Authors: Payal Bhandari M.D, Tejal, Madison Granados 

Contributors: Vivi Chador, Amer Džanković, Hailey Chin 

Key Insights 

A lipid panel measures cholesterol to assess heart disease risk. Cholesterol, made by the liver, intestines, adrenal glands, and gonads, helps produce hormones, bile, vitamin D, and energy.

Cholesterol moves through two pathways: the exogenous pathway carries dietary fats to the liver, while the endogenous pathway transports liver-made lipids to tissues. Lipoproteins (VLDL, LDL, HDL) help carry these fats, with higher density meaning more protein and less fat.

High LDL, TG, and VLDL with low HDL can cause plaque buildup, blood clots, and high blood pressure. Managing cholesterol through diet, exercise, stress control, and, if needed, medication, can prevent heart disease, infections, cancer, and organ damage.

What Are LDL Cholesterol and VLDL Cholesterol?

LDL and VLDL are key lipid panel biomarkers, measuring blood cholesterol and triglycerides. VLDL carries triglycerides and cholesterol, while LDL mainly transports cholesterol to tissues. The liver produces VLDL, some of which converts to LDL. High LDL can lead to atherosclerosis by depositing on blood vessels and causing inflammation. Monitoring these levels helps assess fat metabolism, plaque buildup, and disease risks.

What are LDL-Particles?

The LDL-P test, using NMR, predicts atherosclerosis better than total LDL cholesterol. Small, dense LDL-P, linked to high TG and low HDL, stay in the blood longer, easily enter arteries, and cause plaque and inflammation. Larger LDL-P bind to receptors better, circulate less, and have a lower risk .

Figure 1: LDL particle size inversely correlates with CHD risk. Traditional tests can’t distinguish between large and small LDL. Small LDL binds poorly to liver receptors, stays longer in circulation, oxidizes easily, and penetrates arteries, causing inflammation, plaque, clots, and new vessels.

What is Lipoprotein (A)? 

Lipoprotein(a) [Lp(a)] is a genetic risk factor for atherosclerosis, unaffected by diet or exercise. It binds to LDL, promoting inflammation, plaque, and clots in injured vessels. Poor liver clearance thickens blood, raises pressure, and reduces oxygen delivery, increasing heart attack, stroke, and organ damage risks. Lp(a) is a key marker for early atherosclerosis detection and treatment, even with normal cholesterol 37 36. 

Origin of Cholesterol

Cholesterol and lipids include mono- and diglycerides, phospholipids, sterols, and free fatty acids (FFA), made of carbon, hydrogen, and oxygen. Triglycerides, the main fats, consist of a glycerol backbone and three fatty acids. Saturated fats have no double bonds, while unsaturated fats have one or more.

The body produces most cholesterol, with only a small amount from food like dairy, meat, eggs, fish, and cooking oils. About 20–25% of cholesterol is made in the liver, with 75–80% produced in the small intestine, adrenal glands, and reproductive organs. 

Figure 2: Lipid (Cholesterol) Structure

Figure 3: Lipoproteins are complex particles with a central core containing cholesterol esters and triglycerides surrounded by free cholesterol, phospholipids, and apoproteins, which facilitate lipoprotein formation and function1.

Figure 4: Plasma lipoproteins are classified into seven types: chylomicrons, chylomicron remnants, VLDL, IDL, LDL, HDL, and Lipoprotein(a). Chylomicron remnants, VLDL, IDL, LDL, and Lp(a) are pro-atherogenic, while HDL is anti-atherogenic 1. Since cholesterol and triglycerides are water-insoluble, they bind to apoproteins for transport in the blood. Apoproteins help form lipoproteins and regulate enzymes involved in their metabolism 1.

Regulation of VLDL Cholesterol Synthesis

Peripheral Tissue Cholesterol Synthesis

Peripheral tissues produce about 9 mg/kg of cholesterol daily with less regulation than the liver, which adjusts to dietary, hormonal, and physiological factors.  Around 600–800 mg of cholesterol moves from tissues to the liver for metabolism via reverse cholesterol transport (RCT). This process is regulated by6 SREBPs, which activate cholesterol synthesis when levels are low; LDLRs, which regulate LDL uptake; and LXRs, which promote cholesterol removal to the liver, activated by oxysterols pairing with RXRs.

