Cholesterol-induced toxicity.

Cholesterol is a normal component of all higher animals' cell membranes regulating their functions; it also serves as a steroid hormone and is synthesized into bile. Our bodies produce all the cholesterol we need; therefore, a cholesterol deficiency is extremely rare, whereas excess is toxic, leading to cell dysfunctions and death by disrupting its membrane functions. All our cells are able to synthesize cholesterol, but only liver cells and steroid-producing cells can turn it into bile acid and steroid hormones. Most cholesterol in plasma is produced by hepatocytes (liver cells) and enterocytes (intestinal cells). Under normal/healthy conditions, brain cholesterol is separate from body cholesterol, meaning the dietary and liver-produced cholesterol do not cross the blood-brain barrier. The astrocyte cells in the brain produce and distribute cholesterol there. The liver is a master regulator of cholesterol homeostasis. It stores, metabolizes, and eliminates excess fat, keeping the blood free of it. However, when this protective mechanism is disrupted, excess free cholesterol accumulates in the liver and contributes to diseases.

Large amounts of scientific evidence show that elevated cholesterol levels are detrimental to health. Cholesterol, a major lipotoxin, causes Lipotoxicity, an accumulation of lipids in the nonadipose tissue that triggers inflammation and oxidative stress, leading to cells becoming damaged and dysfunctional. Cholesterol accumulation in various tissues and organs is associated with the progression of multiple diseases, some of which I will discuss in greater detail below.

Pathological changes caused by excess cholesterol play a role in the development of liver disease, kidney disease, diabetes, Alzheimer's, immune disorders, heart disease, and osteoporosis, amongst many others.

Cholesterol is only used by animal cells. Plants produce phytosterol, chemically similar substances that can compete with cholesterol for reabsorption in the intestinal tract and potentially reduce cholesterol absorption.

Liver disease

If you are getting too much cholesterol from your diet, this can increase your risk for fatty liver disease. High cholesterol also can turn fatty liver disease into a more severe and sometimes fatal condition known as NASH -nonalcoholic steatohepatitis.

Cholesterol from food mostly ends up in the liver, which plays a central role in cholesterol metabolism. It can then be taken up via the LDL receptor and may serve as a source of cholesterol in any cell of the body. If the supply of cholesterol in cells exceeds their demand, they may rid themselves of excess cholesterol by transferring it to HDL. HDL delivers it to the hepatocyte, where large amounts of cholesterol may be removed from the body by bile acid synthesis and cholesterol secretion. If the amount of cholesterol exceeds hepatocytes' abilities, then the only way to dispose of cholesterol is by forming cholesterol esters stored in the hepatocyte.

A healthy liver should contain little or no fat; a buildup of it leads to nonalcoholic fatty liver disease (NAFLD), which can progress to severe liver damage. A fatty liver disrupts metabolism, bile production, and hormones, increases inflammation, and drives insulin resistance. As insulin resistance progresses, the pancreas compensates by secreting more insulin, which causes the body to store more fat. Excess liver fat leads to imbalances in hormones that regulate appetite, such as leptin and ghrelin, leading to increased hunger and binge-eating episodes. Fat remains in the blood as triglycerides because the liver cannot process food as efficiently. It accumulates in other body parts, first in the stomach and legs, then around other organs, as visceral fat.

Moreover, when excess cholesterol is stored in the form of lipid droplets, it also damages the liver by causing mitochondria dysfunction, promoting ROS species. The lipid droplets turn into cholesterol crystals, which trigger the formation of crown-like structures, and then a vicious cycle of inflammation ensues, similar to the formation of atherosclerosis. A recent study found that it was high cholesterol and not total fat intake that was the cause of NAFLD. Another large nationwide study showed that high consumption of cholesterol, but not saturated fatty acids, raised the risk of cirrhosis. An animal model showed that a high cholesterol diet, even without other fat, will result in a fatty liver that subsequently will lead to more severe liver inflammation and fibrosis called NASH.

