Endogenous Metabolite

Cellular cholesterol concentration decreased by 20–31% after GT1-7 hypothalamus cells were depleted of cholesterol in vitro. Reduced phosphorylation/activation of IRS-1 and AKT was observed in all cholesterol-depleted neuron-derived cells when stimulated with insulin, insulin-like growth factor 1, or neurotrophic factors (NGF and BDNF). Lowering cellular cholesterol also raises baseline autophagy and hinders glucose deprivation-induced autophagy activation [1].

Models of scaffolded hyperlipidemia can be created using cholesterol in animal models.

Diabetes mellitus is associated with a variety of complications, including alterations in the central nervous system (CNS). We have recently shown that diabetes results in a reduction of cholesterol synthesis in the brain due to decreased insulin stimulation of SREBP2-mediated cholesterol synthesis in neuronal and glial cells. In the present study, we explored the effects of the decrease in cholesterol on neuronal cell function using GT1-7 hypothalamic cells subjected to cholesterol depletion in vitro using three independent methods: 1) exposure to methyl-β-cyclodextrin, 2) treatment with the HMG-CoA reductase inhibitor simvastatin, and 3) shRNA-mediated knockdown of SREBP2. All three methods produced 20-31% reductions in cellular cholesterol content, similar to the decrease in cholesterol synthesis observed in diabetes. All cholesterol-depleted neuron-derived cells, independent of the method of reduction, exhibited decreased phosphorylation/activation of IRS-1 and AKT following stimulation by insulin, insulin-like growth factor-1, or the neurotrophins (NGF and BDNF). ERK phosphorylation/activation was also decreased after methyl-β-cyclodextrin and statin treatment but increased in cells following SREBP2 knockdown. In addition, apoptosis in the presence of amyloid-β was increased. Reduction in cellular cholesterol also resulted in increased basal autophagy and impairment of induction of autophagy by glucose deprivation. Together, these data indicate that a reduction in neuron-derived cholesterol content, similar to that observed in diabetic brain, creates a state of insulin and growth factor resistance that could contribute to CNS-related complications of diabetes, including increased risk of neurodegenerative diseases, such as Alzheimer disease [3].

Cholesterol can be used for constructing aimal models of hyperlipidemia, atherosclerosis, and so on.

---

Induction of hyperlipidemia
Pathogenic principle: Hyperlipidemia is a group of diseases characterized by elevated circulating lipid concentrations, including cholesterol, cholesterol esters, phospholipids, and triglycerides. If the intake of cholesterol is excessive and exceeds the body's metabolic capacity, it may lead to an increase in plasma cholesterol levels and induce hyperlipidemia.
Detailed methods for constructing hyperlipidemia model
Rats: Wistar • male • 18 week old (period: 8 weeks)
Administration: 2% cholesterol; Diet-8 weeks
Note
(1) The rats were placed in a room with 22 ± 2 ° C room temperature and 12 h light dark cycle
(2) Wistar rats were always selected for the study of hyperlipidemia, because the serum cholesterol and triglyceride levels of this species were moderately increased due to high cholesterol diet, and no substantial atherosclerosis occurred; Therefore, it is possible to study the direct effect of hyperlipidemia on myocardium in this model, independent of atherosclerosis.
Markers of successful construction of hyperlipidemia model: Total cholesterol levels in blood samples significantly increase (approximately 20%)

