“Not only genes but also small molecules changed in the course of evolution” says Konrad Bloch in his

book “Blondes in Venetian Paintings, the Nine-banded Armadillo, and Other Essays in Biochemistry.” Professor Konrad Bloch was awarded the Nobel Prize in 1964 for work done elucidating the biosynthesis of cholesterol, an important factor being the necessity of oxygen. Thus at around the time that mammals as we know it appeared – approximately 2.8 million years ago – cholesterol had its own evolution. According to M. Bloom cholesterol relieved us of a bottleneck, providing membranes with a liquid-ordered state, thus introducing the capability of complexity (1). With its ingrainedness in our biology it is no wonder that it has been the focus of health for the past century. Because of Konrad Bloch’s work we have very effective drugs, i.e. statins, that target cholesterol saving millions of lives. The history of my personal cholesterol levels can be seen in Figure 1 and Figure 2. Pre-2009 I was eating a typical western diet, junk food included. In 2009 I began a paleo-diet, convinced by theoretics and my cholesterol responded accordingly (as Plato points: UP). Post-2009, finishing my review of the literature I decided Paleo was likely leading to a quicker death, thus beginning my plant-filled meat absent chewing.

Figure 1 – My Cholesterol Profiles

Figure 2 – Ratios Oddly, as everyone was seeing their cholesterol go up, looking at actual hunter-gatherer populations, cholesterol levels are actually rock-bottom low (Figure 3): the average cholesterol level among 5 huntergatherer populations (Hazda, Inuit, !Kung, Pygmy, San) is 110mg/dl (2.8mmol/l) (45).

Figure 3 – Hunter Gatherer Cholesterol and others For comparison in a group of healthy medical students the average level is 159mg/dl (4.1mmol/l), almost 50% greater: N = 221 Cholesterol HDL LDL Triglycerides Mean ± SD 4.1 ± 0.7 1.44 ± 0.30 2.2 ± 0.6 0.95 ± 0.5 TC/HDL TG/HDL LDL/HDL1 2.85 0.66 1.53

You spend time getting your blood drawn, then visiting the doctor, changing your diet, popping pills, just because of some numbers – these numbers though are quite predictive: a 10-year prospective study on 15,632 healthy women found this pattern of hazard ratios from 464 events (1) (Figure 4):

Figure 4 – Hazard Ratios from Lipid Profile What we all know as “bad” cholesterol has the least predictive value which has been replicated in the general population from one of the largest studies, Framingham Study, which does not include LDL as a risk factor. LDL is indeed bad, and these results are most likely explained by: 1. The general populations LDL levels are too high as only a threshold may be required or 2. The outlook requires longer than 10 years to find an association or 3. May not depend on LDL cholesterol concentration but on particle concentration or 4. Atherosclerosis is multi-factorial and the other measures encompass es this. To better understand this, a review of the metabolism is required. Metabolism of Cholesterol

Figure 5 – Cholesterol Pathways (2) To understand the role of cholesterol in human disease we can start from metabolic beginnings. Cholesterol is a requirement for many processes in our bodies, it helps maintain our membranes, is a precursor for many necessary metabolites (e.g. cortisol, sex hormones, vitamin D), and also forms our bile salts. Considering its necessity a system has been setup to transport it around; the liver being a hub coordinating the supply both from the diet and endogenously from our cells (see Figure 3) With discovery of the pathways and the genes that controls them scientists have discovered diseases that go along with each dysfunction (see Figure 5): LDLR deficiency causing Familial Hypercholesterolemia where people invariably die of heart attacks, LCAT deficiency causing accumulation of esters in cells with patients dying of renal failure, etc. While CETP deficiency leads to higher HDL levels (good cholesterol), patients don’t seem to be protected from heart disease; however a PCSK9 deficiency which leads to lower LDL levels seem to confer protection (2). These pathways can help us understand better the data from clinical trials helping us answer the question of what the right cholesterol level is. Cholesterol Pathways The triglyceride (TG) number on your lipid profile report is a combination of the amount of fat found in two particles: the chylomicrons (CM, t1/2 = 1h) and the very-low-density-lipoproteins (VLDL t1/2 = 6h). CMs come from the intestinal cells and are associated with the protein apoB-48 and VLDLs come from the liver cells and are associated with apoB-100. These lipoproteins usually contain TGs, cholesterol, and the protein particle (e.g. TG/cholesterol in VLDL = 5:1) and it is orchestrated by the enzyme microsomal triglyceride transfer protein (MTP), a deficiency of which would cause abetalipoproteinemia.