Both animal and human studies strongly suggest dietary cholesterol may contribute to the transition from NAFLD to NASH. When cholesterol and its esters accumulate in a hepatocyte, its functions become impaired, and oxidative stress and endoplasmic reticulum stress make it more susceptible to necrotic death. When the cell dies, Kupffer cells gather around it, releasing pro-inflammatory signals that promote inflammation and fibrosis. PMID: 31595236

Emerging evidence shows that hepatic macrophages contribute to NASH severity. Prolonged high dietary cholesterol is shown to induce long-lasting liver damage and expansion of a dysfunctional macrophage population even after cholesterol reduction. PMID: 36159810

Dietary cholesterol drives NAFLD by inducing gut microbiota alteration in mice. Cholesterol inhibitory therapy and gut microbiota manipulation may be effective strategies for NAFLD prevention. PMID: 32694178

Damage to pancreas

Cholesterol accumulation in pancreatic islets (group of cells) causes beta cell dysfunction and death, which in turn impairs insulin secretion, disturbing glucose metabolism as beta cells are the only cells able to synthesize and secrete insulin. When the pancreas no longer produces enough insulin. The result is higher blood glucose levels and, ultimately, type 2 diabetes. Having high blood sugar levels for long periods of time can result in permanent damage to parts of the body, such as the eyes, nerves, kidneys, and blood vessels. 

A meta-analysis with 4513 pancreatic cases showed results suggesting that cholesterol intake level was significantly associated with the risk of pancreatitis, with the risk rising by 8% with 100 mg/day of cholesterol intake.

Low levels of HDL cholesterol and increased LDL and total cholesterol levels were connected to increased levels of proinflammatory cytokines causing cellular inflammation. PMID: 25649888

Another meta-analysis of 21 studies showed that a dose of cholesterol-lowering drug statin reduced the risk of pancreatic inflammation by 23 % in 113,800 individuals compared with placebo. The researchers finding published in Clinical Gastroenterology and Hepatology demonstrated that statins reduce the risk of developing diabetes after acute pancreatitis by 42%. PMID: 35750248

Kidney Dysfunction 

In a recent study, people with high cholesterol displayed an increased risk of chronic kidney disease (CKD). When kidney cells (podocytes) responsible for filtration have an accumulation of cholesterol, they do not function well, causing toxins to be retained in the body. A study has shown that exposing human kidneys to excess cholesterol for 6 days promotes cell death and induces high stress within the cell.  PMID: 26557843, PMID: 25306260

It is scientifically supported that cholesterol induces toxicity in the kidney. A meta-analysis of 59 studies on the use of statins showed that they slowed the decline of the glomerular filtration rate in CKD. Another LDL-lowering drug that physically removes the cholesterol from the bloodstream reduced albuminuria and podocyte cell death in people with renal problems.PMID: 26905361

Induces Alzheimer's disease

Studies have strongly suggested a connection between cholesterol and Alzheimer's disease. 

Alzheimer's disease is a progressive neurodegenerative disorder during which neuron connections start to break down, and brain regions begin to shrink, leading to cognitive and behavioral problems. Development of dementia in Alzheimer's disease starts with mild cognitive impairment, and the evidence has shown that early exposure to elevated cholesterol may be a risk factor for it. A study of patients with Familial hypercholesterolemia (a genetic disorder where the body cannot remove cholesterol from the blood) had a much higher rate (21.3%) of mild cognitive impairment compared to those without familial hypercholesterolemia (2.9%). PMID: 20193836

Alzheimer's disease is characterized by the presence of amyloid β plaques, inflammation, and loss of cognitive function. A well-functioning blood-brain barrier is crucial for the removal of waste such as beta plaques.

Compared to any other tissue, the brain is highly enriched in cholesterol, which is produced on-site by the brain cells. Most (but some can) dietary cholesterol cannot cross the blood-brain barrier, but it can damage its integrity. PMID: 32925052 

The blood-brain barrier protects neurons and maintains the highly regulated brain environment required for proper brain functioning. When the integrity of the blood-brain barrier is disrupted, neurotoxins, debris, cells, and microbial pathogens can get in, causing inflammation, which can lead to neurodegeneration. Neuroimaging studies have shown early blood-brain barrier dysfunction in Alzheimer's disease and other neurodegenerative disorders. 

The human brain has about ~400 miles of blood vessels that supply brain cells with oxygen, energy, and nutrients while removing carbon dioxide and other metabolic waste products from the brain to the systemic circulation. Beta-amyloid or "Senile plaques" are considered to play a central role in Alzheimer's disease. Amyloid plaques are sticky deposits of the amyloid beta protein, mainly in the brain's grey matter between nerve cells. Cholesterol buildup increases amyloid beta production, which fuels plaque accumulation. Normally, cholesterol is kept quite low in neurons, limiting the buildup of amyloid beta. However, in Alzheimer's, the neurons lose their ability to regulate amyloid beta, resulting in plaque formation PMID: 12874399; PMID: 16866911; https://doi.org/10.1073/pnas.2102191118; PMID: 26141492

Increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease. Abnormal cholesterol homeostasis causes an increased concentration of it in the neurons, leading to their death and atrophy in the hippocampus. PMID: 34385305

