Cholesterol 1. Present in tissues as either free cholesterol or cholesterol ester. 2. Synthesized in many tissues from acetyl CoA.

(a) 75% of the cholesterol in the body is synthesized, only 25% comes from the diet (b) major sites of synthesis are liver, intestine, skin and endocrine glands Synthesis of Mevalonate from Acetyl CoA: Acetyl CoA is produced primarily from oxidation of fatty acids.

HMG-CoA Reductase is induced by low cholesterol and regulates the entire pathway. Synthesis of Squalene from Mevalonate:

Synthesis of Cholesterol from Squalene: Cholesterol 1. Present in tissues as either free cholesterol or cholesterol ester. 2. Synthesized in many tissues from acetyl CoA. (a) 75% of the cholesterol in the body is synthesized, only 25% comes from the diet (b) major sites of synthesis are liver, intestine, skin and endocrine glands Synthesis of Mevalonate from Acetyl CoA: Acetyl CoA is produced primarily from oxidation of fatty acids.

HMG-CoA Reductase is induced by low cholesterol and regulates the entire pathway. Synthesis of Squalene from Mevalonate:

Synthesis of Cholesterol from Squalene:

Note: The enzyme that catalyzes "Esterification" of cholesterol is ACAT. 7-Hydroxylase is activated by XS Cholesterol and inhibited by XS Bile Acid. 3. Ultimately eliminated from the body as cholesterol in bile acids. 4. Cholesterol is the precursor of ALL other steroids in the body, i.e. corticosteroids, sex hormones, vitamin D, bile acids. 5. Occurs in foods of animal origin, i.e. egg yolk, meat and liver.

6. Cholesterol is an amphiphilic lipid ----> essential structural component of membranes. 7. Lipoproteins transport cholesterol esters in their hydrophobic core. Low Density Lipoprotein (LDL) mediates cholesterol up-take into tissues. (BAD chol.) High Density Lipoprotein (HDL) removes cholesterol from the tissues to the liver where it is transformed to bile acids and eliminated. (GOOD Chol.) 8. Cholesterol is the major contributor to atherosclerosis (blocking and hardening of the arteries) caused by deposits of LDL (cholesterol) on artery walls. Coronary atherosclerosis correlates with a high plasma LDL:HDL cholesterol ratio. 9. Cholesterol Balance in Tissues: Steps 1, 2, 3, 4, 5 add to the cholesterol "pool"; a, b, and c remove cholesterol.

When the Body Needs to Increase in Cholesterol (a)up-take of cholesterol containing lipoproteins by receptors, i.e. LDL receptor. (b)up-take of cholesterol containing lipoproteins by a non-receptor mediated pathway. (c)up-take of free cholesterol from cholesterol rich lipoproteins to the cell membrane.

(d)cholesterol synthesis. Via HMG-CoA Reductase and LDL Receptor Induction:

(e)hydrolysis of cholesterol esters. When the Body Needs to Decrease in Cholesterol: (a)efflux of cholesterol to HDL, promoted by LCAT. (b)HDL's cleared by the liver as bile acids. (c)esterification of cholesterol for storage by ACAT. (d)utilization of cholesterol for synthesis of other steroids such as hormones. Dietary Measures: Low cholesterol. High mono- and polyunsaturated fats (sunflower, canola, corn, soybean, olive). Low saturated fats (butter, beef, palm). Cholesterol Lowering Drugs: Drug Indications Primary Effect Binds bile acids (Bile Acid Sequestrant) Competitive Inhibition of HMGCoA Reductase

Cholestyramine High LDL Lovastatin High LDL

Mevastatin Clofibrate Gemfibrozil Probucol Low HDL High LDL Familial Hypercholesterolemia Diverts free fatty acids from esterification Decreases the secretion of choles. cont. LDL Decreases accumulation of LDL in arteries Decreases flux of free fatty acids for -oxidation Niacin Low HDL and High LDL Decreases the secretion of choles. cont. LDL Summary of Cholesterol Metabolism:

Dr. Noel Sturm 2013

Note: The enzyme that catalyzes "Esterification" of cholesterol is ACAT. 7-Hydroxylase is activated by XS Cholesterol and inhibited by XS Bile Acid. 3. Ultimately eliminated from the body as cholesterol in bile acids. 4. Cholesterol is the precursor of ALL other steroids in the body, i.e. corticosteroids, sex hormones, vitamin D, bile acids. 5. Occurs in foods of animal origin, i.e. egg yolk, meat and liver.

