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Biochemistry, Cholesterol
Micah Craig; Siva Naga S. Yarrarapu; Manjari Dimri.

Author Information and Affiliations

Last Update: August 8, 2023.

Introduction
Cholesterol is a structural component of cell membranes and serves as a building block for
synthesizing various steroid hormones, vitamin D, and bile acids. Besides their structural role
providing stability and fluidity, cholesterol also plays a crucial role in regulating cell
function.[1][2][3]

Cholesterol is a 27 carbon compound with a unique structure with a hydrocarbon tail, a central
sterol nucleus made of four hydrocarbon rings, and a hydroxyl group. The center sterol nucleus
or ring is a feature of all steroid hormones. The hydrocarbon tail and the central ring are
non-polar and therefore do not mix with water. Therefore cholesterol (lipid) is packaged together
with apoproteins (protein) in order to be carried through the blood circulation as a lipoprotein.

Fundamentals
Humans can synthesize cholesterol de novo and can also obtain it from the diet. De Novo
synthesis occurs in the liver and the intestines, each organ accounting for ~ 10% of total
cholesterol in the body. Dietary triglycerides and cholesterol are packaged together with Apo
proteins in the liver before being released into the circulation as very low-density lipoproteins
(VLDL). Packaging of cholesterol together with Apo protein is essential as the hydrophobic
nature of cholesterol makes it impossible for transportation through the blood. VLDL contains
triglycerides, cholesterol, and phospholipids. Degradation of triglycerides in VLDL results in
smaller low-density lipoproteins (LDL) that are rich in cholesterol.[4] Cholesterol-rich low-density
lipoproteins (LDLs) travel through the blood circulation. They are delivered to the peripheral
tissues, where LDL is recognized by the LDL receptors on the cell membranes and is
endocytosed via receptor-mediated endocytosis.[5] Besides LDL, high-density lipoproteins
(HDLs) carry cholesterol from the peripheral tissues to the liver in a reverse transport
mechanism to get rid of any excess cholesterol.[6]

Cellular Level
While all cells can synthesize cholesterol to a small extent, the liver is the major site of
cholesterol synthesis. The cholesterol synthesis occurs in the hepatic cytoplasm and requires
enzymes n the cytoplasm and the smooth endoplasmic reticulum (SER). The first step of
cholesterol biosynthesis involves condensing 2 molecules of acetyl-CoA to form
acetoacetyl-CoA. Next, a cytosolic enzyme HMG-CoA synthase adds a third molecule of
acetyl-CoA to acetoacetyl-CoA, making a six-carbon compound called 3-hydroxy-3-methyl
glutaryl coenzyme A (HMG-CoA). An isozyme of HMG-CoA synthase in mitochondria catalyzes
the rate-limiting reaction in ketogenesis. HMG-CoA reductase, a regulatory enzyme in the
smooth ER catalyzes the next step, which reduces HMG-CoA to mevalonate. Synthesis of
mevalonate is the key rate-limiting, committed step in the synthesis of cholesterol. A series of
reactions convert Mevalonate to 3-isopentenyl pyrophosphate, farnesyl pyrophosphate,
squalene, and lanosterol. Lanosterol then goes through another19-step ER-associated process
to finally synthesize cholesterol. The terminal step is catalyzed by 7-dehydrocholesterol
reductase that converts 7-dehydrocholesterol to cholesterol.[7]

Molecular Level
Cholesterol synthesis is regulated by modulating HMG-CoA reductase by different mechanisms.
These include covalent modification of enzymes, allosteric feedback inhibition affecting the
reaction rate, hormonal control, and transcriptional control of gene expression.

HMG CoA reductase is regulated covalently through the actions of adenosine monophosphate
(AMP)-activated protein kinase (AMPK) and a phosphoprotein phosphatase which switch the
enzyme between dephosphorylated (active) and phosphorylated (inactive) state. When plenty of
cholesterol is available, high levels cause feedback inhibition to decrease the HMG-CoA
reductase activity. In a well-fed state, with plenty of substrate availability, insulin and thyroxine
cause upregulation of the enzyme. The counterregulatory hormone for cortisol, glucocorticoids,
and insulin is glucagon, which has an inhibitory effect.