While VLDL is identified by apoB-100 throughout its life cycle it acquires various other apolipoproteins (e.g. CI, CII, A-II, E) that helps it deliver its contents to the right cells. One of the ways that the triglycerides get released as free fatty acids (FFAs) are through the action of lipoprotein lipase (LPL) found on endothelial cells. For the VLDL to react with the LPL requires apoCII and apoAV, a deficiency of which leads to hyperlipoproteinemia type IB which consists of xanthomas, pancreatitis, and hepatosplenomegaly. As the VLDL loses its TGs it becomes smaller thus leaving less surface area for the proteins which get picked up by HDL. It then becomes an intermediate density lipoprotein (IDL) which makes it the right size to attach to the low-density-lipoprotein receptor (LDLR) by which the particle is endocytosed by the liver. But IDLs that don’t get taken up end up becoming low density lipoprotein (LDL) particles (t1/2 = 3d) which then help starts the process of atherosclerosis. N.b. in those with normal LDLRs high TGs should be found with high LDL levels because VLDLs become LDL. HDL has the interesting capability of interacting with all the lipoprotein particles. It is formed in the liver as a disc shaped protein called apoAI and as it starts filling up with cholesterol from the tissues (due to ABCA1), the enzyme lecithin cholesterol acyltransferase (LCAT) begins to esterify the free cholesterol making it hydrophobic thus driving the cholesterol towards the center, this results in a round shaped HDL particle. As it travels through the blood the enzyme cholesterylester transfer protein (CETP) transfers cholesterol from HDL to LDL, IDL and VLDL, while in reverse transferring TGs. The more particles of LDL, IDL or VLDL there is, the smaller HDL becomes, thus lowering its measured levels. Looking at how HDL is made it is no wonder that CETP drugs have failed in clinical trials, because its measured level is a surrogate marker for the actual LDL levels. LDL Particles Role Low-density-lipoprotein (LDL) is the left-over of VLDL and it has two fates: 1) receptor mediated uptake by LDLR on cells and 2) diffusion into cells, the former being saturable and the latter being unsaturable. Thus with excessive amounts of particles (which increases the concentration gradient) LDL particles can be found in places it is not supposed to be (e.g. under endothelial cells). Thus apoB100s strong correlation with heart disease risks (5). Receptor mediated uptake is a regulated pathway, the LDL binds to the LDLR, gets taken up, passes through the lysosome and releasing its cholesterol, if and when the cell has enough cholesterol it stops making LDLR and any extra LDL is moved from the interstitial space into the lymphatics and back into the blood. With the arteries it becomes a different story; arteries are not like other tissues, they are surrounded by a thick layer of connective tissue with no lymphatics to drain the area: the LDL concentration in the tissues is 10x lower than the blood while in the artery layer it is 10x higher (37,38). In rabbits it was found that a higher lipoprotein concentration was associated with a higher influx into the arteries (39) which verifies similar results in humans. Another study found that ApoB concentrations in the intima were correlated with plasma concentration in normal vessels, yet in abnormal vessels there was no correlation (41): thus abnormal vessels accumulate these particles, but if you are younger, the rate of accumulation would likely be proportional to your blood levels, thus as a younger individual maintaining a lower concentration is likely beneficial. …Predictive Value Analyzing data from the Framingham study (cox-proportional hazard model) the author’s found that VLDL was an independent predictor of heart disease (this being encompassed by non-HDL) (3). Stratifying the non-HDL then looking for trends in LDL they found no difference (see Figure 6), however

the lower LDL group was 130mg/dl and below, the threshold for atherosclerosis is most likely lower. (This study was also underpowered as there were not enough CHD events).

Figure 6 – Stratification of non-HDL The likely mechanism for VLDL is that this particle can compete for the LDL receptor thus letting LDL loiter in the blood allowing modification and diffusion into the intima. In another study looking at 231,986 hospitalized patients of whom 136,905 patients had lipid levels a distribution was analyzed (see Figure 7) (71). Some people may take these results to mean “look cholesterol levels do not matter" because almost half the patients had LDL levels <100mg/dl, but I take it to mean 100mg/dl may not be low enough. One also has to take into the account that ~20% were on medications for their cholesterol thus without it the numbers would be higher.