6. Cholesterol is an amphiphilic lipid ----> essential structural component of membranes. 7. Lipoproteins transport cholesterol esters in their hydrophobic core. Low Density Lipoprotein (LDL) mediates cholesterol up-take into tissues. (BAD chol.) High Density Lipoprotein (HDL) removes cholesterol from the tissues to the liver where it is transformed to bile acids and eliminated. (GOOD Chol.) 8. Cholesterol is the major contributor to atherosclerosis (blocking and hardening of the arteries) caused by deposits of LDL (cholesterol) on artery walls. Coronary atherosclerosis correlates with a high plasma LDL:HDL cholesterol ratio. 9. Cholesterol Balance in Tissues: Steps 1, 2, 3, 4, 5 add to the cholesterol "pool"; a, b, and c remove cholesterol.

When the Body Needs to Increase in Cholesterol (a)up-take of cholesterol containing lipoproteins by receptors, i.e. LDL receptor. (b)up-take of cholesterol containing lipoproteins by a non-receptor mediated pathway. (c)up-take of free cholesterol from cholesterol rich lipoproteins to the cell membrane.

(d)cholesterol synthesis. Via HMG-CoA Reductase and LDL Receptor Induction:

(e)hydrolysis of cholesterol esters. When the Body Needs to Decrease in Cholesterol: (a)efflux of cholesterol to HDL, promoted by LCAT. (b)HDL's cleared by the liver as bile acids. (c)esterification of cholesterol for storage by ACAT. (d)utilization of cholesterol for synthesis of other steroids such as hormones. Dietary Measures: Low cholesterol. High mono- and polyunsaturated fats (sunflower, canola, corn, soybean, olive). Low saturated fats (butter, beef, palm). Cholesterol Lowering Drugs: Drug Indications Primary Effect Binds bile acids (Bile Acid Sequestrant) Competitive Inhibition of HMGCoA Reductase

Cholestyramine High LDL Lovastatin High LDL

Mevastatin Clofibrate Gemfibrozil Probucol Low HDL High LDL Familial Hypercholesterolemia Diverts free fatty acids from esterification Decreases the secretion of choles. cont. LDL Decreases accumulation of LDL in arteries Decreases flux of free fatty acids for -oxidation Niacin Low HDL and High LDL Decreases the secretion of choles. cont. LDL Summary of Cholesterol Metabolism:

Dr. Noel Sturm 2013

Cholesterol Serum Influx/Efflux Cholesterol Transport

Gianpiero Pescarmona 2007-09-29 Description

Plasma cholesterol is derived from two sources:

1. exogenous (dietary and biliary excretion) 2. endogenous (liver and peripheral tissues)

Exogenous
Dietary and biliary cholesterol are absorbed in the intestine by a saturable transport mechanism. Roughly 2/3 of intestinal cholesterol is from bile and 1/3 from diet.

Diet cholesterol absorption ( percentage of the intake ) is very different from people to people and it has a Gaussian distribution, ranging from almost null to 100% on a genetic base whith an average intake (around 400 mg/d). Roughly 50% f intestinal cholesterol is absorbed and recycled while the remaining part is eliminated with feces.