De Novo Cholesterol Synthesis in the Liver

During fasting or exercise, the body shifts from glucose to fat and protein for energy. The liver regulates cholesterol synthesis and breaks down glycogen, triglycerides, and amino acids to produce glucose or ketones. Glucagon and catecholamines activate lipoprotein lipase (LPL) to convert triglycerides into ketone precursors. HMG CoA synthase forms acetoacetate, which converts to beta-hydroxybutyrate for energy, while some acetoacetate becomes acetone and is exhaled . The liver processes VLDL, NEFAs, lactate, and glycerol, while muscles release proteins and alanine to support energy production.

Figure 5: Circadian rhythm genes regulate liver glucose and ketone synthesis, using fatty acids, amino acids, and glycerol for energy. Ketogenesis, producing ~34 ATP per cycle, stabilizes blood glucose and fat stores, enhances insulin and leptin sensitivity, reduces brain reliance on carbs, and alleviates hunger, mood issues, and inflammation.

Regulation of LDL Cholesterol Synthesis 

LDL cholesterol, or “bad” cholesterol, is mostly cleared by liver LDL receptors (LDLR), which help control its levels and reduce atherosclerosis risk . High LDLR levels lower LDL and IDL cholesterol in the blood, while low LDLR levels raise LDL, causing it to build up in blood vessels and organs. LDLR production increases when liver cholesterol is low and decreases when it’s high. Oxidized LDL and reactive oxygen species (ROS) damage LDLR, leading to inflammation and atherosclerosis.

Figure 6: The LDL receptor pathway links liver cholesterol levels to atherosclerosis risk. High liver cholesterol lowers HMG CoA reductase and LDL receptor production while increasing cholesterol storage. Low liver cholesterol boosts HMG CoA reductase, LDL receptors, and VLDL conversion to LDL. More LDL receptors lower blood LDL, reduce cholesterol oxidation, and support liver and vascular health.

Regulation of Cholesterol Metabolism

Cholesterol metabolism is separate in the brain and body, divided by the blood-brain barrier. The body balances cholesterol from food, liver production, and excretion, while the brain relies on liver-made cholesterol. Glucagon activates an enzyme to break down fat, releasing fatty acids that travel to muscles and organs for energy or storage. In digestion, triglycerides mix with bile, cholesterol, and vitamins, forming chylomicrons that move to the liver. The liver also processes VLDL into LDL, with lower-density lipoproteins containing more fat and less protein. 

In the small intestine, most fatty acids come from dietary fat, while cholesterol mainly comes from bile salts (800–1200 mg vs. 200–500 mg from diet). Chylomicron (CM) size depends on fat intake; more fat leads to larger CMs, increased VLDL synthesis, and higher LDL levels. During fasting, fatty acids are used for energy, reducing liver triglycerides, VLDL size, and LDL levels . 

After a meal, VLDL triglycerides are 44% from plasma FFAs, 10% diet-derived, 15% from CM remnants, and 8% from cholesterol synthesis. During fasting, 77% of VLDL comes from plasma FFAs and 4% from cholesterol synthesis.

Figure 7: Cholesterol Synthesis and Regulation. Multiple enzymes are involved for acetyl CoA to undergo numerous reactions and form cholesterol. It is then converted to various steroid hormones, bile salts, vitamin D, and oxysterols (oxidized form of cholesterol), as well as incorporated into lipoproteins and an integral part of cell membranes.  

Role of Cholesterol in the Body 

Cholesterol maintains cell structure, fluidity, signaling, and communication. It supports skin, hair, temperature regulation, and organ protection. At low temperatures, it prevents lipid packing, while at high temperatures, it reduces membrane fluidity. Cholesterol also synthesizes steroid hormones, vitamin D, bile acids, and aids lipid and fat-soluble vitamin digestion for energy (ATP) production.

