Blocking intestinal cholesterol absorption for optimal lipid lowering

Based on a presentation by David E. Cohen, MD, PhD

NEW ORLEANS?Optimal lowering of serum low-density lipoprotein (LDL) cholesterol levels requires blocking all its sources. Although statin drugs block its synthesis in the liver, they do not address intestinal sources of cholesterol. And, in fact, increased intestinal absorption may compensate to some degree for lower endogenous cholesterol, and increased synthesis may occur if absorption is blocked. So treatment with a combination of statins and substances that inhibit intestinal absorption of cholesterol may best achieve LDL cholesterol goals and potentially further reduce the risk of coronary artery disease.

A complex interplay between the liver and the intestine determines plasma cholesterol concentrations. The liver regulates synthesis, secretion, and clearance of cholesterol-rich lipoproteins. It also determines the amount of cholesterol eliminated into the bile, either as cholesterol or after conversion to bile acids. Cholesterol is broken down and eliminated only by the liver. The intestine plays a key role in regulating the net balance of cholesterol by serving as the site of both absorption of dietary cholesterol and reabsorption of biliary cholesterol. What is not absorbed is excreted in the feces.

David E. Cohen, MD, PhD, described the mechanisms involved in this balance of cholesterol synthesis, absorption, and excretion. He went on to show the necessity of inhibiting both synthesis and absorption to achieve optimal control of serum cholesterol levels.

He noted that the intestine typically absorbs about 50% of the cholesterol that is presented to it, but the amount can vary from 20% to 80% depending on the individual. Of the absorbed cholesterol, approximately 75% comes from bile and only about 25% from the diet. Together they make a substantial contribution to serum cholesterol. The intestine delivers cholesterol to the liver in the form of chylomicron remnants. The liver then incorporates a portion of this cholesterol into very low-density lipoprotein (VLDL), which gives rise to atherogenic LDL particles in the plasma.

Digestive lipid metabolism

The body?s tissues make all the cholesterol they need (eg, for membrane homeostasis), but only the liver can break it down in large amounts. Because of this, transporting cholesterol to the liver is important. High-density lipoproteins (HDLs) are primarily responsible for "reverse cholesterol transport" to the liver, where some cholesterol molecules are converted to bile salts that allow packaging and secretion of cholesterol from the body.

Cholesterol is insoluble in water, and lipoproteins carry it in the serum. In the intestine, bile salts are highly soluble. They are similar in molecular structure to cholesterol but have detergent-like properties, which keep insoluble molecules in solution. Bile salts form micelles consisting of a lipid membrane bilayer of phospholipids into which cholesterol molecules insert themselves. "The liver has a very elegant strategy of taking cholesterol and breaking it down into a molecule that it exploits in the intestine to keep cholesterol in solution," Dr Cohen explained.

The liver secretes about 24 g of bile salts (Figure 1) a day to effect the secretion of about 2 g of cholesterol. The hepatocyte forms a boundary between "inside" (the blood) and "outside" (the biliary tree, leading to the intestinal lumen). HDL transports cholesterol from the blood across the sinusoidal membrane into the hepatocyte.

Micelles are assembled at the membrane in contact with the biliary tree and excreted into bile using an adenosine triphosphate (ATP)-dependent pump. These micelles transport cholesterol from the liver to the intestine via the biliary tree. In the intestine, cholesterol from the diet enters the micellar membrane, as do fatty acids and monoglycerides derived from dietary triglycerides.

Cholesterol is absorbed from micelles into the intestinal wall through a recently identified protein channel, Niemann-Pick C1 Like 1 protein (NPC1L1) (Science. 2004;303:1201-1204) on the enterocyte plasma membrane. Some portion of the cholesterol is immediately pumped out of the body (into the intestinal lumen) by the heterodimeric ATP-binding cassette transporter protein complex of ABCG5/G8. Triglyceride molecules are reassembled from their components in the enterocyte and enter chylomicrons together with cholesterol.

