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March 27, 2023
High Density Lipoprotein - We are going to take a deep look at this very complex biological topic. Bear with me as in the end it will all make more sense as to why "good cholesterol" is not inherently good or bad as much as it just is. Our lifestyle decisions are in effect making a biological process good or bad. That is my scientific understanding at this time.
This week we will look into the history and science behind the high density lipoprotein or HDL for short. The fascinating part of this story starts out immediately with the reality that epidemiological studies had shown that HDL volume was inversely related to cardiovascular disease, CVD, ushering in an era of HDL increasing medicines. Unfortuantely, every pharmaceutical made to increase HDL levels has had no beneficial effect on CVD outcomes to date.
Thus, we are missing a large part of the story of HDL as a particle, it’s benefits in human physiology and how we can leverage it to change our downstream risk. As always, this leaves me heading to the headwaters of HDL biology to find some answers, if there are any!
What is the biology? HDL is the main source of reverse cholesterol transport (RCT) which is to say that HDL particles transfer excess cholesterol molecules from systemic cells, such as arterial wall immune based macrophages or foam cells, into the themselves whereby they are esterified to form cholesteryl esters (CE). Lecithin–cholesterol acyltransferase, LCAT, esterifies cholesterol to CE which is hydrophobic causing it to migrate from the HDL particle surface to the core. This action in effect removes cholesterol from peripheral cells and keeps them away which is thought to be a part of the benefit of HDL. The HDL particle then travels through the blood stream to the liver where the cholesterol as an ester molecule is taken up by the liver by a hepatic scavenger receptor called (SRB1) or other HDL receptors. The liver then recycles it and/or excretes it into the bile for discharge via the bile duct and ultimately in stool.
A major feature of CVD is the deposition of small dense LDL particles in the heart artery vessel wall. When a macrophage, immune cell that engulfs pathogenic molecules, swallows a small dense oxidized LDL, it begins an inflammatory response that leads to a metabolically and immunologically active cell called a foam cell. Oxidation is a process that occurs whereby oxygen radicals released by immune cells attack the LDL particles in the vessel wall leaving them damaged by oxidation and furthering a loop effect more immune activation. HDL particles can prevent this process by releasing certain enzymes that block the oxidation response. This maybe another method of cardio-protection by the HDL molecule.
HDL lipoproteins carry a surface protein called apolipoprotein A1, Apo A1, which is involved in cell signaling leading to the RCT and antioxidant effects of HDL. Interestingly, systemic inflammation reduces the action and volume of Apo A1 protein. Inflammation in the body can raise the levels of acute phase reactants like ferritin, c reactive protein and amyloid which can cause the Apo A1 protein to not function properly leaving the RCT and anti inflammatory effects of HDL dysfunctional.
Therefore, anything that causes systemic inflammation can negatively affect HDL activity worsening CVD by blocking reverse cholesterol transport leaving more oxidized LDL in the heart vessel wall. As we have noted for years in this newsletter, the upstream causes of systemic inflammation are related to nutrition, mental/physical stress, sleep, toxin load, sloth and more. (hypothesis) - It is no wonder that HDL pharmaco-therapies are failures since the upstream targets that render HDL inactive in RCT and/or oxidation are untouched by HDL enhancing medical therapy. (Rader D. 2014)
Other recently discovered desired effects of the HDL particle are: a) the induction of endothelial nitric oxide synthase, eNOS, which is an enzyme that produces nitric oxide relaxing blood vessels, b) the enhancement of insulin secretion and glucose metabolism, c) increased activity of adenosine monophosphate kinase, AMPk, d) increase lipoprotein lipase which helps to metabolize triglycerides and fats, e) enhance immune activity. (Bardagjy et. al. 2019) These effects are all pro health and anti-inflammatory in nature causing a loop effect that enhances HDL function and reducing CVD risk.
What can we learn from disorders of HDL function or volume? There is an inherited rare disease called Tangier disease where the RCT of HDL volume is so low that the activity is minimal leaving affected individuals with cholesterol ester filled macrophages throughout the body, like foam cells of the heart like CVD, orange colored tonsils or enlarged liver and spleen. Other diseases like : Familial HDL deficiency is associated with very low serum HDL concentrations and premature CHD; LCAT deficiency is due to Lecithin cholesterol acyltransferase deficiency. presents with annular corneal opacity, and progressive renal disease with proteinuria. Other causes that make a low HDL including taking Drugs such as beta-blockers, benzodiazepines, and anabolic steroids. (Alshaikhli et. al. 2022) Mendelian randomization studies have failed to show a strong causal link between HDL number and premature CVD risk.