Cholesterol is an Integral Part of Cell Membranes

Figure 8: The cell membrane is a phospholipid bilayer with proteins and carbohydrates, where polar heads face outward and nonpolar tails form a hydrophobic barrier. It controls molecule transport, maintains structure, and regulates fluidity through cholesterol and tail saturation, essential for movement and stress response.

Cholesterol is an Integral Part of Synthesizing All Steroid Hormones

Figure 9: Liver cytochrome P450 enzymes convert cholesterol into steroid hormones, including aldosterone, cortisol, androgens (testosterone, progesterone, estradiol), and DHEA. Defects in this process can disrupt hormones, causing conditions like PCOS or hypogonadism. High cholesterol can increase aldosterone, cortisol, and estradiol while lowering DHEA and testosterone.

Cholesterol is the Precursor for Bile Salt Production

Figure 10: Cytochrome P450 enzymes in the liver convert cholesterol derivatives into bile salts, conjugate bilirubin, and synthesize acids like cholic and chenodeoxycholic acid. Bile is stored in the gallbladder or released into the intestine, where bacterial enzymes deconjugate it to deoxycholic and lithocholic acids. 

Bile acids are 80% organic, with the rest being cholesterol and phospholipids. Bile salts aid in digesting and transporting dietary fats, oils, and fat-soluble vitamins (A, D, E, K) to tissues. They also remove excess cholesterol, protecting cells from oxidative stress. 

Cholesterol is the Precursor for vitamin D Production

Vitamin D is an essential micronutrient with hormone-like functions. There are two major dietary forms of vitamin D: 

1. vitamin D2 (ergocalciferol) is produced by plants and yeast 

2. vitamin D3 (cholecalciferol) is produced by animals

Figure 11: Cholesterol is used to synthesize vitamin D3. Cholesterol is converted to 7-dehydrocholesterol in the skin and then to vitamin D3 with UV-B sunlight. D3 binds to vitamin D-binding protein or chylomicrons and travels to the liver, where 25-hydroxylase forms 25-hydroxy vitamin D [25(OH)D], the primary marker for vitamin D status.

Cholesterol is an Antioxidant

Figure 12: Oxidation of cholesterol to oxysterols activates Liver X receptors (LXRs), facilitating excess LDL removal from cells and tissues to the liver and spleen for destruction. Oxysterols also aid steroid hormone synthesis. Low oxysterol levels trigger SCAP to transport SREBPs, increasing LDL synthesis. Excess oxysterols inhibit SCAP, reducing cholesterol synthesis, and are stored in bile or excreted via urine or stool . 

Oxysterols act as antioxidants, protecting tissues from oxidative stress. When toxins like bacterial byproducts accumulate, oxysterols help store them in fat, shielding organs. Toxins are later expelled via stool, urine, sweat, sebum, bloodletting, or hair growth. 

Clinical Significance of Monitoring Abnormal VLDL and LDL Cholesterol, Lipoprotein (A), and LDL-Particle Levels 5 

Figure 13: Extremely high or low cholesterol can cause multi-organ damage (brain, liver, kidneys, bones, joints, glands) leading to hormonal imbalances, infections, cancer, osteoporosis, osteoarthritis, diabetes, and vascular diseases.

Hyperlipidemia, or high blood lipids, results from poor lifestyle habits, leading to excess fat storage and metabolism issues . It involves high TG, VLDL, LDL, and low HDL. Low cholesterol isn’t concerning if TG, VLDL, and LDL are low and HDL is normal or high. Dysbiosis and poor circulation often cause abnormal lipid levels, as gut microbiota regulate digestion, nutrient absorption, and waste removal. Delayed stomach emptying disrupts gut bacteria, leading to deficiencies . 

Figure 14: Healthy gut microbiota maintains energy, hormonal, and metabolic balance, aiding digestion, nutrient absorption, and waste removal. Dysbiosis, a loss of healthy bacteria, disrupts metabolism, promotes pathogens, cancer cells, and foreign invaders, and alters immune responses. 