Hypercholesterolemia is an early risk factor for Alzheimer's disease. A study on deceased subjects ages 40-55 years old found that increases in cholesterol from 181 to 200 almost tripled the odds of developing amyloid deposits in the brain. This confirmed that Although dementia is usually a late-life syndrome, the pathological changes begin quite early in adulthood PMID: 12874399

Early exposure to elevated cholesterol may be a risk factor for mild cognitive impairment. A study of patients with Familial hypercholesterolemia (a genetic disorder where the body cannot remove cholesterol from the blood) had a much higher rate (21.3%) of mild cognitive impairment compared to those without familial hypercholesterolemia (2.9%). PMID: 20193836

Statins easily cross the blood-brain barrier and have been proposed as potential neuroprotectors. Animal studies have shown that statins may ameliorate cognitive disorders. Also, reduced membrane cholesterol levels in nerve terminals may protect neurons under stress conditions PMID: 32445746 PMID: 20633110 PMID: 22713486

The blood-brain barrier is a continuous endothelial membrane within brain microvessels. It protects neurons from factors present in the systemic circulation and maintains the highly regulated environment required for proper synaptic and neuronal functioning. The blood-brain barrier disruption allows influx into the brain of neurotoxic blood-derived debris, cells, and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. PMID: 29377008

Pituitary- Thyroid Dysfunction

The link between high cholesterol and hypothyroidism has been long established.

A cohort study of the Chinese population study showed that patients with mild hypothyroidism who had high cholesterol had a significantly higher risk (6-15 times) of progressing to overt hypothyroidism (severe) than those with normal cholesterol. A consecutive study that employed the use of statins observed an increased remission of 50% of mild hypothyroidism in comparison with the control group -15.38%. PMID: 28302959 

Thyroid hormones regulate lipid metabolism, including TC. Lipid profiles can influence the prevalence of hypothyroidism as lipid disorders such as elevated cholesterol were witnessed even in subclinical hypothyroidism patients. 

A study measuring a correlation between thyroid dysfunction and total plasma cholesterol reported a dramatic increase in subclinical hypothyroidism from 4.0% to 10.3% in women with total cholesterol (TC) higher than >309.4 mg/dL. They also observed that the occurrence of overt hypothyroidism increased as total cholesterol rose in both sexes. Mild hypothyroid subjects with total cholesterol between 201.0- 240.0 mg/dL had a five times greater risk of developing overt hypothyroidism compared with patients with TC <201.0 mg/dL. The risk was 15 times greater in patients with TC >240.0 mg/dL. PMID: 10396365

Abnormal accumulation of cholesterol negatively impacts the pituitary thyroid axis, disrupting the levels of hormones. Several animal studies showed that the high-cholesterol diet increased the levels of hormones such as TSH, LH, and FSH. The rats developed hypercholesteremia (but not hypertriglyceridemia) as well as increased cholesterol and cell size of the aforementioned serums in the anterior pituitary gland.

Besides, previous studies demonstrated that cholesterol was a major component of the endoplasmic reticulum (ER), and excess cholesterol could induce ER stress, which was associated with thyroid dysfunction. Thus, the abnormal synthesis of thyroid hormones caused by the above mechanism contributed to the hypothyroidism progression. PMID: 12829694

Testosterone deficiency

Testosterone is an important steroid hormone we produce from the cholesterol our cells naturally make, not from the dietary cholesterol we consume. The biosynthesis starts in testicular cells, where progesterone is produced and then converted to testosterone. Testicular Leydig cells are the primary source of testosterone in males. Recent animal studies suggest that high dietary cholesterol intake leads to the accumulation of cholesterol in the testis, downregulating the enzymes and disturbing the testosterone synthesis pathway. PMID: 30884106

Chinese and US population studies found lower testosterone levels were associated with higher total cholesterol and triglyceride levels. Conversely, higher testosterone levels were associated with higher HDL cholesterol. PMID: 18097527; PMID: 24394726 

Excess cholesterol accumulation may cause osteoporosis. 

Cholesterol plays a very important role in bone metabolism; High levels of cholesterol tend to decalcify bones. Vitamin D maintains bone calcification, and a study on the Spanish population showed an association between high cholesterol levels and low Vit D. Although few participants in the study were being treated with statins, serum vitamin D was significantly higher among those taking statins. PMID: 24516690

A cross-sectional study on the Amish population tested their hypothesis that hyperlipidemia may be a common predisposing factor to both atherosclerotic heart disease and bone fragility. The results of the study provided evidence to support the role of high cholesterol in lowering bone mineral density PMID: 24106285.

