I am also curious about the preferred energy source of CLL cells.
Particularly the cholesterol role. If the CLL cells use cholesterol do they use whatever is present, or is there a signaling going on telling/initiating production—that causes cholesterol to rise?
Studies suggest that rates of dyslipidemia are higher among CLL patients than age-matched healthy controls [15]. One study showed that CLL patients suffer from hypercholesterolemia, observing elevated LDL levels in 75% of CLL patients [16]. Another study reported lower serum levels in CLL patients compared to healthy individuals, with CLL patients averaging 151.2 +/− 11.2 mg/dL compared to 195.3 +/− 8.5 mg/dL in healthy, aged-matched controls [17]. CLL patients with hypocholesterolemia have a shorter overall and treatment-free survival [18], possibly due to increased catabolism of LDL and impaired hepatic lipoprotein synthesis [17], or increased expression of the LDL receptor (LDLR) on CLL cells [19], leading to increased cellular uptake.
Hypercholesteremia may be due to an increase in the hepatic secretion of cholesterol into the blood stream; this may potentially fuel the rapid proliferation of leukemic cells in patients with a poor prognosis [20]. This notion is supported by a study that focused on patients with high-risk disease, defined by unmutated IGHV status (UM–IGHV). Using a metabolomic approach, significantly higher levels of serum cholesterol and LDL fatty acid side chains were observed in patients with high-risk disease [20]. This study also determined that UM–IGHV patients had higher levels of VLDL and lower levels of HDL cholesterol compared to patients with mutated IGHV genes (M–IGHV), while LDL levels were similar between the two groups of patients [20]. Hyperlipidemia may lead to inflammation, which helps drive CLL cell proliferation [21]. It is not surprising that statins, commonly used to treat hypercholesteremia, delayed the need for treatment by nearly 3 years [16].
In another study, no association between serum levels of LDL, HDL, total cholesterol and triglycerides, and clinical outcomes was observed [22]. However, this study included samples from a relatively small number of patients (n = 26), which raises the possibility that discrepancies between the studies may, at least in part, be due to the heterogeneity among CLL patients, and that much larger cohort studies are warranted. While there are conflicting reports concerning the role of cholesterol in CLL, there is clear evidence that cholesterol uptake and metabolism is disordered in CLL cells compared to healthy B-cells and other blood cancers, including acute lymphoblastic (ALL), acute myeloid (AML), and chronic myeloid leukemia (CML) [23].
Studies of the relationship between blood cholesterol levels and leukemia have yielded conflicting results. Lower cholesterol concentrations were reported in patients with chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL) than in healthy controls (108, 109), but a different report documented high cholesterol levels in patients with CLL (110). The results of another study demonstrated that in patients with CLL, elevated SREBP2 expression resulted in increased LDLR, thus cholesterol accumulation in the tumor cell cytoplasm was noted as a possible cause of this cancer (111).
Low cholesterol levels may be accompanied by solid tumors or hematological malignancies such as multiple myeloma. Decreased cholesterol levels have been reported in some experimental studies about chronic lymphocytic leukemia (CLL). It may be associated with tumoral cell metabolism. Herein, we examine blood lipid profiles of patients with newly diagnosed CLL (284 male, 276 female, mean age 64 ± 11 years) as defined by National Cancer Institute criteria. The control group consisted of 71 healthy subjects with mean age 55 ± 9 years (28 male, 43 females). 60% of patients with Binet A, while 25% were Binet C. Decreased levels of total cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) were observed in patients with CLL than control group (p < 0,001). There was no statistical significance between CLL and control group for triglycerides (TG) and very low density lipoprotein (VLDL), also between HDL-C, VLDL, TG and grades. Cholesterol may metabolized by abnormal lymphocytes in CLL patients.
In an a priori hypothesis-driven analysis, we found that use of low-potency lipophilic statins was associated with lower CLL risk, OR = 0.64 (95% CI, 0.45–0.92), with some indication of a dose–response effect. We did not detect a similar association with the use of either high-potency lipophilic statins or hydrophilic statins.
