February 21, 2022 6 min read
Despite receiving a bad rap for much of the 1990s and early 2000s, lipids like dietary fats and cholesterol are critical nutrients without which biological life would be impossible. Cholesterol is the precursor to all steroid hormones and bile acids and serves as an essential component of cellular membranes. Meanwhile, fats are converted into bioactive signaling molecules, assembled into membranes, and serve as a direct primary fuel source for all the organs in the body outside of the brain. Moreover, the cellular breakdown of long chain fatty acids is the primary source of metabolic heat in all warm-blooded animals and is what allows us to maintain a stable body temperature.
Introduction to Lipoproteins
Following their consumption, dietary fats and cholesterol undergo transport into the circulation by particles known as lipoproteins. Although they themselves are composed primarily of cholesterol and fat, lipoproteins are responsible for shuttling cholesterol, phospholipids (a special kind of fat that is used to construct membranes), triglycerides (the storage form of fatty acids), and fat-soluble vitamins between organs. Lipoproteins are also adorned with special proteins known as apoproteins, with each lipoprotein having a unique apoprotein signature.
There are four primary lipoproteins: chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs).
Chylomicrons are the largest of the four particles and are constructed by the small intestine. They are responsible for transporting dietary fat and cholesterol directly from the small intestine to the circulation. The primary function of chylomicrons is to deliver fats to organs to support tissue energy production in the post-prandial (fed) state. With a half-life of 15 to 20 minutes, chylomicrons are rapidly cleared from the blood by the liver. A half-life is the amount of time it takes for the number of particles in the bloodstream to be reduced by half.
Following their clearance from the circulation, any triglycerides and cholesterol that remain inside the chylomicrons are repackaged into VLDLs by the liver and excreted into the circulation. The primary function of VLDLs is to deliver fats to organs to support energy production in the post-absorptive (fasted) state. VLDLs have a half-life between 4 and 6 hours.
After this time, the VLDLs will return to the liver and be repackaged once more as LDLs which are excreted into the blood where they will remain for about 3 days. LDLs are the most cholesterol-rich of the lipoprotein particles, and the lab measurement for LDL cholesterol, LDL(c), is frequently used by medical professionals to estimate the number of LDL particles in the blood.
Unlike the other lipoproteins which transport fat and cholesterol to the tissues of the body, HDLs are primarily responsible for transporting cholesterol away from the tissues of the body and back to the liver for processing and excretion. This so called “reverse cholesterol transport” is believed to be cardioprotective by slowing down the development of atherosclerosis (hardening of the arteries). The half-life of HDLs is about 5 days.
The Role of Apolipoprotein E (APOE) in Lipid Transport
ApoE is one of over a dozen apoproteins and can be found on chylomicrons, VLDLs, and some HDLs. It promotes the clearance of chylomicrons and VLDLs from the circulation by allowing them to bind tightly to lipoprotein receptors on the surface of liver cells. This is, in part, why chylomicrons and VLDLs have such short half-lives compared to LDLs. In the brain, which can’t access circulating lipoproteins due to the presence of the blood brain barrier, ApoE directly serves as the primary lipid transporter, shuttling cholesterol and phospholipids between cells.
An Overview of the ApoE Variants
Genetically, there are three variants of ApoE within the human population: ApoE2, ApoE3, and ApoE4. Each variant, or isoform, differs by only one or two amino acids (the building blocks of proteins), however the structural and functional consequences of these differences is significant. ApoE3 is the dominant isoform of ApoE and is considered to be the “normal” form of this protein. Around 77% of the population possesses one or two copies of E3.
ApoE4 is the second-most dominant isoform with about 15% of the population possessing one or two copies. It preferentially binds to VLDLs in the circulation, whereas E2 and E3 bind preferentially to HDLs. ApoE4 binds even more tightly to certain lipoprotein receptors than does E3. Individuals with two copies of ApoE4 have a significantly higher risk of developing cognitive decline, neuroinflammation, and late-onset Alzheimer’s disease (AD). In fact, E4 is the strongest genetic risk factor for AD currently identified. Individuals with one copy (i.e. carriers) of E4 also have a higher risk of developing AD, but to a lesser extent than those with two copies. The precise role of ApoE4 in AD progression has not yet been well-characterized.
ApoE2 is the least common isoform, with about 8% of the population possessing one or two copies. E2 is only capable of binding to lipoprotein receptors in the liver at 2% the efficacy of the E3 isoform. As a result, E2 is no longer able to effectively facilitate the clearance of chylomicrons and VLDLs from the circulation. The result, for individuals with two copies of E2, is a condition known as type III hyperlipoproteinemia, which presents as extremely elevated levels of chylomicrons and VLDLs. As these lipoproteins remain in the circulation, they begin concentrating cholesterol and contribute to the development of atherosclerosis and accelerated cardiovascular disease. On the flipside, ApoE2 confers a protective benefit against AD.
ApoE and Gut Microbiome
Interestingly, the ApoE isoforms an individual possesses are linked to specific shifts in the composition of the gut microbiome. These shifts are believed to contribute, at least partially, to the deleterious physiological effects associated with ApoE4. Higher levels of the bacteria Prevotellaceae have been observed in E3/E3 individuals relative to other genotypes, and higher levels of Ruminococcaceae have been observed in E2/E3 individuals relative to ApoE4 carriers. In alignment with these findings, clinical reports note a depletion of these two bacterial families in the microbiomes of individuals with Parkinson’s disease and AD.
Gut Optimization Strategies for ApoE4 Individuals
In light of this information, it is advisable for ApoE4 carriers to implement dietary and/or supplementation strategies to support SCFA production and reduce gut permeability. Because Bifidobacteria produce key metabolites that feed SCFA-producing bacteria in the gut, bolstering their populations will allow individuals to optimize intestinal SCFA production. Bifidobacteria thrive on molecules known as human milk oligosaccharides such as 2’-fucosyllactose (2’FL), dark colored fruits like berries and pomegranate, as well as resistant starches like those found in semi-green bananas, raw oats, and beans. To reduce gut permeability, eating red apple skins or supplementing with an apple peel powder is prudent. A special pigment molecule in red apple skins feeds Akkermansia muciniphila, a species of bacteria that lives in the mucus layer of the gut and enhances the integrity of tight junctions (i.e., the connections between intestinal cells). Together, these nutritional strategies have the power to directly modulate the microbiome and help to mitigate the potential health consequences of ApoE4.
Written by: Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions. Follow Dr. Cowan on Instagram: @dralexisjazmyn
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