Multiple studies have reported that high cholesterol, triglycerol, or LDL have a negative influence on bone mineral density in the spine and total body. Men were more affected by this than pre and postmenopausal women. PMID16400063

Those with the largest increases in serum cholesterol showed the greatest decreases in spine bone mineral density regardless of their BMI. PMID: 12584030

After adjustment for BMI and age, a study with 1303 postmenopausal women also reported a higher risk of osteopenia for participants with higher plasma LDL concentrations. Postmenopausal women with increased plasma LDL cholesterol levels had a greater probability of being classified as osteopenic than women with normal plasma LDL cholesterol levels. Our data, if confirmed, suggest that elevated levels of plasma LDL cholesterol should be regarded as an additional risk factor for reduced bone mineral density. PMID: 14672464

Cholesterol and its waste products reduce bone mineralization by inhibiting the functions of osteoblasts and thereby induce reduced bone mineralization. Studies have shown that oxidized lipids inhibit osteoblastic differentiation from preosteoblasts in vitro and bone formation in vivo. Products of lipoprotein oxidation inhibit preosteoblast differentiation and result in reduced bone mineralization. Several studies indicated that statins, which are widely used as lipid-lowering agents, seem to provide benefits in the prevention of bone loss and fractures. 

This experimental model demonstrates that high cholesterol increases joint tissue damage in chronic arthritis, with foam macrophages being key players in this process. PMID: 23941259

Although few participants in our study were being treated with statins, serum vitamin D was significantly higher among those taking statins.

High cholesterol levels are a risk for osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease in which the tissues in the joint break down over time. It is a complex systemic disease involving problems with bone cell differentiation as well as lipid deposits in bone tissues. 

Osteoarthritis is the most common form of age-related degenerative whole-joint disease, primarily characterized by cartilage destruction and synovial inflammation. Osteoarthritis patients have been shown to have excessive cholesterol in the synovial fluid as well as a high concentration of fatty acids in joint cartilage. Synovial fluid is a thick fluid that lubricates and reduces friction between joints. Lipid levels are extremely low in normal human Synovial fluid. It has been well documented that inflammatory arthritis patients had a high concentration of cholesterol in their synovial fluid. HDL, however, had an anti-inflammatory effect, reducing pro-inflammatory proteins. PMID: 22037510 

Because an excessive accumulation of free cholesterol is toxic for the cells, this is tightly regulated in most cells. Genes responsible for cholesterol outflow were significantly lower in osteoarthritic cartilage compared to normal. Chondrocytes (cartilage cells) with osteoarthritis had lipid deposits within them. PMID: 20108316

Hypercholesterolemia, being a risk factor for atherosclerosis, plays a role in the development of OA. This was shown in the study done on mice fed a high-cholesterol diet, leading them to develop osteoarthritis on the inner side of the joint PMID: 23625977

Current information also suggests that mitochondria dysfunction and oxidative stress may be the major mechanism of cholesterol-induced chondrocyte disorder. Mitochondria dysfunction and elevated ROS production were found in human articular chondrocytes treated with high cholesterol.

In a study (animal model) that tried to determine how high cholesterol affects the progression of osteoarthritis, doses of cholesterol caused cell dysfunction, a high number of reactive oxygen species, degeneration, and breakdown of the cartilage. These high cholesterol diet-induced changes were resolved when statin medicine and an antioxidant were used. The antioxidant that targeted cell mitochondria was able to stop oxidative damage to restore homeostasis to the cells found in the bone cartridge. Hypercholesterolemia has been shown to cause osteoarthritis to progress rapidly. PMID: 27737897

In the Osteoarthritis Initiative (OAI) 8-yearlong study, statin use was shown to be associated with reduced risk of knee osteoarthritis joint space narrowing progression in patients with nodal osteoarthritis. PMID: 31502936

Excess cholesterol causes Atherosclerosis and induces Immune System dysfunctions.

 Autoimmune diseases like SLE and RA are associated with reduced plasma HDL levels.

Cholesterol induces the foaming of macrophages, causing the formation of plaque in the arterial walls. The high-density lipoprotein (HDL) prevents the accumulation of cholesterol by returning it to the liver; however, having high cholesterol, elevated inflammation in the body, and/or high blood pressure inhibits this process. Circulating HDL and its major protein -apolipoprotein A-I, protect against atherosclerosis by promoting a process in which excess cholesterol from tissues is transported back to the liver to be metabolized and excreted. HDL also regulates cholesterol bioavailability in the plasma membrane, which affects the cell's immune response. Furthermore, a compound carried by HDL has a role in the development of several immuno-inflammatory disorders as it modulates macrophage and lymphocyte functions. In humans, HDL levels and functions are negatively altered in several immune disorders, such as lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn's disease, and Multiple Sclerosis, as well as during inflammatory responses. PMID: 20018934

Patients with autoimmune diseases, including SLE and RA, have a higher incidence of atherosclerosis and are at significant risk of premature cardiovascular disease.  