The association between statin use and CLL risk has been studied before. Using questionnaires to measure statin use, a study conducted in 6 European nations (including 410 patients with CLL) reported an OR of 0.83 (95% CI, 0.51–1.34) for all statins combined (16). A prospective U.S. cohort study found, based on biannual questionnaires, that cholesterol-lowering drugs (93% of which were statins) had a risk ratio of 1.01 (0.59–1.74) for former users, and 0.91 (0.66–1.27) and 0.85 (0.58–1.23) for current users for less and more than 5 years of use, respectively (17). The number of patients with CLL in this study was relatively small (326) with only 50 recent statin users and 49 long-term users; ref. 17). Our estimates for statin use as a class (OR = 0.89; 95% CI, 0.76–1.04) are in line with these results, despite differences in study design and data sources.
To the best of our knowledge, this is the first study to examine the association between low-potency lipophilic statins and CLL incidence (the analyses in the abovementioned studies were limited to studying the effects of statins as a class). Pharmacokinetic differences between lipophilic and hydrophilic statins may explain the differences in their association with CLL risk. The water solubility of statins affects their absorption and distribution in tissue (33, 34). Hydrophilic statins cannot easily penetrate cell plasma membranes through passive transport and their distribution is more hepatoselective (4, 35). However, this does not explain differences we observed between low-potency and high-potency lipophilic statins. The indications for individual statins are overlapping and clinical guidelines do not recommend certain types over others (36, 37), even though high-potency statins are prescribed when a larger reduction of low-density lipoprotein cholesterol (LDL-C) levels is desired (38). There is no clear connection between the type of statin and its effect on the MVA pathway in CLL cells. This remains an unexamined area as most animal and laboratory studies are limited to studying a specific statin (39).
Simvastatin has shown cytotoxicity against cultured B-CLL cells with higher levels of apoptosis with increased dosage (6). Fluvastatin showed higher cytotoxicity against lymphoma cells than atorvastatin and simvastatin (39). The statins have been shown to downregulate the anti-apoptotic protein BCL2 in some leukemias (40), and the complete remission rate in CLL is increased when simvastatin is combined with venetoclax, another agent that selectively reduces BCL2 levels in CLL cells (41, 42). Elevated LDL levels in CLL cells may decrease apoptosis of CLL cells; this was not observed for acute leukemia cells or normal lymphocytes (43).
Strengths and limitations
A major strength of this study is the availability of high-quality, population-based health administrative databases in Manitoba. The completeness and accuracy of the MCR and MH databases are well established (20, 21). We had a relatively large number of cases compared with other CLL studies, but some of our estimates were imprecise due to infrequent use of certain statins (especially low-potency lipophilic statins). Reporting of cancer cases to the MCR is mandated by provincial law (44). The MCR currently obtains data for all persons diagnosed with CLL cells using flow cytometry (but excludes cases with monoclonal B lymphocytosis). CLL incidence was underreported before reporting of flow cytometry became a standard practice (45). It is possible that some diagnosed cases during that time were not included in the MCR, this misclassification was likely nondifferential with respect to statin use.
A limitation of this study is that the DPIN database started in 1995. Statins prescribed before that time could not be identified. Statins were not, however, frequently prescribed before 1995 (46, 47) and have only been available since around 1990 (Supplementary Table S1). Also, any resulting misclassification is likely nondifferential with regard to the outcome (CLL diagnosis) as it excludes all exposure information before 1995. Although we adjusted our analysis for several confounding factors, we could not adjust for undiagnosed chronic cardiovascular disease. We also lacked information on aspirin use unless it was prescribed which is the likely the case for regular users. As a result, we cannot rule out residual confounding. We did not have information on some potential confounders, such as smoking, alcohol use and environmental exposures, albeit the literature suggests this does not cause significant confounding (2).
Although dyslipidemia has been associated with the development of CLL (48), the effect of the severity of dyslipidemia has not been studied. Our study is limited by a lack of data on cytokine and lipid levels; we could not stratify our analysis by severity of dyslipidemia. The low-potency statin users in our study used a relatively low dose of statins and were generally older and more likely to have chronic cardiovascular disease and other comorbidities. Confounding by indication may have biased our results if risk factors for CLL influenced statin prescriptions.
In summary, our results suggest that use of low-potency lipophilic statins might be associated with a lower risk of CLL, possibly in a dose-dependent manner. Even though a causal relationship cannot be proven, a 35% reduction in CLL risk is a promising, clinically relevant result that warrants further investigation into the effects of low-potency lipophilic statins on CLL risk.