Figure 7 – Cholesterol of hospitalized patients

Figure 8 – Statin Trials In the end the success of statins show that lower LDL-C is better (see Figure 8). Combining both the possible pathogenesis with the results of these large trials it is likely the lower your LDL the better. But as mentioned atherosclerosis is multi-factorial and in the literature this is called residual risk (Figure 9).

Figure 9 – Residual Risk Despite lowering LDL by ~30% the risk is still not zero, the residual risk probably includes many things:  Non-modifiable risks: polymorphisms, family history, age, gender, ethnicity  Modifiable: smoking, drinking, exercise, obesity, blood pressure  Inflammatory: hs-CRP, SAA, IL-6, healthy teeth  Metabolic: hyperglycemia, insulin resistance (6), NAFLD, non-HDL, HDL, hyperuricemia

Lipids: post-prandial TGs (5), oxLDL, oxHDL, chylomicron remnants.

Beyond Cardiovascular Risk There has been a worry that low cholesterols both increase overall mortality risk, and may also increase Alzheimer’s risk: this being supported by some large studies showing a J/U-shaped association (7-9). These results are likely due to reverse-causation as diseases such as cancer and Alzheimer’s may cause pre-clinical decreases in cholesterol. During a follow-up of 14.8 years in 7735 40-59 aged men the inverse association between cholesterol and mortality seemed to attenuate when the follow-up was over 10 years (10). In a Japanese cohort after excluding cancers in the first 3 years, the inverse association no longer remained, except for liver cancer (11). When looking at 25 years the association also disappears (12): “The results suggest that to fully analyze the association of serum cholesterol with all-cause mortality, the follow-up period should be sufficiently long--possibly more than 10 years--and the possibility of a change in the direction of the association studied should always be considered.” In the year leading up to your illness cholesterol levels begin to drop (13). From the Framingham Study that spanned 30 years since the study (14), subjects experienced an 8.06mg/dl drop in the previous 4 to 6 year period with evidence of drops even before that. [In (8) there was a 15 year period however I do not think that is the follow-up, since I do not have access to the paper I cannot confirm this]. Indeed the low cholesterol is probably not causing cancer; it is instead an effect of the cancer (16). [N.b.The Japanese cohorts may not be relevant to the rest of the world because their stroke incidence is higher and CHD incidence lower. Thus many studies showing benefits of higher cholesterol may indeed represent this difference. Things such as SAFA that increases cholesterol seem to be protective against stroke (15), again there are other things besides cholesterol that play into stroke, such as, salt intake, fermented foods, etc...] There has also been a lot of fear of statins due to this idea of low cholesterol causing cancer however a large retrospective study of over 11 million adults found no association. This is going to be put to the test by the NIH with regards to colon cancer (21) so we will see soon. There are also other studies showing low cholesterol is better for cancer (17-22,65) Besides looking at these long-term studies (some of which I reference in the section below >25years) a very smart and new way of looking at this situation is mendelian randomization (Wiki). The idea is that you find polymorphisms that affect your variable thus getting rid of a lot of confounding variables when comparing two groups. Two studies (66,67) that look at polymorphisms that give subjects low LDL found that low cholesterol levels are not causally associated with cancer and low LDL provides cardioprotective benefits. What about Alzheimer's? With Alzheimer's it's harder to study because the endpoint is smeared on a spectrum however when comparing cholesterol levels to autopsy results there is a clear association between cholesterol and autopsy pathology (24-25). In these studies they use pre-defined neuropathological criteria with regards to dementia and Alzheimer's and the more plaque there is the higher there cholesterol was 10 years back. Indeed even in terms of cognitive function as it declines it affects both lipid metabolism and blood pressure (23).

