Synthesis
Mevalonate pathway
Cholesterol’s synthesis pathway overlaps with the synthesis of ketone bodies. The steps of this process include:
- Thiolase catalyzes the joining of 2 acetyl-coenzyme A (CoA; precursor) molecules → acetoacetyl-CoA
- 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) synthase adds another acetyl-CoA → β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)
- HMG-CoA reductase → mevalonate:
- Critical role in cholesterol synthesis
- Only regulated enzyme step in the process (feedback inhibition by cholesterol)
- Target for cholesterol-lowering medications ( statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins)
- Mevalonate → isoprenoid precursors (by decarboxylating mevalonate):
- Isopentenyl pyrophosphate (IPP)
- Dimethylallyl pyrophosphate (DMAPP)
- IPP and DMAPP are combined → geranyl pyrophosphate (geranyl-PP)
- Another IPP is added → farnesyl pyrophosphate (farnesyl-PP)
- 2 farnesyl-PP molecules are joined → squalene
- Squalene is modified → lanosterol (Note: Acetyl-CoA is the exclusive building block up to this point.)
- Lanosterol → cholesterol
- 19 steps
- Requires a great deal of energy
The synthesis of cholesterol by the mevalonate pathway:
Image by Lecturio.
The number of carbons within each chemical structure is noted to the left.
ER: endoplasmic reticulum
HMG-CoA: 3-hydroxy-3-methyl-glutaryl-coenzyme A
PP: pyrophosphatase
Diagram showing the steps of the mevalonate pathway in the synthesis of the isoprenoid precursors, which are the building blocks of cholesterol:
Image by Lecturio.
HMG-CoA: 3-hydroxy-3-methyl-glutaryl-CoA
Diagram showing the steps of the mevalonate pathway from the isoprenoid precursors to lanosterol
Image by Lecturio.
Diagram numbering the rest of the steps needed for the transformation of lanosterol into cholesterol:
Image by Lecturio.
The image provides a good comparison between the 2 molecules. Note how the cyclical structures are maintained throughout the conversion process.
Importance
Cholesterol is a:
- Precursor to:
- Bile acids
- Steroid hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview
- Vitamin D
- Component of cell membranes
Transport and Uptake
Basics of lipoproteins
- Function: transport of different lipids between target cells
- Cholesterol
- Fatty acids
- Triacylglycerol (triglyceride)
- Composition:
- Triglyceride
- Cholesterol
- Cholesterol esters
- Phospholipids
- Proteins (apoproteins (apo) A, B, C, and E)
- Types of lipoproteins (in order of density):
- Chylomicrons
- VLDL
- IDL
- LDL
- HDL
- Lipoprotein density:
- Chylomicrons are the least dense.
- ↑ Triglyceride content
- ↓ Protein content
- HDL is the densest.
- ↓ Triglyceride content
- ↑ Protein content
- Chylomicrons are the least dense.
Composition of lipoproteins
| Lipoprotein | Cholesterol/ cholesterol ester |
Triglyceride | Protein | Phospholipid |
|---|---|---|---|---|
| Chylomicrons | 1%/3% | 85% | 2% | 8% |
| VLDL | 7%/10% | 55% | 9% | 20% |
| IDL | 8%/30% | 26% | 11% | 22% |
| LDL | 10%/35% | 10% | 20% | 20% |
| HDL | 4%/12% | 5% | 45% | 25% |
Transport
- Emulsification of cholesterol with bile salts in the intestine → emulsion travels through the intestinal wall
- Cholesterol and triglycerides are packaged as chylomicrons (synthesized in intestinal epithelial cells):
- Travel to the lymphatic circulation → bloodstream → capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries
- Chylomicrons lose some of their contents → chylomicron remnants
- Apo C activates lipoprotein lipase (LPL) → triglycerides are digested to fatty acids
- Most commonly occurs in muscle and adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue
- Chylomicron remnants travel to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver → contents are stored
- Liver can package and release these contents as VLDL into the bloodstream:
- Travels to peripheral tissue
- VLDL loses some of its contents (again, via LPL) → converted to IDL
- IDL can either:
- Travel to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver → degraded
- Convert to LDL in peripheral circulation
- LDL taken up by various cells → digested → cholesterol released
- HDL produced by the
liver
Liver
The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood.
Liver:
- Scavenges lipid components, especially cholesterol, from:
- Cell membranes
- Other lipoproteins
- Lecithin:cholesterol acetyltransferase (LCAT) converts cholesterol → cholesterol esters
- Cholesterol esters are transferred to other lipoproteins → transported to the
liver
Liver
The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood.
Liver to either be:
- Packaged with VLDL
- Converted to bile acids → excreted
- Scavenges lipid components, especially cholesterol, from:
Movement of cholesterol throughout the body:
Movement in the blood is highlighted in green.
FFA: free fatty acid
Cellular uptake
Mechanism:
- LDL binds to cell surface receptor
- Clathrin-mediated endocytosis → brings cholesterol into cells
- Low pH in endosome-lysosomes → LDL released from receptor
- LDL receptor is recycled → returns to the cell surface
- LDL is broken down by proteases and lipases.
- Cholesterol and cholesterol esterases can be:
- Used for:
- Bile acids
- Steroids
- Stored
- Used for:
Regulation:
- Within the cell, cholesterol inhibits:
- LDL receptor expression → further ↓ LDL uptake by the cell
- HMG-CoA reductase → ↓ cholesterol synthesis
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme:
- Secreted by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
- Binds to LDL receptors → promotes LDL receptor endocytosis and degradation
Cellular uptake of LDL and regulation:
Image by Lecturio.