These diseases show in principle that HDL is important to the progression of CVD, however, this is likely through inflammation and infection reduction and not directly through RCT. The question remains, how and through what mechanisms? More data is needed to answer this question as we are clear that raising HDL number is not changing CVD risk.
Let us switch gears and think outside the box here as we did with the LDL cholesterol discussion. Why would we have evolved with HDL molecules other than energy and cholesterol movement? The answer as it was with LDL particles belongs in the immune sphere of influence. From the Journal Cardiovascular Research: “During infections or acute conditions high-density lipoprotein levels decrease very rapidly and HDL particles undergo profound changes in their composition and function. These changes are associated with poor prognosis following endotoxemia or sepsis and data from genetically modified animal models support a protective role for HDL. The same is true for some parasitic infections, where the key player appears to be a specific and minor component of HDL, namely apoL-1. The ability of HDL to influence cholesterol availability in lipid rafts in immune cells results in the modulation of toll-like receptors, MHC-II complex, as well as B- and T-cell receptors, while specific molecules shuttled by HDL such as sphingosine-1-phosphate (S1P) contribute to immune cells trafficking. Animal models with defects associated with HDL metabolism and/or influencing cell cholesterol efflux present features related to immune disorders. All these functions point to HDL as a platform integrating innate and adaptive immunity.” (Catapano et. al. 2014)
A critical role of HDL particles, like LDL, is the natural innate ability to grab bacterial cell wall debris in circulation, bind it and clear it via the liver. This action reduces immune activation locally and systemic inflammation in total. Bacteria have lipid outer membranes like lipopolysaccharide, (LPS), of Gram-negative bacteria, or lipoteichoic acid, (LTA), of most Gram-positive bacteria. These cell wall membrane pieces are highly inflammatory if found in circulation. We know this to be true based on animal models with reduced HDL activity leading to increased inflammation in response to a bacterial infection.
As discussed with LDL and innate immunity, reduced HDL lipoprotein levels pre-infection increases the overall risk of sepsis post infection. If HDL levels are high pre-infection, then they will drop rapidly as they clear the bacterial cell wall debris leading to a better outcome overall. Although the absolute number matters, I think that the function or lack there of for the HDL particles likely matters more.
HDL volume has been highly associated with inflammation, immune activation and disease in study. HDL knockout mice models have shown enlarged peripheral lymph nodes and spleen with increases in immune cells of the T and B cell lineage and macrophages. As note earlier in the low HDL disease Tangiers, these immune cells have an altered function and the lack of HDL molecules leads to an inability to remove cholesteryl esters from macrophages leaving them dysfunctionally prone to stimulating inflammation. Over time these problems can develop an autoimmune or inflammatory immune polarity. The abnormal immune activity can lead to problems with infection as there is a direct effect of the action of these Apo A1 particles and immune activation in a necessary response to bacterial, parasitic and viral infections. (Bonacina et. al. 2021)
Many autoimmune diseases like rheumatoid arthritis, Crohn’s disease and Systemic Lupus Erythematosus are are associated with a significantly higher risk of CVD and are noted to have HDL particles that are low in absolute number, but also have a characteristic dyslipidemia with high triglycerides (TG), high LDL with the low HDL particle number. The macrophages and white blood cells conversely have high volumes of cholesterol esters inside them rendering them prone to innate immune activation and inflammation. The abnormal HDL particles are enriched with TG and depleted in CE resulting in attenuated anti-oxidative activity, reduced anti-inflammatory effects, and lower capacity to promote cholesterol efflux.Therefore, as the data emerges, it appears that the function is key to health outcome although absolute number matters in the case of infection or sepsis. In autoimmune conditions, HDL functional activity is broken. The composition of the HDL cell membrane and thus it’s activity appears to be pro inflammation and pro autoimmune disease.
Look at this statement by Dr. Catapano. "Also patients with type 2 diabetes mellitus, a clinical condition recently redefined as an autoimmune disease rather than just a metabolic disorder, exhibit an impaired HDL metabolism and the presence of dysfunctional HDL. Whether the immune-related activities of HDL have a role also in this context beyond the known metabolic functions is an intriguing hypothesis, which is so far supported by circumstantial observations." (Catapano et. al. 2014)
Remember that ApoA-I is the main structural and functional apoprotein of the lipoprotein HDL and plays a key role in the induction of cholesterol removal from peripheral cells with the plan to take them back to the liver for clearance. This interaction with cells results in cholesterol depletion and disruption of intracellular signaling in the cell membrane lipid rafts. These lipid rafts allow for receptors with key immunological functions like toll-like receptors (TLRs) and T- and B-cell receptors (TCR and BCR) to be active and immune stabilizing. We now know that the lipid composition of rafts determines their function and that any modification of lipid raft composition can modulate signaling altering immune cell biological functions. (Catapano et. al. 2014) More data is emerging that the HDL molecule will deplete cholesterol from the lipid rafts altering cell signals to be anti-inflammatory and pro resolution of systemic inflammation. When infusing HDL into an arthritic mouse with bacterial inflammation, the response was to reduce all inflammation via the downregulation of Toll like receptors and immune cell signaling. I assume that these HDL cells were fully functional. This may be the key to the failed HDL pharma trials. If the drug was increasing a person's HDL number, but not improving function, ..... failure.