So endogenous cholesterol levels affect your future health, what factors besides your genetics affect its levels. We have been told that eggs probably are not that big of a deal considering that 80% of the cholesterol in our bodies is created by the body. Is that true? Dietary Cholesterol Eggs are great to look at for studying because they are not confounded by saturated fat. One large egg has about 180mg of cholesterol; does this have an adverse or neutral effect on your health? When looking at studies what I want is to find a cohort that has low cholesterol intake in the first place, considering that the US population consume approximately 300mg (27) of dietary cholesterol on average (a lot of this is probably due to egg consumption) adding 1 extra egg may not make a physiologically measurable difference, however what about vegetarians? Looking at a cohort of 27,529 Seventh Day Adventists, mostly vegetarian with healthy lifestyle (they have the highest proportion of centenarians in the US) egg consumption was positively correlated with all-cause mortality, including cancer and CHD (28). When comparing subjects that are insulin sensitive to insulin resistant, with the latter having higher cholesterol, 4 eggs/day lead greater increase in serum cholesterol (7.8% vs 3.0%). In a great study which utilized ileal resection (removing the part of the intestine which absorbs your bile acids, which are made from cholesterol), after 25 years, yes 25, there was statistically significant difference in survival and disease-free years between the control group and intervention group. This study is known as the POSCH study (30). If you thought 25 years was long what about 46 years! yes 46 years (64). Looking at a group of men from the Helsinki Business men cohort the authors found: “A strong and graded relation was found between the cholesterol level and total mortality, with the men with a cholesterol level ≤4 mmol/L (154 mg/dl) having the lowest mortality. In all, the men with the lowest cholesterol gained the most life years. However, no association was found with the cholesterol level in 2000 (when 16% were using statins) and subsequent mortality. Thus in our era of statins finding a difference between control and intervention may be harder considering that if the control groups cholesterol gets high they will be put on a statin nullifying the difference.” A great meta-analysis looking at this issue and taking into account baseline levels (31) found that the lower your baseline cholesterol the greater the effect of dietary cholesterol was (see Figure 9).

Figure 9 – Effect of dietary cholesterol It definitely seems that around 300-500mg a day, extra cholesterol does no harm. Thus current recommendations to lower cholesterol <200mg may not be good enough. Personally I keep it lower then 100mg per meal, however I don't always have meat every meal, thus my per day is lower than 25 mg/day. One may argue based on numbers that if you are willing to accept the risk of 300mg/day then any extra does not alter risk as it does not alter levels. However the numbers do not catch all that is happening. The current thinking that macrophages consume these LDL particles that get into the intima and as the cholesterol moves through the lysosome it can gunk it up (33). By increasing your cholesterol intake one could potentially be increasing the flux through the lysosome and clogging it up thus leading to pathology. Indeed one of the reasons we age may be because we cannot empty lysosomes (LysoSENS), thus keeping it clean in the first place is best for your health. Again in insulin sensitive-folks egg consumption seems to increase serum amyloid (bad), inflammation and also non-HDL levels, while in IR folks (who are already presumably inflamed with high non-HDL levels) there was no effect (36). In a great study comparing vegans to omnivores (35) the authors injected both groups with "triglyceriderich emulsions labeled with (14)C-cholesterol oleate and (3)H-triolein" and determined "fractional clearance rates (FCR, in min(-1))." What the authors found was that the clearance of cholesterol in vegans was much faster than omnivores, however triglyceride clearance was the same. This is important because remnants particles are correlated with heart disease. The longer the particles stick around, the more likely it is to get damaged and cause problems, the difference may be due to: “The fact that in vegans atherogenic remnants were removed faster than in omnivores may possibly be related to the effects the different fat and cholesterol content on the function of LDL receptors. LDL

receptors are considered to mediate at least in part the remnant uptake of by the liver [31]. The in vitro activity of the receptors is diminished by exposure to SFA [32].” Both groups had similiar MUFA intakes (and also fat intakes 25g(V) vs 32g(O)). However what they differed most in was SAFA (4.7g (V) vs 12.3g (O) and cholesterol (51mg (V) vs 250mg (O)). Thus while SAFA does play a part in affecting remnant removal (by downregulating LDLRs on the liver) since we know cholesterol increases LDL it probably played a role here too. Outside of the developed world in the Tarahumara Indians [Wiki] (who have very low baseline cholesterol intake) 1 egg/day was associated with higher cholesterol levels (34 More Traditional Populations Data Canada's current LDL targets are set at <2.0mmol/l (77mg/dl).

In comparing Nigerians, Tanzanians, Fulani, Thai, Puerto Rico, Delhi, Northern India, Yugoslavia and more one sees that rural area have cholesterol levels approaching the hunter-gatherers (44-52).