---

Induction of atherosclerosis
Pathogenic principle: High levels of cholesterol in the blood, especially low density lipoprotein cholesterol (LDL-C), may accumulate on the vascular wall to form plaque, a process known as atherosclerosis. Over time, these plaques may block blood flow, leading to serious health problems such as myocardial ischemia or myocardial infarction.
Detailed methods for constructing atherosclerosis model
Rabbits: Oryctolagus cuniculus • male • 4-6 month old (period: 16 weeks)
Administration: 0.3% cholesterol and 3% soybean oil; DIET • 16 weeks
Note
(1) High cholesterol rabbit is a model widely used in experimental research of atherosclerosis, because cholesterol can only cause atherosclerosis changes in the intima of rabbit arteries, which is very similar to human atherosclerosis.
(2) Due to the absorption of dietary cholesterol requiring fat, oil must be added to the diet. Otherwise, rabbits will use their internal fat to make them thin or sick. In addition, using soybean oil containing unsaturated fatty acids can prevent high plasma cholesterol levels. Other vegetable oils, such as peanut oil or corn oil, can also be used because they are unsaturated fatty acids. It is not recommended to consume animal fats (saturated fatty acids), such as butter and lard.
(3) Most experiments recommend using a cholesterol diet of 0.3-0.5%. Rabbits cannot tolerate a cholesterol diet of 1-2% for more than a month as they can develop severe liver dysfunction.
(4) Adult rabbits over 4 months old can consume approximately 150 grams per day. Free feeding or restricted feeding (100-150 grams/day/adult rabbit) is allowed.
(5) Blood lipids should be measured weekly, especially for the first 4 weeks, as you need to determine whether the plasma cholesterol levels of each animal are elevated. If the plasma cholesterol level of non responsive rabbits does not increase after feeding with cholesterol feed, they can be excluded from the experiment.
(6) Plasma lipoprotein can be measured at 8 and 16 weeks, during which plasma cholesterol levels remain stable.
(7) The age of rabbits should be considered, because even though their plasma cholesterol levels are similar, young rabbits are more likely to suffer from atherosclerosis than older rabbits. Rabbits aged 4-6 months are typically used for cholesterol feeding experiments.
(8) Male and female rabbits have different responses to cholesterol diet and atherosclerosis. Based on our experience, female rabbits suffer from higher levels of hypercholesterolemia and larger aortic lesions than male rabbits. In general, it is recommended to conduct experiments on male rabbits as estrogen may affect the results.
Markers of successful construction of therosclerosis model: Histological changes: HE staining of aortic arch and sections of thoracic aorta showed atherosclerosis

Absorption, Distribution and Excretion
Found in all body tissues, especially in the brain, spinal cord, and in animal fats or oils. Main constituent of gallstones.
Cholesterol is distributed universally in all animal tissues. It can be derived either from intestinal absorption of dietary cholesterol or from synthesis de novo within the body.
The fraction of dietary cholesterol absorbed is dependent on the intake; after reaching a plateau, the amount absorbed decreases with increased dietary intake. Most people in western societies ingest between 500 and 800 mg/day and absorb from 300 to 400 mg/day.
Cholesterol is absorbed from the gut via lymph. The primary site of absorption of dietary cholesterol is the proximal small intestine. Cholesterol is absorbed from the intestine after incorporation into chylomicrons, which are mixed micelles composed of triglycerides, phospholipids, protein and free and esterified cholesterol.
For more Absorption, Distribution and Excretion (Complete) data for CHOLESTEROL (6 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Cholesterol itself in the animal system is the precursor of bile acids, steroid hormones, and provitamin D3.
Cholesterol is the substrate for steroid biosynthesis. Conversion of cholesterol to pregnenolone occurs in the mitochondria, and oxidative reactions catalyzed by P450 enzymes occur in the smooth endoplasmic reticulum and mitochondria. Sources of cholesterol include lipoprotein uptake from serum (LDL and HDL), de novo synthesis from acetate via the acetyl coenzyme A pathway, and hydrolysis of cholesteryl ester (CE) by neutral CE hydrolase (nCEH). The storage pool in the form of lipid droplets is derived principally from the conversion of free cholesterol to CE catalyzed by acyl coenzyme A: cholesterol acyltransferase (ACAT). Direct uptake of CE from serum to the storage pool is minimal in the rat.
Cholesterol introduced into the cecum of rats is changed to lithocholic and isolithocholic acids, which are partly excreted in the feces. In the guinea pig, the gut bacteria can metabolize cholesterol to estradiol and estrone, which are excreted in the urine.
Cholesterol is metabolized in the liver, the main metabolic pathway being conversion to the two primary bile acids, cholic acid and chenodeoxycholic acid. These, after conjugation with either glycine or taurine, pass into the intestine via the bile, where they may be further metabolized by bacterial enzymes to yield the secondary bile acids, deoxycholic acid and lithocholic acid. Cholesterol is also converted to other neutral sterols; in the liver, reduction yields cholestanol. In the intestine, the main metabolites produced by bacterial enzymes are coprostanol (a stereoisomer of cholestanol) and cholestanone. Although both bile acids and neutral sterols undergo enterohepatic recirculation, there is a net loss daily of about 250 mg cholesterol as bile acids and about 500 mg as neutral sterols.
For more Metabolism/Metabolites (Complete) data for CHOLESTEROL (6 total), please visit the HSDB record page.

