Cholesterol Homeostasis

David E Cohen, MD, PhD
Director, Harvard-MIT Division of Health
Sciences and Technology
Associate Professor of Medicine and
Health Sciences and Technology
Harvard Medical School
Boston, MA

Introduction

Cholesterol is an essential component of cell membranes and is also the precursor of steroid hormones, bile acids, and vitamin D.¹ Cholesterol is synthesized by virtually all cells in the body but cannot be catabolized. Therefore, complex metabolic pathways involving biosynthesis, absorption, distribution, and elimination are involved in maintaining cholesterol homeostasis.²

This selective review will cover the principal metabolic pathways involved in cholesterol homeostasis.

• Cholesterol Biosynthesis
• Intestinal Elimination and Absorption
• Hepatic Regulation
• Cholesterol Production and Secretion by the Liver
• Cholesterol Uptake by the Liver
• Conclusion

Cholesterol Biosynthesis

Cholesterol is synthesized by virtually all cells in the body.³

Because of its critical role in maintaining cell membrane structure and function, cells sense and control cholesterol levels. The ratio of cholesterol to other lipids (mostly phospholipids) in the cell's plasma membrane is tightly controlled. Imbalance in these lipids can trigger the cellular synthesis of cholesterol.⁴

De novo synthesis is the major contributor to the body pool of cholesterol. Each day about 800 mg of cholesterol is synthesized, 90% of which is produced in extrahepatic tissues.^5,6

In addition to synthesis, stored cholesterol can be redistributed to the cell's plasma membrane or cells can import cholesterol from plasma low-density lipoproteins (LDL).^3,4,7

Removal of cholesterol: Excessive amounts of cholesterol can destroy cellular membrane function.² Cholesterol is returned from tissues to the liver through a pathway known as "reverse cholesterol transport."^3,5

The principal mechanism for removal of excess cholesterol from extrahepatic tissues is the efflux of cholesterol from cellular plasma membranes to high-density lipoproteins (HDL).³

HDL particles take up cholesterol, transferring some of it to other plasma lipoproteins, or HDL can deliver cholesterol directly back to the liver via specialized receptors that take it up for processing and/or elimination.³

Summary: In extrahepatic tissue, cholesterol homeostasis is maintained by a balance of de novo synthesis, use of stored cholesterol, importation of cholesterol (via LDL), and removal of excess cholesterol (via HDL).

John Dietschy, MD
Professor of Internal Medicine
Division of Digestive and Liver Diseases
University of Texas Southwestern
Medical School
Dallas, TX

Intestinal Elimination and Absorption

Diet contributes to intestinal cholesterol content and it accounts for approximately a quarter of the total. The source of most intestinal cholesterol is bile.^3,5

Cholesterol loss: While the liver secretes an average of 1200 mg/day of biliary cholesterol into the small intestine, and the average Western diet contributes another 400 mg for a total of 1600 mg/day, only about half of this cholesterol is absorbed. It should be noted that there is marked variability in absorption among individuals. The remaining cholesterol in the intestinal lumen is eliminated from the body.^3,8

Additionally, most bile acids (produced in the liver by conversion of cholesterol) are recycled to the liver, but some are eliminated by fecal excretion, which represents a source of cholesterol loss from the body amounting to about 400 mg/day. Therefore, coupled with the loss of 800 mg/day of dietary and free cholesterol in bile, the total loss of cholesterol is about 1200 mg/day.³

Absorption of cholesterol: Enterocytes within the small intestine are responsible for the packaging of absorbed cholesterol and triglycerides into Apo B–containing lipoprotein particles, chylomicrons (CM).^3,9

Chylomicrons deliver triglycerides to peripheral tissues, becoming smaller as they give up their triglycerides. The resultant particles, chylomicron "remnants" (CMR), contain remaining triglycerides and intestinally absorbed cholesterol. Nearly all of these particles are rapidly taken up by the liver, where the intestinally derived triglycerides and cholesterol are stored or packaged into other lipoproteins.^3,10,11

Summary: The intestine contributes to cholesterol homeostasis through the absorption of dietary and biliary cholesterol, which adds to the body pool, and the elimination of unabsorbed free cholesterol from bile, which depletes the body pool.

In addition, a portion of cholesterol-derived bile acids are not re-absorbed from the intestine, and this also represents a loss of cholesterol from the body.

Hepatic Regulation

The liver is the principal regulator of lipid metabolism.¹² The liver synthesizes cholesterol, packages it into lipoproteins for distribution to the tissues, receives it from intestinal lipoprotein remnants as well as from plasma lipoprotein remnants, and receives it as excess cholesterol from the tissues.⁶

The liver eliminates cholesterol^3,13 by converting it into bile acids, some of which are excreted via the intestine, and by secreting it unchanged into the bile, where about half of this cholesterol is subsequently lost by fecal elimination.³

John Dietschy, MD
Professor of Internal Medicine
Division of Digestive and Liver Diseases
University of Texas Southwestern
Medical School
Dallas, TX

Cholesterol Production and Secretion by the Liver

De novo synthesis: The liver contributes relatively little cholesterol to the total body pool, synthesizing only about 10%.^5,6

Secretion of lipoproteins: In order to ensure a continuous supply of fatty acids for delivery to muscle tissue at times when dietary triglycerides are low or nonexistent (such as during a fast), the liver assembles and secretes a triglyceride-rich Apo B–containing lipoprotein, very low-density lipoprotein (VLDL).