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Lavinia-Blue
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From my experience cholesterol has no bearing on the progress of CLL. I was found to have high cholesterol, I think HDL, around 1997. I was put on statins , initially Lipitor. I was switched to Simvastatin in 2008 and the blood test after switching found I had CLL. My WBC at the time was 15 and Lymph count 12. My CLL has, so far, run an indolent course with my WBC andLymph counts around the 30s. The most recent is WBC of 40 and Lymphs of 36. I have not needed treatment for the CLL. Around 2016/7 my GP took me off the statins but a blood test last October and this April found I had high Cholesterol and triglycerides so it is now debatable whether I go back to taking statins. My twin brother has also been on statins for a long time but I think he doesn't take the full dose to reduce the cost. He has never been diagnosed with CLL. I don't think all the scientific papers show any link between cholesterol and CLL
Ouch, this is very complex. Here are a few simple thoughts in layman's terms.
First let's quit using the cholesterol term because it is confusing.
There are lipoproteins and there are lipids transported on them. That's because fat doesn't mix with water (blood). So lipids need a transport vehicle to be moved around in the blood.
The size of the lipoprotein molecules is very important here.
It divides them into Chylomicrons, high density lipoproteins, low density lipoproteins, very low density lipo proteins.
That is why the term "cholesterol - C" , which indicates the total blood lipid content is indicative of nothing.
Because it says nothing about how many of each lipoprotein particle is there in the blood and the distribution of all those lipids among the lipoprotein particles.
We want lots of lipids to be traveling on high density lipoproteins, that is to have a high HDL level. We want very few of them to be traveling on the subset of very low density lipoproteins that are called ApolypoproteinB (ApoLypoB for short), because that is the dangerous one.
All the other lipoprotein sizes are okay and not dangerous.
Now the chicken or the egg problem. Do people with CLL have higher total cholesterol levels because they have CLL?
Or is it just because these patients tend to be on the older side and older people usually have high cholesterol?
Or do people with high cholesterol levels get CLL more often?
How many of the patients are on statins to lower their blood cholesterol content?
Now how this ties into diet. Most people's metabolism runs on carbohydrates day in Day out. They practically never get to use their circulating blood lipids as a source of energy,because there is always enough glucose in their blood to fuel the cells,and glucose has to be burned off first because it is toxic if it's level is higher than it should be. Hence the lipids keep circulating in the blood. The longer they stay the more they oxidize. And the more damage they do. Do CLL cells feast on these excess blood lipids? Or do they feast on the high blood glucose available all the time?
As opposed to this, people on zero or very low carb diets, have a metabolism mostly running on lipids instead of glucose When blood sugar is low to very low, lipids are converted into ketones in the liver. Ketones are a very good energy source for the cells. At the same time the liver produces just enough glucose for the few cells that absolutely need it.
This way of eating leads to: high HDL, low triglycerides, high LDL (Very low ApolypoproteinB but high levels of other LDL subsets). These are all favorable things. But they tell us nothing about CLL metabolism.
The only way to figure out the effect of such a diet in an individual case, is to try it and see whether it helps. No amount of theoretical research will tell anybody with any degree of certainty that he should or should not embark on such a diet. Even scientists are lost in the woods here. How could a layperson figure it all out.
Thanks for the information. It would be interesting to know if CLL raises cholesterol (or lipoproteins). I don't think cholesterol causes CLL in any way.
I refer to cholesterol because the papers use that terminology.
I don't think that CLL raises cholesterol in any direct way. About 85% of the cholesterol in the blood is made in the liver. Consuming high cholesterol meals or avoiding them, doesn't have much effect on our cholesterol levels, which are quite tightly regulated. If we don't eat enough cholesterol, our liver will just make more. I read somewhere that if the immune system is a machine gun, the cholesterol is like the bullets into it. The immune system uses cholesterol to fight cancers. One of the first signs of liver cancer can be a dramatic drop in cholesterol levels without any apparent reason. I read this somewhere too but I don't remember where. Nevertheless I considered the source credible that's why I still remember it. Cholesterol content is never a problem anyways. It's all about the types of lipoprotein particles and their respective numbers.
I would make healthy decisions because it is good for your overall health to make sure nothing else falls apart. The more health problems we have the more complex our treatment options get. Also, we could miss out on clinical trials.
I am skeptical of trying to find ways to beat the CLL by starving its food, etc. Perhaps in combination with an effective treatment it could help at the margins.
I wonder if a person would actually be creating a new bottle neck that encourages the meaner CLL cells to out complete the less durable CLL clones.
It really boils down to how aggressive someone’s CLL biology is.