Within a hepatocyte, LDL can bind with LDL receptors, allowing for endocytosis. LDL is released from the receptor, which returns to the cell surface. The LDL particle is broken down, releasing cholesterol. This cholesterol can down-regulate expression of LDL receptors and inhibit further cholesterol synthesis and can then either be stored or used (in this case, converted to bile acids).
ACAT: acyl cholesterol acyltransferase, which converts cholesterol to cholesterol esters
HMG-CoA: 3-hydroxy-3-methyl-glutaryl-coenzyme A
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme secreted by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver into the bloodstream that binds to LDL receptors (both inside and outside the hepatocyte) and subsequently promotes LDL receptor endocytosis for degradation.
Image by Lecturio.
LDL-R: LDL receptor
Excretion
- The body cannot degrade cholesterol’s ring structure → must be excreted as bile acids in the feces
- Primary bile acids (cholic acid, deoxycholic acid) are synthesized from cholesterol in the
liver
Liver
The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood.
Liver:
- 7-alpha-hydroxylase converts cholesterol → 7-alpha-hydroxylcholesterol
- Multiple steps are required to produce:
- Cholic acid
- Chenodeoxycholic acid
- Can then be conjugated with either:
- Glycine → glycocholic acid or glycochenocholic acid
- Taurine → taurocholic acid or taurochenocholic acid
- Stored in the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract
- Secreted into the intestinal lumen → aid in digestion and absorption of lipids
- Most are reabsorbed in the ileum → returned to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver through the enterohepatic circulation → inhibit further bile acid synthesis
- Some are modified by bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview → secondary bile acids → can return to enterohepatic circulation
- Approximately 5% are excreted in the feces
Chemical structures of bile acids
Image by Lecturio.Steroid Hormones
- Steroid
hormones
Hormones
Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments.
Hormones: Overview are lipophilic compounds synthesized from cholesterol and include:
- Progestins
- Estrogens
- Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
- Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
- Mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids
- Synthesized by endocrine glands:
- Gonads:
- Testes
- Ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries
- Adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands
- Gonads:
- Hormone synthesis:
- 1st step is conversion of cholesterol → pregnenolone
- Pregnenolone is then converted → progesterone
- Progesterone is the precursor to other hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview.
- Functions:
- Sexual maturation and characteristics
- Metabolism
- Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and immune function
- Salt/water balance
- Blood pressure regulation
Overview of the steroidogenesis pathways:
Cholesterol is initially converted to pregnenolone and then to progesterone. From there, the pathway diverges, with many potential end products, including glucocorticoids, mineralocorticoids, androgens, and estrogens.
Image by Lecturio.
Diagram showing a simplified version of the synthesis pathways of steroid hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview
Image by Lecturio.
| Synthesis location |
Class | Primary hormone | Functions |
|---|---|---|---|
| Adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands | Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids | Cortisone |
|
| Mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids | Aldosterone |
|
|
| Gonads | Progestins | Progesterone |
|
| Estrogens | Estradiol | Sexual development, differentiation, and maturation of primary and secondary sex characteristics | |
| Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens | Testosterone |
Clinical Relevance
- Statins: competitive inhibitors of HMG-CoA reductase in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Indications for prescribing include prevention of primary or secondary cardiovascular disease in individuals with dyslipidemia.
- PCSK9 inhibitors: monoclonal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins to PCSK9, which block binding of this enzyme to LDL receptors. This binding prevents degradation of the LDL receptors, allowing for increased LDL cellular uptake and clearance from the bloodstream. For this reason, PCSK9 inhibitors are prescribed for hyperlipidemia.
- Dyslipidemia: commonly occurs as high plasma cholesterol and/or triglycerides. There are many potential etiologies, including genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics, dietary intake, medications, and medical conditions (e.g., diabetes, CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease, hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism). Sequelae may include cardiovascular disease, stroke, pancreatitis, and hepatic steatosis.
- Atheroslerosis: common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis manifests as vessel stenosis and a source of thromboembolic disease. The clinical manifestations depend on the specific vessels affected and include, most notably, coronary artery disease, carotid disease, and peripheral vascular disease.
References
- Botham KM, Mayes PA. (2018). Cholesterol synthesis, transport, & excretion. Chapter 26 of Rodwell BW, Bender DA, Botham KM, Kennelly PJ, Weil PA (Eds.), Harper’s Illustrated Biochemistry, 31st ed. McGraw-Hill Education. Retrieved from accessmedicine.mhmedical.com/content.aspx?aid=1160189958
- Chumsri S, Howes T, Bao T, Sabnis G, Brodie A. (2011). Aromatase, aromatase inhibitors, and breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer. Journal of Steroid Biochemistry and Molecular Biology 125:13–22. https://doi.org/10.1016/j.jsbmb.2011.02.001
- Alphonse PA, Jones PJ. (2016). Revisiting human cholesterol synthesis and absorption: the reciprocity paradigm and its key regulators. Lipids 51:519–536. https://doi.org/10.1007/s11745-015-4096-7
- Luo J, Yang H, Song BL. (2019). Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol 21:225–245. https://doi.org/10.1038/s41580-019-0190-7
- Infante RE, Radhakrishnan A. (2017). Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol. Elife. https://doi.org/10.7554/eLife.25466
- Robinson JG. (2020). Disorders of lipid metabolism Lipid Metabolism Lipid metabolism is the processing of lipids for energy use, energy storage, and structural component production. Lipid metabolism uses fats from dietary sources or from fat stores in the body. A complex series of processes involving digestion, absorption, and transport are required for the proper metabolism of lipids. Lipid Metabolism. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine, 26th ed. Elsevier.