Effects During Pregnancy and Lactation
◈ What is cholesterol?
Cholesterol is a waxy substance that our bodies make to help build healthy cells. There are two types of cholesterol: the high-density lipoprotein cholesterol (HDL) often called “good” cholesterol and the low-density lipoprotein cholesterol (LDL) called “bad” cholesterol.People also get some cholesterol from eating certain foods. Foods high in cholesterol include butter, fatty meat, and full fat cheese. Lack of exercise, being overweight, and eating foods with high cholesterol can all increase levels of LDL cholesterol. Smoking cigarettes lowers the amount of HDL cholesterol in the body. Some people have a genetic condition called Familial Hypercholesterolemia (FH) that causes very high levels of LDL cholesterol. For people with FH, medication is usually needed to lower their LDL cholesterol levels.High cholesterol can reduce blood flow and increase the chance for acute pancreatitis (inflamed pancreas) and heart disease, which can lead to heart attacks and strokes. A blood test can tell your levels of cholesterol.
◈ I have high cholesterol. Can it make it harder for me to get pregnant?
It is not known if high cholesterol can make it harder to get pregnant. One study suggests it might take longer to get pregnant if a person has high cholesterol. However, related factors like diabetes and obesity may make it harder to get pregnant. For more information on obesity and diabetes, see our fact sheets here https://mothertobaby.org/fact-sheets/obesity-pregnancy/ and here https://mothertobaby.org/fact-sheets/diabetes-pregnancy/.
◈ I just found out I am pregnant. Should I stop taking my medication for high cholesterol?
Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ Will pregnancy affect my cholesterol levels?
For most people, cholesterol levels lower slightly in early pregnancy but then increase. Diet, exercise, and the use of medications can affect cholesterol levels. Talk with your healthcare providers if you are worried about your cholesterol levels.
◈ Does having/getting high cholesterol increase the chance for miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Based on the studies reviewed, having high cholesterol alone is not expected to increase the chance for miscarriage. Related factors like diabetes and obesity may increase the chance for miscarriage.
◈ Does having/getting high cholesterol increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, having high cholesterol alone is not expected to increase the chance for birth defects above the background risk. Related factors like diabetes and obesity can increase the chance for birth defects.
◈ Does having/getting high cholesterol increase the chance of other pregnancy-related problems?
Based on the studies reviewed, it is not known if high cholesterol can increase the chance of other pregnancy-related problems. Some studies have reported an increased chance for gestational diabetes, preeclampsia (dangerously high blood pressure in pregnancy), preterm delivery (birth before 37 weeks) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth). Other studies have reported no increase in pregnancy complications.
◈ Does having high cholesterol in pregnancy affect future behavior or learning for the child?
Based on the studies reviewed, it is not known if high cholesterol can cause behavior or learning issues. Related factors like diabetes and obesity may increase the chance for behavior or learning issues.
◈ Breastfeed while taking medication for high cholesterol:
There are different medications used to treat high cholesterol. For information on your specific medication see our fact sheets https://mothertobaby.org/fact-sheets/ or contact MotherToBaby. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male has high cholesterol, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies on sperm quality and high cholesterol have mostly looked at the use of cholesterol medication. High cholesterol alone could reduce the chance of conceiving a pregnancy. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[1]. Cholesterol as an Endogenous ERRα Agonist: A New Perspective to Cancer Treatment. Front Endocrinol (Lausanne). 2018 Sep 11;9:525.

[2]. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res. 2004 Aug;45(8):1375-97.

[3]. Effect of Cholesterol Reduction on Receptor Signaling in Neurons. J Biol Chem. 2015 Sep 14.