If a person has a sophisticated diet and their CLL isn’t very active it seems more likely their disease is indolent rather than the diet snuffing out growth.
We see people get different types of cancer who are perfect models of how to eat and exercise. We’ve had marathon runners join our group. If their cancer continues to grow or not be kept in check it isn’t because they ate the wrong things. Bad cancer biology is going to overcome our efforts. If you have indolent CLL, lucky you!
Another point: Suppose you cut out fat while on venetoclax treatment. According to the package insert it will not absorb quite as well so it might not be a good decision.
Thank Lavinia-Blue, this is certainly an interesting topic and one that is open to much debate. Here are some of my comments.
The level of cholesterol in the body, including the sub-fraction breakdown, is under the control of your genes which have evolved over the course of approximately at least 4.5 billion years. The level fluctuates during the day depending upon the body's needs. The human body knows what it is doing when it comes to cholesterol, unfortunately humans do not.
As mentioned by LeoPa the majority of cholesterol is made endogenously rather than from dietary intake. It seems highly unlikely that a molecule produced by the body that is essential for life would be harmful to humans without the influence of an underlying disease process. Humans would have died out a long time ago if this was the case.
The war on cholesterol over the last 50 years or so has moved the human diet to significant increases in highly processed plant foods and an uptake in the use of pharmaceutical drugs, especially in Western countries. This has been associated with a rise in many chronic diseases such as metabolic disease, auto-immune conditions, gut dysfunction, mental illness, cardio vascular disease and cancer. While diet is a major contributor is not the sole cause of this, rather evolutionary inappropriate lifestyles causing toxicities and deficiencies resulting in chronically elevated levels of systemic inflammation in the body. This is where epigenetics come into play. What environment are you placing your body in?
Potentially the best chance to improve health is to adopt a lifestyle that aims to reduce chronically elevated systemic inflammation. This will mean different things to different people, but some of the usual common sense things are eating a species appropriate diet (as a species what are we evolved to eat?), an adequate amount of exercise at the right intensity, getting out into nature, de-stressing, avoidance of environmental toxins, sufficient good quality sleep, circadian rhythm maintenance . It has been suggested that statins may provide some benefit by having a secondary anti-inflammatory effect on the body rather than lowering cholesterol being helpful. However statins come with a variety of unpleasant side effects which I'm sure many people on here can attest to.
There are no cause and effect studies to support these notions as the science does not and can not exist. Trying to figure out our evolutionary history is possibly our best chance to thrive. I believe questionable studies, especially in the field of 'nutritional science', over the last few decades has led us to worse health outcomes.
Could CLL be considered an underlying disease (if CLL does influence [raise] cholesterol)?
While cholesterol may not be the bad guy, it is one of the factors involved in atherosclerosis plaque formation. There are many who do all the right things, don't have high blood pressure, inflammation, etc. and still end up with plaque in their arteries.\_(ツ)_/¯
"Atherosclerosis is thickening or hardening of the arteries caused by a buildup of plaque in the inner lining of an artery. Risk factors may include high cholesterol and triglyceride levels, high blood pressure, smoking, diabetes, obesity, physical activity, and eating saturated fats." --Johns Hopkins
Herein lies the problem. Risk is the conjugate of cause and effect. Studies can only reveal incidence of outcomes in certain populations under certain reported conditions over various time periods. These are merely associations which should lead to hypothesis formulations only. Unfortunately cause and effect cannot be proven as properly controlled, properly randomised studies in humans over multiple decades cannot be carried out. In the absence of actual science these associative studies and mechanistic speculations form the basis for recommendations. This is problematic as the human body is far too complex and our current knowledge base is not advanced enough to determine cause and effect using this approach. Given everyone is exposed to a different set of conditions during their lifetime there isn't a single study that can determine any one individual's 'risk' of anything.
It's likely that plaguing in the arteries takes many decades to build up. How long have people who do all the right things been doing that for? What were they doing for their first 40, 50, 60 years of life? The right thing is also difficult to determine. Many people would argue that a plant heavy diet is best, however I do not believe homo sapiens sapiens have the metabolic machinery to fully extract the nutrients from plants without causing a move away from homeostatis. Genetic factors will play a part as well. Atherosclerosis is composed of many things including scar tissue from injury. While hard plagues in arteries may contain cholesterol and LDL particles they could simply be the firemen there to repair the damage rather than being the pro-inflammatory fire starters.