Dysbiosis disrupts metabolism, reduces protein and vitamin synthesis, and increases proinflammatory proteins and LDL, leading to hypoxia, liver fat production, and fat storage21 . Chronic dysbiosis raises ROS, causing cell damage and gene mutations . WBCs prioritize waste clearance over pathogen defense, triggering autoantibodies. Oxidative stress-induced atherosclerosis increases infection, cancer, autoimmune disease, and organ damage risks, while dyslipidemia worsens outcomes. 

The Consequences of Dyslipidemia: 

Liver Dysfunction and Damage

Figure 15:  The liver metabolizes cholesterol and proteins, synthesizes apoproteins and amino acids, and detoxifies waste. Liver dysfunction causes excess proinflammatory cholesterol and proteins, depriving organs of nutrients and oxygen. Chronic inflammation (dyslipidemia) leads to liver damage, including steatohepatitis, fibrosis, and cirrhosis.

Dysregulated Hormonal and Energy Balance Resulting in Atherosclerosis-Induced Vascular Diseases

A high-cholesterol diet increases LDL receptor expression, clearing LDL from bloodand boosting hormones like LH, FSH, and TSH. LH supports androgen production, FSH aids estrogen synthesis, and TSH enhances thyroid hormone production, raising energy and ROS levels.

1. Excess androgens (e.g., in PCOS) or long-term hormone therapy increase cholesterol, lower HDL, and promote atherosclerosis by embedding LDL in arteries .  This reduces fat metabolism, raises LDL, glucose, and insulin, and shifts fat storage to visceral fat . A 5–10% weight loss improves insulin sensitivity, PCOS, and hyperlipidemia . 

Figure 16: Atherosclerosis causes tunica intima thickening, excess clotting, restricted blood flow, high blood pressure, and blood backup in organs like the liver, heart, and pancreas. It overactivates white blood cells and platelets, forming clots and scar tissue that damage cells and disrupt metabolism . 

2. Hyperthyroidism and short-term thyroid hormone use boost fat metabolism and HDL, while long-term therapy and thyroid dysfunction increase LDL and fat storage , thereby increasing the concentration of total cholesterol and TG-rich VLDL and LDL particles in the circulation. A Chinese study found high cholesterol (>200–240 mg/dL) raises hypothyroidism risk, while statins improve remission rates .

3. Animal-based high-cholesterol diets lower enzymes needed for testosterone production, while plant-rich diets improve steroid pathways, boosting testosterone.

Autoimmune Disorders

Autoimmune diseases like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ankylosing spondylitis, Sjögren’s syndrome, polymyalgia rheumatica, periodontal disease, multiple sclerosis, and HIV/AIDS are linked to atherosclerosis-induced vascular inflammation . A meta-analysis of 111,758 patients found RA increased vascular death risk by 50%, with cardiovascular risks similar to diabetes . Lipid abnormalities are common in autoimmune conditions137: 

1. Decrease in HDL-cholesterol and apolipoprotein A-I. 

2. Elevated serum triglyceride and lipoprotein (a) levels. 

3. Decreasing total and LDL cholesterol is associated with severe autoimmune cases. 

Chronic Kidney Dysfunction and Damage

High-cholesterol diets lower HDL and increase kidney atherogenic cholesterol deposits, raising CKD risk 55. A 2020 Zhejiang study linked high triglycerides, total cholesterol, and LDL to eGFR decline and CKD incidence due to free fatty acids and reactive oxygen species causing kidney inflammation and scarring .  Lowering cholesterol with statins slows eGFR decline . A plant-based, nut, and oil-free diet also benefits CKD patients by reducing further kidney damage.

Skin Disorders 

Excess cholesterol on the skin triggers sebum production, disrupting microbiota and allowing bacteria like P. acnes to cause comedones and inflammatory disorders like acne, psoriasis, and xanthomas . Acne is linked to low HDL, high cholesterol, and androgen levels, raising risks for diabetes, gonad dysfunction, and other hyperlipidemia-related conditions. Hyperandrogenism worsens acne, causes hirsutism, and accelerates hair loss (alopecia).  The skin uses cholesterol to produce glucocorticoids, estrogen, and DHT. Excess DHT and oxysterols impair scalp hair growth and increase hair loss 128  . 

