Cholesterol Metabolism

Objectives Review the regulatory mechanisms of cholesterol metabolism Discuss various agents affecting cholesterol metabolism This slide curriculum will: Review the regulatory mechanisms of cholesterol metabolism. Discuss various agents affecting cholesterol metabolism.

Net Cholesterol Balance in Humans Key point: Cholesterol remains in balance as the result of the interplay between three major systems: the extrahepatic organs, the liver, and the intestine. Three major systems, the extrahepatic organs, the liver, and the intestine, are responsible for maintaining cholesterol balance in humans. [Dietschy 1997, page 1581S] Using acetyl-CoA, the body synthesizes ~3 times as much cholesterol (~900 mg) as is ingested each day (~300 mg), [Homan 1997, page 30, 31] primarily in extrahepatic organs [Dietschy 1997, page 1583S] and, each day, this 1200 mg cholesterol load is excreted as fecal sterols. [Dietschy 1997, page 1581S] Although the liver plays a small role in cholesterol synthesis, its primary role is in maintaining net cholesterol balance. [Dietschy 1997, page 1582S] Cholesterol synthesized by extrahepatic organs is carried by high-density lipoproteins (HDL) and LDL to the liver, where it is taken up by the scavenger receptor class B, type I (SR-BI) pathway. [Krieger 1999, page 523] In addition, the LDL receptor (LDL-R) on liver cells removes cholesterol in LDL and VLDL remnants from the circulation. [Dietschy 1997, page 1582S] This hepatic cholesterol can be stored for further use, repackaged in VLDL in order to transfer triacylglycerol from the liver to extrahepatic organs, or excreted into the intestine, either directly or following conversion to bile. [Dietschy 1997, page 1582S] The intestine receives both the dietary and excreted hepatic cholesterol and is the primary means of cholesterol elimination. However, ~50% of the cholesterol which enters the intestine, regardless of source, is absorbed. [Homan 1997, page 31] This occurs through a process in which mixed lipid micelles formed with bile acids transport cholesterol to the brush border of enterocytes, where it enters the enterocyte, is esterified, assembled into chylomicrons, secreted into mesenteric lymph for transport to the circulation, and ultimately cleared from the plasma by the liver, the “enterohepatic circulation.” [Homan 1997, page 31, 32][Dietschy 1997, page 1581S, 1582S] Synthesized Cholesterol (900 mg/day) Fecal Sterols (1200 mg/day) Adapted from Dietschy JM. Am J Clin Nutr. 1997;65(suppl):1582S.

Liver Regulates Concentration of Cholesterol in LDL Key point: The liver plays a central role in maintaining cholesterol balance by responding to variations in cholesterol uptake and export and regulating steady-state concentrations of LDL. The liver is the primary organ responsible for regulating the steady-state concentration of LDL. It is responsible for the uptake of cholesterol from the circulation in a variety of forms (synthesized cholesterol in HDL via the scavenger receptor class B, type I [SR-BI] pathway, cholesterol in LDL and VLDL remnants via the LDL receptor [LDL-R], and cholesterol in chylomicrons via both LDL-R and another receptor, the LDL-receptor-related protein [LRP]). [Krieger 1999, page 523][Dietschy 1997, page 1582S] In addition, it is responsible for the excretion of cholesterol into the intestine through either bile acid or neutral sterol formation. [Dietschy 1997, page 1582S] A portion of this intestinal cholesterol is reabsorbed as part of the enterohepatic circulation and the remainder excreted as fecal sterols. [Dietschy 1997, page 1582S] These pathways permit several strategies for reducing LDL cholesterol levels. One strategy is to reduce cholesterol synthesis. Statins are potent inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. [Illingworth 2000, page 31] In addition, they reduce the hepatic synthesis of VLDL and LDL and increase the expression of hepatic LDL-R, further reducing LDL levels. [Illingworth 2000, page 31] Another strategy is to limit the uptake of cholesterol from the intestinal lumen, decreasing the amount of cholesterol in the enterohepatic circulation and increasing the excretion of fecal sterols. [Homan 1997, page 29] Bile acid (BA) sequestrants such as cholestyramine and colestipol have been used for over 20 years. By binding to BA they block intestinal resorption, leading to increased fecal excretion. To compensate for the reduced BA pool, the liver increases the production of BA from cholesterol, leading to an up-regulation of hepatic LDL-R and decreased LDL plasma levels. [Illingworth 2000, page 33] Stanols differ from cholesterol at the carbon 24 position. Because of their structural similarity, they compete with cholesterol for incorporation into mixed micelles, ultimately reducing cholesterol absorption by ~50%. In compensation for this reduced absorption, cholesterol synthesis is increased, hepatic LDL-R activity increases, and plasma LDL level falls. [Cater 2000, page 122] (BA Sequestrants, Stanols) Adapted from Dietschy JM. Am J Clin Nutr. 1997;65(suppl):1582S.