This chart compares urban, rural Yugoslavians to the Framingham Study and as you can see the rural folks have the lowest serum cholesterol levels with the majority at 140-180mg/dl. If we think these levels aren't attainable because of genetics then how about folks who practice calorie restriction (CR). CR is one of the only ways known to extend maximum lifespan, while whether it works in humans is under contention (considering our environmental factors differ from most species) there is no doubt that they are at much lower risk for the various chronic diseases, and their lipid profiles definitely look like the hunter-gatherers (53): Table 2. Risk factors for atherosclerosis Value Parameter Tchol, mg/dl LDL-C, mg/dl HDL-C, mg/dl Tchol/HDL-C ratio TG, mg/dl TG/HDL-C ratio Systolic BP, mmHg Diastolic BP, mmHg CR (n = 18) Controls (n = 18) P value 158 ± 39 86 ± 28 63 ± 19 2.6 ± 0.5 48 ± 15 0.8 ± 0.3 99 ± 10 61 ± 6 205 ± 40 127 ± 35 48 ± 11 4.5 ± 1.3 147 ± 89 3.5 ± 2.8 129 ± 13 79 ± 7 95 ± 8 5.1 ± 2 1.6 ± 2.2 0.001 0.0001 0.006 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.001

Fasting glucose, mg/dl 81 ± 7 Fasting insulin, mIU/ml 1.4 ± 0.8 Hs-CRP, μg/ml 0.3 ± 0.2

Looking back at one more study in food deprivation during the world wars (54): “Heart infarctions were seldom observed during the years 1945–1948 in the area of West Germany which was the occupational zone of the United States, Great Britain, and France. The autopsy records of seven Institutes of Pathology showed neither death from heart infarction nor peripheral atherosclerotic

arterial occlusion. Advanced forms of atherosclerosis in all arteries were rare between 1945 and 1948 as compared with 1939 and 1955 based on autopsy analyses in Marburg/Lahn and Basel, Switzerland. Gangrene of the feet or toes was seen in this time period only in occupied southern Germany, an area which was largely agricultural and therefore had no severe food shortage. The lipid values (cholesterol and total lipids in serum) were significantly higher in this region as compared with those in other regions experiencing scarcity. Total cholesterol of the adults was on the average 230 ± 14 mg/dl (SE) compared with 140 ± 11 mg/dl, total lipids 540 ± 32 mg/dl in contrast to 190 ± 24 mg/dl. The average value of total cholesterol in the starving peoples of Western and Northern Europe were extremely low, with an average of 130–150 mg/dl. Pathologic observations of starving prisoners of war showed mainly smooth arteries with low atherosclerotic lesions. This contrasts with the findings in American soldiers who died in Korea, in whom advanced lesions, arteriostenosis, and occlusions were seen. Thromboembolism was also seldom seen in conjunction with undernutrition. The probable causes for these findings are the low total energy consumption (an average of 1000–1200 calories per day), the unavailability of fat, limiting intake to under 10 g of oil or fat per day, the low consumption of animal protein (15–20 g), and the abundance of high-fiber vegetables. These dietary factors can also explain the lack of moderate and advanced diabetic complications. With normalization of the diet in Germany in 1948, a concurrent jump in the incidence of fatal and nonfatal heart infarction and lung embolism was observed. The extremely low cholesterol values and total lipid values climbed rapidly and reached average values comparable with those seen today. Other possible explanations for these increases could be changes in smoking habits, the frequency of high blood pressure, increased body weight, and decreased activity levels, as well as the so-called stress of modern civilization. These explanations were less likely, since from 1948 until 1950 when the dramatic increase in coronary infarction was noted, these risk factors had changed only slightly. The epidemiologic data on coronary heart disease in the years of scarcity in Western Europe are somewhat comparable to those in the People's Republic of China and in rural areas of Japan.” Actually Lowering Cholesterol

This graph from (55) is the result of a meta-analysis on 27 metabolic ward studies (very well controlled) which controlled for cholesterol and only varied fatty acids. They came up with various formulas and the chart above. As you can see while SAFA increased HDL the most, it also increased TC and LDL. This would result in the best TG/HDL ratio, but the other ratios would be worse. MUFA seems to have the best effect on our lipid profile. What about overall fat intake? When comparing moderate fat (MF) diets to low fat diets (LF), moderate fat comes out on top. The authors performed a literature search in the databases, and used this inclusion criteria: (1) controlled feeding with a crossover or parallel design comparing MFand LF diets; (2) designed to lower plasma total cholesterol (TC) and LDL-C with the primary purpose of reducing the risk of cardiovascular disease; (3) comparison diets were isoenergetic; (4) participants maintained a constant weight during the study; (5) dietary protein and cholesterol were kept constant between diets; (6) diet periods lasted >2weeks to stabilize plasma cholesterol concentrations; and (7) studies were published in English. (57) These are the results:

Low-fat diets do not work well for your lipid profile because any intake below ~25% of calories is not able to support levels of a healthy lipid profile (68-70). Thus a moderate fat diet, which in the study was 40%, combined with a high MUFA intake will most likely give one the most beneficial and low risk lipid profile. Beyond just the lipid profile, a high MUFA intake may also decrease oxLDL (58). In another study looking at post-prandial stress, MUFA gave the best results again (59):

What is the role of ox-LDL in all this with regards to atherosclerosis? “The ‘response-to-retention’ hypothesis represents what may be considered a paradigm shift in the pathophysiological concept of early atherogenesis. The important roles of lipid retention, endothelial dysfunction and influx of inflammatory cells in the developing atherosclerotic lesion are all well recognized, but which pathological cue comes first? A widely accepted model is that pro-atherosclerotic conditions such as hypertension cause endothelial injury, making the endothelium more permeable to inflammatory cells, which then invade the arterial wall. In this earliest stage in atherosclerosis, infiltrated monocytes are thought to start taking up and thereby retaining ox-LDL as they transform into foam cells in what is termed the ‘fatty streak’. This view on the pathogenic sequence of events may be referred to as the ‘response-to-injury’ hypothesis as elegantly described by Russell Ross *3+. Although many studies

support this hypothesis, some incongruent observations were made. For example, autopsy findings in children and young adults included lipid-rich areas in the walls of coronary arteries without the presence of macrophages *8+. In 1995, Williams and Tabas *4+ published a hallmark paper describing a ‘responseto-retention’ hypothesis, suggesting that the accumulation of oxidized LDL precedes the influx of monocytes in the vascular wall and forms the critical cue in atherogenesis. This would require that oxLDL retention can occur without the presence of inflammatory cells. The findings by Nakano et al. provide evidence for this crucial prerequisite. The reason why monocytes do not home to the mesenteric sites of ox-LDL retention in this model even though Ox-LDL is chemotactic for monocytes [9] remains to be established.” (60) Mechanism of MUFAs? There is a mechanism by which saturated fat raises LDL: the saturated fatty acids DOWNREGULATE LDLRs, thus leading to higher LDL levels thus leading to more time for modification (which is bad) (61). But I haven't read a mechanism by which MUFAs would be beneficial. An interesting study looking at other factors beyond just the lipid particles came up with some interesting results when pitting a Mediterranean diet to a Control diet (62). The MUFA in the diet came from olive oil and the Med Diet consumed 2x as much fiber. Despite the differences in fiber intake, I find the results interesting. Both total cholesterol and LDL concentration of cholesterol and particle number went down. They attribute this change to a protein called proprotein convertase subtilisin/kexin-9 (PCSK9). PCSK9 (wiki) is a protein who's main job it seems is to cleave the LDL receptor molecule in the liver. Which is bad. It seems that a non-sense mutation in African Americans in the PCSK9 leading to a loss-of-function results in lower LDL levels (63). While in mice they found that gain-of-function mutations lead to hypercholesterolemia. This is a relatively new function and molecule so not much has been done on it (however there are drugs targeting this protein being developed, but I find it odd that the only function of PCSK9 would be to raise LDL levels. It could be that in a Darwinian sense this protein exists to punish overfeeding? What about PUFAs? Do not overdo it. I recommend 20-30g a day with a 2:1 - 4:1 ratio of n-6:n-3 with the n-3 mostly being alpha linoleic acid. This topic will be covered in another post as it will also be quite long. References 01. JAMA. 2005 Jul 20;294(3):326-33. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. 02. Nat Genet. 2008 Feb;40(2):129-30. A treasure trove for lipoprotein biology. Lusis AJ, Pajukanta P. 03. Am J Cardiol. 2006 Nov 15;98(10):1363-8. Epub 2006 Sep 29. Non-high-density lipoprotein and verylow-density lipoprotein cholesterol and their risk predictive values in coronary heart disease .Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. 04. Am J Cardiol. 2006 Nov 15;98(10):1363-8. Epub 2006 Sep 29. Non-high-density lipoprotein and verylow-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. 05. Nature. 2011 Sep 25;478(7367):110-3. doi: 10.1038/nature10426. Dynamics of human adipose lipid

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