Infections

Cholesterol is vital for cell membranes, but excess atherogenic cholesterol damages cells and promotes pathogen binding, leading to chronic inflammation . Severe infections lower total cholesterol, HDL, and apolipoprotein A-I, predicting higher mortality . Infections are linked to gluconeogenesis, reduced ketogenesis, high blood pressure, obesity, and systemic inflammation. The lipid abnormalities for infections typically involves137: 

1. Decrease in HDL-cholesterol and apolipoprotein A-I 

2. Elevated serum triglyceride and lipoprotein (a) levels 

3. Decreasing total cholesterol and LDL-cholesterol 

Cancer Growth and Migration

Many studies have shown that various cancers are associated with excess total, VLDL, LDL, and triglycerides in the circulation that are ingested by tumor cells, thereby enhancing cancer growth and metastasis48. Extremely high and severely low 25-hydroxycholesterol levels are associated with lower survival rates. The following cancers have a direct correlation with dyslipidemia: pancreatic cancer , colon cancer , breast cancer (especially in overweight and obese individuals) , prostate cancer , liver cancer , lung cancer   , ovarian cancer , and chronic lymphocytic leukemia (CLL) .

Figure 17: Excess cholesterol oxidation fuels tumor growth and metastasis. Damaged vessels let tumor cells bind to cholesterol, interact with platelets, and form clots. Neutrophils protect tumor cells, aiding vessel formation and blocking natural killer (NK) cells. Inflammatory proteins from these reactions damage red blood cells, promoting infections, tumor growth, and vessel invasion.

Brain and Nerve Damage 

The brain contains high cholesterol levels, synthesized locally as lipoproteins cannot cross the blood-brain barrier . Impaired fat metabolism increases ROS, damaging the barrier and brain cells . White blood cells focus on repairs, reducing clearance of proinflammatory proteins like beta-amyloid. Excess protein deposits disrupt neurons, triggering cholesterol synthesis and mitochondrial activity, leading to neuroinflammatory and neurodegenerative disorders : 

• Learning disabilities 

• Cerebrovascular dysfunction

• Mild cognitive impairment (familial hypercholesterolemia) 

• Cognitive impairment with impaired blood-brain barrier and neuroinflammation (such as dementia 169 )

• Depression, anxiety, and other mental health disorders

Prevalence and Statistics of Abnormal VLDL and LDL Cholesterol, Lipoprotein (A), and LDL-Particle Levels

Hypercholesterolemia raises the risk of vascular diseases, autoimmune disorders, infections, cancers, and organ damage, causing 2.6 million deaths and 29.7 million disability-adjusted life years (DALYs) globally. In 2008, 39% of adults worldwide had high cholesterol (≥5.0 mmol/L), with the highest rates in Europe (54%) and the Americas (48%), where diets are rich in animal protein. Africa (22.6%) and Southeast Asia (29%) had the lowest rates due to plant-based diets. High-income countries showed over 50% prevalence, compared to 25% in low-income countries 51.

A 2018–2020 Global Diagnostics Network study of 461 million lipid results from 17 countries found cholesterol levels peaked in women at 50–59 years and men at 40–49 years 185.  Countries like Japan, Australia, Germany, and Switzerland exceeded average cholesterol levels, reflecting regional differences in diet, genetics, and healthcare practices .

Figure 18: From 2018 to 2020, global data from 17 countries showed dyslipidemia is widespread. High total and LDL cholesterol levels were linked to diets high in animal products or food poverty. Addressing social and economic factors is key to reducing hyperlipidemia in affected regions.

Conclusion

Managing dyslipidemia involves lifestyle changes like a plant-based diet, exercise, intermittent fasting, stress management, avoiding tobacco and alcohol, addressing medication side effects, and maintaining a healthy weight. Medication may help temporarily. Beyond lipid profiles, monitoring apoproteins, lipoprotein size, and concentration can better assess risks for metabolic, inflammatory, and neurological complications. Family history, age, gender, and other health factors are also crucial in determining treatment and promoting overall health.

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