Transcriptional control of gene expression is another important mechanism that regulates

HMG-CoA reductase. This involves the special transcription factors, known as sterol regulatory
binding proteins, to be present in the membranes of ER. In cholesterol-depleted cells, the
SREBPs are transported to the Golgi complex, where they are processed to release an active
fragment that enters the nucleus to bind the SRE (sterol regulatory element) and activate the
transcription of the genes encoding HMG-CoA reductase and other enzymes involved in
cholesterol biosynthesis. When cholesterol levels are high in the cells, the transport of SREBPs
to the Golgi complex is blocked as the enzyme binds to another set of proteins that retain to the
ER called ‘insigs’ (insulin signaling proteins). This prevents the proteolytic release of the active
fragment of SREBPs from ER membranes. Since the fragment is not available to bind the SRE
in the nucleus, the transcription of the target genes no longer occurs, and HMG-CoA reductase
is not activated. [8]
Function
Cholesterol fulfills several biological functions and is necessary for successful cellular
homeostasis. It acts as a precursor to bile acids, assists in steroid and vitamin D synthesis, and
plays a central role in maintaining cellular membrane rigidity and fluidity.[9]

All classes of steroid hormones, glucocorticoids, mineralocorticoids, and sex hormones, are
derivatives of cholesterol. Synthesis occurs in the placenta and ovaries (estrogens and
progestins), testes (testosterone), and adrenal cortex (cortisol, aldosterone, and androgens).
The initial rate-limiting reaction converts cholesterol to pregnenolone, which is then oxidized and
isomerized to progesterone. It is further modified in the ER and mitochondria by various
hydroxylation reactions to other steroid hormones (cortisol, androgens, and aldosterone).
Aldosterone acts primarily on the renal tubules, stimulating potassium excretion and uptake of
sodium and water. Its ultimate effect is an increase in blood pressure. Cortisol allows the body to
handle and respond to stress through its effects on intermediary metabolism, in other words,
increased gluconeogenesis and the inflammatory and immune responses. The androgens,
specifically testosterone, estrogens, and progestins, are responsible for sexual differentiation,
libido, spermatogenesis, and ovarian follicle production.

Vitamin D3 (cholecalciferol) from either the skin or the diet undergoes hydroxylation by 25-alpha
hydroxylase to form 25-hydroxycholecalciferol (calcidiol) in the liver from lipid-soluble
compounds with a 4-ringed cholesterol backbone. It is then further hydroxylated by 1-alpha
hydroxylase to an active form 1,25-dihydroxycholecalciferol (calcitriol) in the kidneys. Vitamin D
plays an integral role in the terminal differentiation of hypertrophic chondrocytes, subsequent
calcification of the bone matrix. In addition, it plays an important role in calcium homeostasis
helps by mobilizing calcium from the bones and stimulating intestinal absorption and
reabsorption in the kidneys.[10]

Bile is a watery mixture of both inorganic and organic compounds, of which phosphatidylcholine
and conjugated bile salts/acids are quantitatively the most important. Between 15 and 30 grams
of bile salts/acids are secreted from the liver each day, but as a result of bile reabsorption, only
about 0.5 grams are lost daily in the feces. As a result, to replace the amount lost, roughly 0.5
grams per day is synthesized from cholesterol in the liver. Cholesterol is incorporated as the
backbone in bile acid synthesis, a complex multistep, multi-organelle process. This synthesis
accomplishes 2 goals. First, it creates a way for the body to excrete cholesterol as there is no
way to break it down physiologically, and it allows lipids to be digested via emulsification and
subsequent break down by pancreatic enzymes.

Clinical Significance
While cholesterol is vital for the functioning of our cells, elevated levels can cause serious
problems. In addition, it is implicated in many genetic diseases, such as cholelithiasis, and is
also the target of many therapeutic pharmacologic drugs.

Cholelithiasis
The formation of gallstones occurs if there is either a bile salt deficiency or excess cholesterol
secreted into the bile. In other words, when the liver secretes cholesterol, there must be a
proper balance of bile salts, cholesterol, and phospholipids, as an imbalance causes cholesterol
to precipitate. In pathologic states of hypercholesteremia, gallstones are often formed, leading
to cholecystitis or even ascending cholangitis. Understanding this precarious relationship led to
the invention of two important types of antihyperlipidemic drugs: bile acid-binding resins
(cholestyramine/colestipol/colesevelam) and cholesterol absorption inhibitors (ezetimibe). The
former acts by blocking the reabsorption of bile acids in the small intestine, which then forces
the liver to synthesize more bile acids to use up excess cholesterol in the process, thus lowering
serum cholesterol levels. Ezetimibe acts similarly by blocking the absorption of cholesterol in
jejunal enterocytes, allowing the body to take excess cholesterol and again secrete it into bile. It
is interesting to note that Fibrates, another class of antihyperlipidemic drugs, can cause
cholelithiasis. This occurs simply by causing cholesterol excretion into the bile, and as
previously mentioned,