VLDL also contains some cholesterol, which the liver contributes from its own cholesterol pool.³

Generation of Apo B remnants: As VLDL gives up its triglyceride to the tissues, the particles become smaller and proportionally more cholesterol is contained within their cores. When about 50% of the triglyceride content of these particles has been transferred, and Apo E is acquired from HDL, the particles convert to VLDL remnants (VLDLR) and approximately half of these are taken up by receptors in the liver. Those that remain in circulation continue to give up triglyceride, and as they become smaller they convert into another remnant lipoprotein, intermediate-density lipoprotein (IDL).³

Generation of LDL: About half of these remnant IDL particles are taken up by receptors in the liver, but those that are left continue to give up triglyceride and also take on cholesterol from HDL particles via the action of cholesteryl ester transfer protein (CETP) in the process of reverse cholesterol transport. Through this process, these remnant particles eventually acquire enough cholesterol that it becomes the principal lipid contained within their cores.³

As IDL continues to give up triglycerides, and acquire more cholesterol from HDL via CETP, IDL particles transfer Apo E to HDL, eventually leaving only a single protein on their surface (Apo B-100). At this point, these particles have completed their conversion to low-density lipoproteins (LDL).³

CETP action can increase plasma LDL concentrations by assisting the remnant IDL particles in acquiring cholesterol from HDL. As detailed above, some of these IDL particles are converted into cholesterol-rich LDL particles.³

LDL is the principal cholesterol-carrying lipoprotein in circulation, accounting for 65% to 75% of total cholesterol in the plasma. If cells in the periphery need to import cholesterol, they can do so by upregulating LDL receptors that will bring these particles into the cell, releasing unesterified cholesterol from their core for use or storage. The liver can also take up LDL particles via LDL receptors.^3,14

LDL particles that are not taken up by extrahepatic cells (or cleared by the liver) remain in the plasma, where they have a half-life of 2 to 4 days—significantly longer than that of other lipoproteins such as chylomicron and VLDL remnants that have a half-life of approximately 30 minutes.³


Cholesterol Uptake by the Liver

The liver receives intestinally derived cholesterol via chylomicron remnants, and as discussed above, cholesterol is also returned to the liver via remnant lipoproteins derived from VLDL (VLDLR, IDL, and LDL). Additionally, some excess extrahepatic cholesterol is returned directly via HDL particles.³

Apo B remnants assist HDL in reverse cholesterol transport: As mentioned previously in the "Cholesterol Biosynthesis" section, HDL particles transfer some of the excess cholesterol taken up from peripheral cells to other circulating lipoproteins, specifically remnant Apo B–containing lipoproteins (VLDLR, IDL, and LDL).³

CETP facilitates the transfer of cholesteryl esters from HDL particles to these Apo B remnants, thus increasing the cholesterol concentration in the cores of these particles. In this way, the remnant Apo B lipoproteins assist in reverse cholesterol transport by carrying cholesterol acquired from HDL back to the liver.^3,13

CETP also transfers triglycerides from the Apo B remnant particles to HDL. This helps to increase size and buoyancy of the HDL particles, making them more efficiently hydrolyzed by hepatic lipase, thus facilitating the uptake of HDL by the liver. As a result, plasma HDL concentrations can fall.^13,15

Clearance of LDL: The liver expresses about 70% of the body's LDL receptors, which are upregulated if hepatic cellular concentrations of cholesterol fall. By upregulating the LDL receptors, the liver accelerates the uptake of LDL, increasing the importation of cholesterol, thus restoring hepatic cholesterol concentration while at the same time effectively clearing these lipoproteins from the plasma. Because of its ability to express so many LDL receptors, the liver is the principal remover of LDL particles from the plasma.^3,5

Summary: The liver maintains cholesterol homeostasis by synthesizing cholesterol, regulating its distribution to tissues via lipoproteins, and taking up cholesterol from intestinal lipoproteins (CMR), plasma lipoprotein remnants (VLDLR, IDL, LDL), and HDL.

Additionally, the liver is capable of eliminating cholesterol, either by converting it into bile acids or excreting it unchanged into the bile.


Conclusion

Complex metabolic pathways have evolved to maintain cholesterol homeostasis across the body.²

The principal pathways of biosynthesis, intestinal elimination and absorption, and hepatic regulation of lipoproteins act interdependently to maintain the body's cholesterol pool.

The intestine, the liver, and diet contribute to the cholesterol pool.

The intestine absorbs dietary and biliary cholesterol, but perhaps more significantly, it absorbs only about half of the cholesterol presented to it, and since some of this cholesterol was contributed from bile (recycled from the liver cholesterol pool), the intestine is a source of cholesterol loss from the body pool.

Additionally, bile acids, produced from cholesterol, also recycle between the liver and intestine, and some are eliminated by the intestine.

The liver maintains cholesterol homeostasis by synthesizing cholesterol, regulating its distribution to tissues via lipoproteins, and taking up cholesterol from intestinal lipoproteins, plasma lipoprotein remnants, and HDL.

Thus, both the liver and the intestine participate in complex, interdependent processes involved in cholesterol homeostasis.

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