Cholesterol is a cholestanoid consisting of cholestane having a double bond at the 5,6-position as well as a 3beta-hydroxy group. It has a role as a human metabolite, a mouse metabolite, a Daphnia galeata metabolite and an algal metabolite. It is a 3beta-sterol, a cholestanoid, a C27-steroid and a 3beta-hydroxy-Delta(5)-steroid.
The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.
Cholesterol has been reported in Acanthus ilicifolius, Amaranthus hybridus, and other organisms with data available.
Cholesterol is an animal sterol found in the body tissues (and blood plasma) of vertebrates. It can be found in large concentrations within the liver, spinal cord, and brain. Cholesterol is an important component of the membranes of cells, providing stability. It is the major precursor for the synthesis of vitamin D, of the various steroid hormones, including cortisol, cortisone, and aldosterone in the adrenal glands, and of the sex hormones progesterone, estrogen, and testosterone. Cholesterol also has an important role for the brain synapses as well as in the immune system. In conditions featuring elevated low density lipoproteins (LDL), cholesterol often forms plaque deposits in the walls of arteries, a condition known as atherosclerosis, which is a major contributor to coronary heart disease and other forms of cardiovascular disease.
The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.
See also: Calendula Officinalis Flower (part of); Bos taurus bile; cholesterol; malmea depressa bark (component of); Tachysterol (annotation moved to) ... View More ...

---

Mechanism of Action
Cell degeneration in Alzheimer's disease is mediated by a toxic mechanism that involves interaction of the AbetaP peptide with the plasma membrane of the target cell. PC12 cells become resistant to the cytotoxic action of AbetaP when incubated in a medium that enriches cholesterol levels of the surface membrane. On the other hand, making cholesterol-deficient membranes by either cholesterol extraction with cyclodextrin or by inhibiting de novo synthesis of cholesterol makes PC12 cells more vulnerable to the action of AbetaP. Increasing cholesterol content of PS liposomes also suppresses AbetaP-dependent liposome aggregation. /The authors/ suggest that by modifying the fluidity of the neuronal membranes, cholesterol may modulate the incorporation and pore formation of AbetaP into cell membranes. This idea is supported by the finding that the enhanced cytotoxicity generated by lowering the membrane cholesterol content can be reversed by AbetaP calcium channel blockers Zn2+ and tromethamine.

---

Therapeutic Uses
Pharmaceutic aid (emulsifying agent).
Cholesterol is used in liposomes to encapsulate and deliver chemotherapeutic drugs to diseased tissues.
Cholesterol-C14 is used clinically as an organ imaging agent. Organs visualized by the technique include ovaries, adrenals, and spleen.

C27H46O

386.66

386.354

C, 83.87; H, 11.99; O, 4.14

57-88-5

Cholesterol (Water Soluble);Cholesterol-d7;83199-47-7;Cholesterol-d6;60816-17-3;Cholesterol-d6-1;92543-08-3;Cholesterol-13C2;78887-48-6;Cholesterol-d4;956029-28-0;Cholesterol myristate;1989-52-2;Cholesterol-13C5;150044-24-9;Cholesterol-13C3;Cholesterol-d;51467-57-3;Cholesterol-18O;59613-51-3

5997

White to off-white solid

1.0±0.1 g/cm3

360 ºC

148-150 °C

250 ºC

0.0±2.7 mmHg at 25°C

1.525

Endogenous Metabolite

9.85

1

1

5

28

591

8

O([H])[C@@]1([H])C([H])([H])C([H])([H])[C@@]2(C([H])([H])[H])C(C1([H])[H])=C([H])C([H])([H])[C@]1([H])[C@]2([H])C([H])([H])C([H])([H])[C@]2(C([H])([H])[H])[C@@]([H])([C@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])[C@]21[H]

HVYWMOMLDIMFJA-DPAQBDIFSA-N

InChI=1S/C27H46O/c1-18(2)7-6-8-19(3)23-11-12-24-22-10-9-20-17-21(28)13-15-26(20,4)25(22)14-16-27(23,24)5/h9,18-19,21-25,28H,6-8,10-17H2,1-5H3/t19-,21+,22+,23-,24+,25+,26+,27-/m1/s1

(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol

AI3 03112 CCRIS 2834; AI303112; AI3-03112

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Ethanol : ~20 mg/mL (~51.73 mM)
DMSO :< 1 mg/mL

Solubility in Formulation 1: ≥ 1.43 mg/mL (3.70 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 1.43 mg/mL (3.70 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix well.

---

 (Please use freshly prepared in vivo formulations for optimal results.)