Accelerated atherosclerosis occurs in patients with autoimmune disorders, and data suggest that immune dysregulation during SLE and similar disorders promote atherogenesis (formation of fatty plaques in the arteries). Findings also indicate an interaction between atherogenesis and autoimmune disease. High lipids in the blood may contribute to the severity of autoimmune disease by promoting the accumulation of apoptotic debris PMID: 123753219; PMID: 28479366

Chronic inflammation in the cell plays an important role in the progression of atherosclerosis; lesions occur as a result of injury to the endothelium by oxidized low-density lipoprotein (Ox-LDL), inflammatory cytokines, and immune complexes. Mice fed a high cholesterol Western versus normal diet developed higher levels of apoptotic (dead) cell debris in lymph nodes and a lower number of macrophages that ingest that debris. The Western diet also increased circulating autoantibody (antibody directed at its own body) levels and caused an abnormal size of lymph nodes and spleen enlargement. Lysophosphatidylcholine (LPC) is a bioactive pro-inflammatory lipid. It is also a component of Ox-LDL, and it is believed to play an important role in atherosclerosis and inflammatory diseases by altering various functions in a number of cell types, such as endothelial cells, smooth muscle cells, monocytes, macrophages, and T-cells. Constant infusion of LPC in mice was shown to interfere with apoptotic cell clearance. LPC is the “find me “signal dying cells send out to phagocytes that clear them. Hence, high levels of LPC caused by high cholesterol might interfere with signals that are required for the normal clearance process. PMID: 18220755

In patients with systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic systemic inflammation, there is an increase in uncleared apoptotic cells in lymph nodes suggesting failed clearance PMID: 11817590

Apoptotic cells interact with their engulfing phagocytes to generate important immune responses, and modulation of such responses can influence pathology. Every day, billions of cells in the body undergo apoptosis, which is a programmed death necessary for the normal functioning of our organism. Phagocytes are white blood cells that engulf such apoptotic cells as well as bacteria, pathogens, and other debris. Uncleared dead cells lose their membrane and release their contents, which may result in systemic inflammation. Moreover, when phagocytes consume apoptotic cells, they produce anti-inflammatory cytokines, inhibiting the release of pro-inflammatory cytokines. All this is very important to reduce immune responses and suppress local inflammation. Correct clearing of apoptotic cell debris from tissues is essential in an organism to maintain homeostasis. When this removal is interrupted, immune system functioning becomes disturbed, which can affect cancer progression as well as cause various inflammation-associated disorders such as autoimmunity, atherosclerosis, and airway inflammation. Recent studies have shown that the clearance process can also influence how our immune system responds to tumors. PMID: 27558816

Defects in the engulfment of apoptotic cells often result in systemic inflammation, causing autoimmunity.

It is difficult to ascertain the connection between cholesterol and disease severity in patients because most are treated with steroids; nonetheless, an analysis of young SLE patients not treated with medications determined that hyperlipidemia (abnormal amounts of triglyceride and cholesterol) was associated with the disease. PMID: 15096538.

Moreover, cholesterol-reducing diet programs have been shown to improve the quality of life in patients with SLE. PMID: 12375321

Statins that lower cholesterol have been shown to lessen physical symptoms and improve executive functions in patients with secondary progressive multiple sclerosis. A clinical trial on the safety and efficacy of statin for MS had shown a significant reduction of inflammatory lesions in the brain in patients with relapsing MS. PMID: 29392731

The treatment of hypercholesterolemia must include nonpharmacological measures, which are recommended for all patients, as well as the use of pharmacological therapy that may be indicated in specific situations.10 The drugs currently available for the treatment of hypercholesterolemia include statins (hydroxy-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors), ezetimibe (a selective inhibitor of cholesterol absorption), and resins or bile acid sequesters. Statins should be used as the first choice due to their powerful effect on LDL-cholesterol reduction (25-55%) and because they are the most study-validated drugs for the reduction of cardiovascular events. Ezetimibe has a moderate effect on LDL-cholesterol reduction (15-25%). Resins may be associated with statins when the target LDL-cholesterol is not achieved despite the use of statins, leading to a reduction of 30% in LDL-cholesterol levels.4,8,10 —-sources and finish

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