Steps Involved in Cholesterol Absorption ABCA1 Key point: The process of cholesterol absorption is complex and currently only partly understood. Cholesterol absorption is complex and only partially understood. Cholesterol entering the intestine from either dietary (~300 mg/day) or biliary sources (~900 mg/day) is first emulsified by bile acids in the lumen of the duodenum forming mixed lipid micelles. [Homan 1997, page 30, 31][Hernandez 2000, page 232] Peristalsis transports these micelles to the jejunum, where at the brush border of enterocytes, cholesterol is transferred from the micelles into the enterocyte. [Homan 1997, page 30, 31, 32] It is currently unknown whether this transfer occurs via active or passive processes or a combination thereof. [Homan 1997, page 32] Once inside the enterocytes, cholesterol is esterified by the action of acyl-coenzyme A: cholesterol acyltransferase (ACAT), transferred to the endoplasmic reticulum, assembled into chylomicrons (CM), and secreted from the basolateral aspects of the enterocyte into the lymph. [Homan 1997, page 32][Hernandez et al, p232, 233] Enterocyte cholesterol homeostasis is partially maintained by the ATP-binding cassette transporter 1 (ABCA1). ABCA1 is up-regulated by cellular cholesterol and functions to transport cholesterol out of the cell. [Oram 2001, page 1173][Schmitz 2001, page 129][Repa 2000, page 1526]

Steps of Cholesterol Absorption Emulsification Transfer from bile acid micelle to brush border Transport to endoplasmic reticulum Esterification (ACAT) Incorporation into chylomicrons Secretion from basolateral surface Movement into lymph Key point: The process of cholesterol absorption is complex and currently only partly understood. The cholesterol which enters the intestine from either dietary (~300 mg/day) or biliary sources (~900 mg/day), is first emulsified by bile acids in the lumen of the duodenum forming mixed lipid micelles. [Homan 1997, page 30, 31][Hernandez 2000, page 232] These bile acid micelles are then transported to the brush border of enterocytes in the jejunum, where cholesterol is transported across the membrane by processes still not clearly understood. [Homan 1997, page 30, 31, 32] Once inside the enterocytes, cholesterol is esterified by acyl-coenzyme A: cholesterol acyltransferase (ACAT) and transferred to the endoplasmic reticulum where it is assembled into chylomicrons (CM), and secreted from the basolateral aspects of the enterocyte into the lymph. [Homan 1997, page 32][Hernandez 2000, page 232, 233] Hernandez M, et al. Biochim Biophys Acta. 2000;1486:232-242.

Pathways Affecting Cholesterol Balance Liver (Intake) (Excretion) ABCA1 HMG CoA Reductase (Esterification) (Synthesis) Key point: Multiple processes are involved in cholesterol absorption and synthesis. Dietary cholesterol can be reduced simply by decreasing intake. Bile acid sequestrants such as cholestyramine and colestipol bind to bile acids, blocking their normal resorption. This leads to increased hepatic conversion of cholesterol to bile acids to maintain the bile acid pool, with a resultant decrease in plasma cholesterol concentrations. [Illingworth 2000, page 33] [Knopp 1999, page 504] Plant stanol esters, such as sitostanol, are structurally similar to cholesterol but are poorly absorbed. They compete with cholesterol for incorporation into micelles, reducing micellar cholesterol and increasing cholesterol excretion. [Cater 2000, page 122][Homan 1997, page 33] [Hallikainen 2000, page 772] [Ikeda 1988, page 1573] (Bile Acids) (Micellar Cholesterol) (Uptake)

Pathways Affecting Cholesterol Balance Dietary Cholesterol Biliary Cholesterol Intestinal Epithelial Cell (Intake) CM (Excretion) Cholesterol Esters Luminal Cholesterol ACAT ABCA1 ABCG5 ABCG8 Bile Acids (Esterification) (Bile Acids) Key point: The process of cholesterol absorption is complex and currently only partly understood. Cholesterol absorption is a complex, multistep process. Methods of affecting these processes include reducing dietary cholesterol by decreasing intake. Bile acid sequestrants such as cholestyramine and colestipol bind to bile acids, blocking their normal resorption. This increases bile acid excretion resulting in a net cholesterol loss. [Illingworth 2000, page 33][Knopp 1999, page 504] The packaging of cholesterol in micelles can be reduced through the use of plant stanol esters, such as sitostanol. These esters are structurally similar to cholesterol and competitively compete with cholesterol for incorporation into micelles. [Cater 2000, page 122][Homan 1997, page 33][Hallikainen 2000, page 772][Ikeda 1988, page 1573] Since cholesterol must be packaged in micelles in order to cross the basement membrane of enterocytes, this effectively decreases cholesterol uptake and increases cholesterol secretion. ABCG5 and ABCG8 are proteins involved in sterol excretion. [Berge, 2000, page 1771] ABCA1 is up-regulated by cellular cholesterol and functions to transport cholesterol out of the cell. [Oram 2001, page 1173][Schmitz 2001, page 129][Repa 2000, page 1526] (Sequestrants, Ursodeoxycholate, Stanols) Micellar Cholesterol (Micellar Cholesterol) Cholesterol Transporter Cholesterol (Uptake)

Conclusions Cholesterol metabolism depends on the delicate interplay of multiple pathways These pathways maintain a net cholesterol balance between cholesterol synthesis and absorption on one side and cholesterol excretion on the other Cholesterol metabolism depends on the delicate interplay of multiple pathways. These pathways maintain a net cholesterol balance between cholesterol synthesis and absorption on one side and cholesterol excretion on the other.