Importantly, individual variability exists with regard to the proportion of cholesterol that is absorbed or synthesized, depending on sensitivity of HMG-CoA reductase to inhibition by exogenous cholesterol. (Physiological and therapeutic factors affecting cholesterol metabolism: does a reciprocal relationship between cholesterol absorption and synthesis really exist? ) Evaluation of the relative role of cholesterol absorption or synthesis in determining its serum level is difficult even using radioactive tracer. Therefore in most studies the ratio between cholestanol/cholesterol and fitosterols/cholesterol is used as indirect marker of these fluxes. This kind of measurements is affected by large incertainities and therefore appliable only to very large samples. New insights into the regulation of HDL metabolism and reverse cholesterol transport.2005 Cholestanol: A serum marker to guide LDL cholesterol-lowering therapy The interaction of cholesterol absorption and cholesterol synthesis in man Effects of dietary cholesterol on the regulation of total body cholesterol in man

The number of receptors involved in intestinal cholesterol uptake explains the variability and umpredictability of the process

Endogenous
Daily synthesis in healthy man is around 750/1000 mg cholesterol (ca 2/3 of daily requirement), with an intake of around 250/400 mg. But increased dietary intake can reduce the net synthesis Cholesterol synthesis takes place in both liver (around 20%) and other peripheral tissues (mainly gut) and it strongly dependent on intestinal uptake as de novo cholesterol synthesis is inhibited at the level of HMG-CoA reductase by exogenous cholesterol. (Diurnal and dietaryinduced changes in cholesterol synthesis correlate with levels of mRNA for HMG-CoA reductase) Circadian rythm of cholesterol synthesis

Evidence for diurnal periodicity in human cholesterol synthesis

Cholesterol efflux from the cell

The cholesterol efflux from the cell is mediated by a carrier called ABCA1 belonging to the family of ABC transporter

Cholesterol transport

LuXuRies of Lipid Homeostasis: The Unity of Nuclear Hormone Receptors, Transcription Regulation, and Cholesterol Sensing 2009 Regulation of ABC1 activity

The ABC1 belongs to the family of the ABC-transporter including also the MDR1/pgp Cerebral vascular dysfunction during hypercholesterolemia.

Metabolic and Hormonal regulation of Cholesterol Metabolism

The stringent regulation of the different metabolic pathways is achieved through a set of interactions including nutrients concentration, hormones and Nuclear Factors, leading to a tight dependence from any environmental change (diet, fasting, etc). ***

Transcriptional Regulation of Metabolism 2006 FullText

See Cartoon Role of intestinal sterol transporters Abcg5, Abcg8, and Npc1l1 in cholesterol absorption in mice: gender and age effects. 2006 Glucose and Insulin release

Insulin effects

Regulation of cholesterol metabolism by Nuclear Factors

Sterol response element binding protein (SREBP)-2 and SREBP-1c at the branching point of cholesterol and fatty acid metabolism

The coordinated action of FXR, LXR, and SREBP-2 in the cholesterol metabolism

The major source of cholesterol is the diet, while de novo synthesis of cholesterol is stimulated by SREBP-2 if supplies are too low. If cholesterol is in excess, its efflux from the cells and its conversion into bile acids for excretion in the feces are favored by the activation of liver X receptor (LXR). High bile acid production in turn activates farnesol X receptor (FXR), which limits the toxic accumulation of these metabolites in the liver, by increasing their cell efflux and limiting their production. The plain blue arrows correspond to the action of these transcription factors on the genes acting in the cholesterol metabolic pathway. The gray arrows correspond to the action of these gene products. Some bile acid and cholesterol metabolites are ligands for FXR and LXR, respectively (blue dotted line), while high cholesterol levels directly inhibit SREBP-2. Metabolic adjustment of glucose metabolism upon fasting.

Summary of the network established by the transcription factors involved in metabolic regulation

Summary of the network established by the transcription factors involved in metabolic regulation. Each of the transcription factors mentioned in this figure participates in the regulation of at least one aspect of metabolism, often by sensing metabolite levels and adapting the cell response through transcriptional regulation of enzymes belonging to different pathways. In addition, each of them may influence the activity of the others, creating a regulatory network by which homeostasis is achieved.

