear you being insulin resistant, so address genetics of Protein Phosphatase 2A (PP2A), which has components involved in it’s regulation and is subject to different structure. How PP2A parts interact with distinct parts of the Akt molecule can impair some interactions, yet leave other parts of Akt responsive ( to do what Akt is normally designed to do). Palmitate can raise PP2A levels in the liver by 30%; so basically the more PP2A around and/or the molecule’s genetic tweaks the weaker a key part of the liver’s Akt response is going to be.
Since palmitate being in the liver does not stop insulin there from fostering more trigs there are still post-prandial trigs going into the VLDL . In other words the liver insulin resistance and rogue genetics can leave the part of Akt that governs lipo-genesis still responsive to insulin. Doc warns us about trig enriched VLDL & chylomicrons promptly driving smLDL that doesn’t degrade & small particle numbers measure high; he is more adamant about post-prandial trigs but genetic high overnight trigs can occur.
I don’t think coconut oil acts the same way high animal fat sometimes does on Akt . We internally make palmitate when acetyl-CoA acted on by enzyme acetyl CoA carboxylase to make malonyl-CoA that fatty acid synthase converts to palmitate. I think most of coconut oil’s fatty acids are metabolized before getting into that pathway so maybe coconut oil is worth parsing when genetics or insulin resistance drives up smLDL.
Hi Dr. Davis,
I’m 47 yrs old. I’ve had migraines since I was a teen and I developed Athsma this past January (hate it). During the process of discovery the drs found I have a 50% blockage in one of the 5, non critical, arteries running along the back of my heart. Scared me, to say the least. I’ve always eaten quite healthfully (for what I knew), am thin @ 6′ 1″/155lbs (was 175lbs in Jan.). Had total cholesterol of 200/LDL of 146/HDL of 50. Drs wanted me to do Lipitor. Researched and said, “No, thanks.” Started exercising 5-6 days/wk (lifting + walk/run), taking red yeast rice, fish oils, fish, no meat, no dairy, no eggs, lots of veggies/fruit, etc., but still eat beans, oats (every AM), occasional wraps. After 6 wks my blood work (VAP) was as follows: LDL=86, HDL=43, VLDL=17, TOT. CHOL=146, Trigycerides=66, Non-HDL (LDL+VLDL)=103.
Seemed GREAT to me! The dr wasn’t impressed. Said my ‘particle size’ was small: LDL1(a)=8.1, LDL2(a)=0, LDL3(b)=39.5, LDL4(b)=24.9. Density Pattern=B.
I’ve continued but don’t know how to elevate my HDL and reduce the particle size/change the pattern to the more favorable ‘A’. Getting down about this. Working hard but, seems like I can’t find answers that work, anywhere! What might you would work in my situation? Also, Is niacin ANDRed Yeast Rice a bad idea?
I’ll hang up and listen. Thank you,
Mark
PS – I left this post on another page, as well.