If cholesterol was causative of atherosclerosis on its own, it would also occur in veins as well as this side of the circulatory system is exposed to the same cholesterol. The main difference being arteries are under higher blood pressure than veins. But if just cholesterol and higher blood pressure was sufficient for atherosclerosis then the plaguing would occur evenly throughout the arteries and not just in certain areas. My understanding that the usual clog points are at bifurcations and curves in the vessels where more turbulence is present.
Notice the use of the word 'may' in the Johns Hopkins extract. This means cause and effect is not proven, they are associations only. The reality is atherosclerosis is complex and multi-factorial. I am of the belief that saturated fat has been integral to the development and vitality of humans for almost our entire existence. Afterall the human brain is approximately 60% saturated fat once the water is taken out. Things have only started going awry health wise since the onset of agriculture some 10,000 years ago. This decline has really accelerated in the last 100 years or so.
Of the atherosclerosis 'risk factors' listed by most medical establishments, I believe one needs to ask themselves which habits are evolutionary appropriate and which are not?
Blood cholesterol levels are just inadequate for estimating risk of CVD, see ahajournals.org/doi/10.1161... In the UK a lipids profile including Apo A1 and Apo B costs £85, or you can get a worthless profile for free.
I'm really surprised at JH's lack of precision here.
"High Cholesterol" - meaningless. There are several kinds of cholesterol, and none of them are predictive. See my reply to FredNerk.
"Triglyceride" - not an independent risk factor.
"Physical Activity" - perhaps they mean "sedentary lifestyle".
"Eating saturated fats" - a popular myth long since debunked. Processed carbohydrate is the main dietary driver of metabolic syndrome, a strong risk factor for CVD.
A gene expression analysis revealed that CLL cells’ signature is similar to that of fat or muscle cells [7]. Particularly, lipoprotein lipase (LPL), normally expressed in adipocytes and muscle cells[59], was found to be aberrantly expressed in CLL cells [60–62]. Increased LPL mRNA levels correlated with an aggressive disease and unfavorable prognosis [4,60–63] whereas in CLL patients with a mutated IgHV, low LPL mRNA levels a hypermethylated LPL promoter was found [64,65].
LPL has non-catalytic and catalytic functions. It induces cellular uptake of lipoproteins and prompts the hydrolysis of triglycerides into free fatty acids (FFAs) [76]. Driven by constitutively activated STAT3, LPL induces storage of lipoproteins in cytoplasmic lipid vacuoles and reprograms CLL cells to preferentially use lipids as an energy source. Although levels of LPL are higher in IgHV-unmutated cases, utilization of FFA is operative in CLL regardless of clinical characteristics or IgHV mutation status.
In newly diagnosed CLL patients the levels of cholesterol, high density lipoprotein-cholesterol (HDL-C), very low density lipoprotein-cholesterol (VLDL-C) and triglycerides are relatively low [77], likely because of an increased uptake of cholesterol mediated by LPL. Lipid-mediated signaling might be disrupted in CLL cells. For example the expression of sphingosine 1-phosphate receptor-1, known to mediate lipid-dependent signaling, is low in CLL patients’ lymph nodes and upon BCR inhibitor treatment its level increases, likely contributing to mobilization of CLL cells from lymph nodes to the peripheral blood [78].
Unlike normal B lymphocytes CLL cells store lipids in cytoplasmic vacuoles and utilize FFAs to produce energy via oxidative phosphorylation [75]. Metabolomic analysis of CLL cells identified increased levels of FFAs and triglyceride degradation products, suggesting that these changes are induced by downregulation of microRNA (miR)-125 and a reciprocal increase in lipolysis-facilitating enzymes [79]. FFAs, the substrate for oxidative phosphorylation, are also ligands of the nuclear receptor peroxisome proliferator activated receptor (PPAR)-α. After FFAs bind PPARα, the FFA-PPARα complex functions as a transcription factor and activates the transcription of enzymes necessary for oxidative phosphorylation [80]. Hence, LPL generates FFAs through its catalytic activity thereby supplying fuel for oxidative phosphorylation, and in addition, drives the transcription of PPARα (Figure 1). Remarkably, PPARα is overexpressed in circulating CLL cells and its levels correlate with advanced-stage disease [81].
Thus, STAT3-driven aberrantly expressed LPL, plays a major role in metabolic reprogramming by skewing the metabolism of CLL cell towards utilizing lipids. This phenomenon provides a rational for targeting lipid metabolism in CLL cells.
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