Thyroid hormones and cholesterol

Hypothyroidism is associated with hypercholesterolemia and hyperthyroidism with hypocholesterolemia

Thyroid hormone has a stimulatory effect on HMGCoA-reductase increasing de novo cholesterol synthesis, but has an inhibitory effect on cholesterol absorption Which is the molecular mechanism? Shin DJ et al propose that the decreased LDL receptor and increased serum cholesterol associated with hypothyroidism are secondary to the thyroid hormone effects on SREBP-2. These results suggest that hypercholesterolemia associated with hypothyroidism can be reversed by agents that directly increase SREBP-2. Additionally, these results indicate that mutations or drugs that lower nuclear SREBP-2 would cause hypercholesterolemia. (Thyroid hormone regulation and cholesterol metabolism are connected through Sterol Regulatory Element-Binding Protein-2 (SREBP-2).) The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study. 2007 Pathways

Cholesterol Transport Private Il colesterolo

Items

Tangier Disease

MeSH Cholesterol Comments 2010-04-26 17:48:42.366484 - Gianpiero Pescarmona PgP and efflux

Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis. 2006 may PgP be involved in loading of Chol on HDL? TH and lipoproteins Beneficial effects of a novel thyromimetic on lipoprotein metabolism. 1997 THYROMIMETIC LIPOPROTEIN Thyroid hormones and thyroid hormone receptors: effects of thyromimetics on reverse cholesterol transport.2010 Fulltext World J Gastroenterol. 2010 Dec 21;16(47):5958-64. Pedrelli M, Pramfalk C, Parini P. Fig. 1 Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, development, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TR and TR, and several isoforms (e.g. TR1, TR2, TR1, and TR2). Activation of TR1 affects heart rate, whereas activation of TR1 has positive effects on lipid and lipoprotein metabolism. Consequently, particular interest has been focused on the development of thyromimetic compounds targeting TR1, not only because of their ability to lower plasma cholesterol but also due their ability to stimulate RCT, at least in pre-clinical models. In this review we focus on THs, TRs, and on the effects of TR1-modulating thyromimetics on RCT in various animal models and in humans.

full figure

Figure 1: HDL-C mediated reverse cholesterol transport. Reverse cholesterol transport (RCT) can be divided into four phases. 1) transfer of free cholesterol (FC) to pre-b HDL via ABCA1, 2) esterification of surface-associated FC by the enzyme Lecithin:acyl CoA Transferase (LCAT), 3) transfer of FC and triglycerides (TG) between HDL-C and Apo Bcontaining lipoproteins mediated by the enzyme cholesteryl ester transfer protein (CETP),

and 4) uptake by the scavenger receptor B1 (SR-B1) and catabolism of mature HDL-C into bile or small HDL-C particles by hepatic lipase (HL). Apo B-containing lipoproteins can be acquired by the LDL-receptor (LDLr) for hepatic catabolism. High density lipoprotein cholesterol: an evolving target of therapy in the management of cardiovascular disease

Fig. 1: Postprandial lipoprotein metabolism in diabetes. Insulin resistance plays a central role in the development of diabetic dyslipidemia. Under normal physiologic conditions, insulin suppresses lipolysis from adipose tissue and hepatic very low density lipoprotein (VLDL) production. However, hyperinsulinemia in the postprandial state and insulin resistance in type 2 diabetes initiates a dyslipidemic triad of high triglyceride, low high-density lipoprotein (HDL) cholesterol and high small, dense low-density lipoprotein (LDL) levels. Prolonged residence of triglyceride-rich lipoproteins (TRLs) in the circulation promotes the transfer of HDL or LDL cholesteryl esters for triglyceride, mediated by cholesteryl ester transfer protein (CETP). LDL can undergo hydrolysis by hepatic lipase (HL) or lipoprotein lipase (LPL), which hydrolyzes triglycerides from the core of LDL, resulting in production of smaller, denser particles. Moreover, triglyceride-enriched HDL particles become smaller, denser (HDL 3b and 3c) and are more rapidly catabolized, contributing to low plasma HDL in

insulin resistance and type 2 diabetes. apo apolipoprotein; CM chylomicron; FFA free fatty acid; RLP remnant lipoprotein