Mice with intact NPC1L1 genes absorb about 50% of cholesterol from their intestines. With 1 intact gene, they absorb about 45%. But if both copies are knocked out, absorption drops to about 15%.

Cholesterol balance

Cholesterol in the digestive system must be considered in both its forms, bile salts and cholesterol per se. Dr Cohen explained that bile salt balance is tightly regulated, with about 95% of the 24 g secreted a day into bile being reabsorbed through high-affinity receptors in the terminal ileum and returned to the liver for resecretion into bile. This recycling is referred to as the "enterohepatic circulation." The small amount not absorbed accounts for about 400 mg of cholesterol lost per day, which, Dr Cohen emphasized, "represents a substantial loss of cholesterol from the body."

The liver is capable of sensing bile salt loss in the feces and matches loss with increased synthesis. So when bile salt sequestrants increase cholesterol loss as bile salts, the liver compensates with more synthesis, depleting its store of cholesterol and adding to the total amount of cholesterol excreted in the feces.

Cholesterol is synthesized in the body at a rate of up to 1.2 g/day compared with a dietary intake of about 0.4 g/day. "The important thing here to take home is that we are synthesizing far more cholesterol than we are eating," Dr Cohen said. "If we want to assault our cholesterol balance in the interest of lipid lowering, a ripe target is what we have synthesized within the body, and trying to keep that out by directing it outside the body."

Cholesterol control

Statins inhibit cellular synthesis of cholesterol from acetate by inhibiting hydroxymethyl glutaryl coenzyme A reductase, the rate-limiting enzyme in the synthesis. Cells need cholesterol for membrane synthesis, so if they do not get enough cholesterol from synthesis, they upregulate their LDL receptors, take LDL from the plasma, and thereby lower plasma LDL.

Another class of molecules to control serum cholesterol is inhibitors of intestinal absorption. While they inhibit absorption of dietary cholesterol, "the real target in cholesterol balance is inhibiting reabsorption of biliary cholesterol," thereby inhibiting LDL formation, according to Dr Cohen. Available agents include plant sterols, stanols in the form of dietary supplements, and the new drug, ezetimibe, the only approved drug in the class.

Ezetimibe appears to be a specific inhibitor of the NPC1LI channel in the enterocyte, slowing the rate of cholesterol uptake. It blocks the channel to about the same degree as if the NPC1L1 gene were deleted, as shown in knockout mice (Figure 2). Lower intestinal absorption means less cholesterol input into chylomicrons.

Cholesterol-poor circulating chylomicrons return to the liver and are cleared with whatever cholesterol they contained. They are essentially a shunt for moving cholesterol from the intestine to the liver. Lowering the rate of this shunting by inhibiting absorption in the first place is important "because a good proportion of that cholesterol is packaged right back up and made into VLDL particles, which downstream turn into LDL," Dr Cohen explained.

Dual inhibition by blocking cholesterol absorption with ezetimibe and synthesis with statins is a highly effective strategy for reducing serum LDL levels, he continued. Blocking absorption reduces the amount of cholesterol in chylomicrons, which eventually return to the liver with their cholesterol loads and contribute to VLDL production. In response to this decrease in cholesterol absorption, the liver upregulates cholesterol synthesis, and this tends to negate the effectiveness of reducing absorption.

Statins reduce the compensatory upregulation that occurs in the liver and restore the effectiveness of inhibiting cholesterol absorption in reducing VLDL output by the liver. Therefore, in addition to promoting clearance of LDL particles from plasma, in the setting of dual therapy, statins help to reduce the formation.

Cholesterol balance is regulated by both synthesis and absorption. Each pathway may compensate for changes in the other, partially negating any beneficial therapeutic effect. "Optimal LDL lowering may be best achieved if we inhibit both pathways by separate mechanisms that have complementary overlapping efficacy," Dr Cohen concluded.