When looking at the diverse immune actions of APO A1 HDL cells we see so many that are involved in immune homeostasis and reduced inflammation! Decreased Toll like receptor signaling; white blood cell activation and proliferation; dendritic cell differentiation, maturation, and antigen presentation; interferon response; macrophage activity; M1 macrophage polarity. For the non medical professionals, this is the key: These changes are ALL associated with reduced inflammation, autoimmunity and disease in general.
Covid death was highly associated with dyslipidemia and especially a low HDL level. "Low and high LDL-C, low HDL-C, and high TG levels were negatively associated with COVID-19-related mortality." (Aydin et. al. 2022) Coincidence? I think not! These dyslipidemic changes are all a sign a broken lipoprotein functionality and this leads to poor immune infection action, clearance and resolution.
There was a reason all along for the generation of abnormally high or low volumes of lipoproteins in human history. That reason was survival from infection. As always, the genetics of CVD are less about a mistake of humanity’s evolution and more a mistake of our modern lifestyle in relation to our evolving genetics.
The biggest and most profound understanding for me after doing this deep dive into LDL and HDL biology in humans is the understanding that our lifestyle choices are driving dyslipidemia altering immune lipid functional capacity leaving us in a pro inflammatory state and prone to disease of aging including autoimmunity, CVD and more.
What is the answer? Everything discussed in last weeks newsletter! See more in section III below.
Dr. M
Rosenson Nature
Bonacina Curr Opin Lipidology
Xiang Lancet Diabetes Endo
Bardagjy MDPI
Rader Cardiovascular Research
Alshaikhli Stat Pearls
Catapano Cardiovascular Research
Bonacina Cells
Aydin Angiology
Peltonen Human Molecular Genetics
From Cells: A powerful tool to appreciate the role of HDL comes from studies on monogenic disorders resulting in extremely low or high HDL-C levels. Monogenic disorders associated with low HDL-C levels include those related to loss-of-function mutations in APOA1, the gene encoding apoA-I, LCAT, encoding lecithin-cholesterol acyl transferase (LCAT), and ABCA1, encoding ABCA1. Genes implicated in monogenic disorders associated with high HDL-C levels include CETP, encoding cholesteryl ester transfer protein (CETP), SCARB1, encoding scavenger receptor class B member 1 (SRB1), and LIPC, encoding hepatic triacylglycerol lipase [142]. Patients with Tangier disease, despite having very low HDL-C levels due to ABCA1 deficiency, do not manifest premature coronary artery disease, but rather present an increased inflammatory status [143]; this has been associated to an increased inflammasome activation triggered by reduced cholesterol efflux from myeloid cells [144]. Moreover, mendelian randomization studies failed to demonstrate a causal link between HDL-C and CVD risk [145], but rather indicate that low HDL-C levels increase the risk of infections [6]. In addition, elevated peripheral blood leukocyte counts were reported in subjects with low HDL-C levels of any origin [146]. In line with this observation, subjects carrying a low HDL-C polygenic score have been shown to present an increased risk of hospitalization for infections [147]; this is consistent with the increased mortality for sepsis reported in subjects with gain-of-function mutation on CETP, who present a dramatic reduction of HDL-C levels during infection [148]. It is tempting to speculate that CETP, beyond transferring cholesteryl esters from HDL to apolipoprotein (apo) B-containing triglyceride-rich lipoproteins (TRLs), could also participate to immune response following a bacterial insult. This hypothesis is supported by the evidence that CETP is predominantly produced by Kupffer cells, specialized liver macrophages, and that its expression is reduced during inflammation; in turn, this leads to an increase in HDL-C levels that may contribute to LPS clearance during infections [149]. Similarly, LCAT deficiency in mice was associated with the presence of immature discoidal HDL and a reduced LPS-neutralizing capacity [150], thus suggesting that not only the concentration but also the type of HDL subclasses differently modulates immune responses [151] (Bonacina et. al. 2021)
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