R

CH2 CH2 O-(p~(P) Mevalonate 3-phospho-5-diphosphate

DIPHOSPHOMEVALONATE KINASE

ch3 oh

CH2 CH2 O-(p~(P) Mevalonate 5-diphosphate

HMG-CoA

trans-Methyl- i CH3

glutaconate [ I

DIPHOSPHOMEVALONATE KINASE

ISOPENTENYL-DIPHOSPHATE ISOMERASE

3,3-Dimethylallyl diphosphate

ISOPENTENYL-DIPHOSPHATE ISOMERASE

Isopentenyl tRNA

C/S-PRENYL TRANSFERASE

Isopentenyl diphosphate

Prenylated proteins

CH2 C CH2

Side chain of ubiquinone

Heme a

Side chain of ubiquinone

SQUALENE SYNTHETASE

Farnesyl diphosphate

C/S-PRENYL TRANSFERASE

SQUALENE SYNTHETASE

Farnesyl diphosphate

Dolichol

2PP|

NADP+

Squalene

Figure 26-2. Biosynthesis of squalene, ubiquinone, dolichol, and other polyisoprene derivatives. (HMG, 3-hydroxy-3-methylglutaryl; x, cytokinin.) A farnesyl residue is present in heme a of cytochrome oxidase. The carbon marked with asterisk becomes C11 or C12 in squalene. Squalene synthetase is a microsomal enzyme; all other enzymes indicated are soluble cytosolic proteins, and some are found in peroxisomes.

Triparanol

Figure 26-3. Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. Asterisks: Refer to labeling of squalene in Figure 26-2.

Triparanol

Figure 26-3. Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. Asterisks: Refer to labeling of squalene in Figure 26-2.

HMG-CoA LDL-cholesterol

Cholesterol

Oxysterols ■

HMG-CoA

REDUCTASE

(active)

Pi^

©

----v

---Insulin

---Insulin

Glucagon

Figure 26-4. Possible mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin has a dominant role compared with glucagon. Asterisk: See Figure 18-6.

Glucagon

Enzyme synthesis

Figure 26-4. Possible mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin has a dominant role compared with glucagon. Asterisk: See Figure 18-6.

membrane; cholesterol synthesis; and hydrolysis of cholesteryl esters by the enzyme cholesteryl ester hydrolase.

Decrease is due to efflux of cholesterol from the membrane to HDL, promoted by LCAT (lecithin:cholesterol acyltransferase) (Chapter 25); esterification of cholesterol by ACAT (acyl-CoA:cholesterol acyltransferase); and utilization of cholesterol for synthesis of other steroids, such as hormones, or bile acids in the liver.

The LDL Receptor Is Highly Regulated

LDL (apo B-100, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the membrane, the B-100 binding region being at the exposed amino terminal end. After binding, LDL is taken up intact by endocytosis. The apoprotein and cholesteryl ester are then hydrolyzed in the lysosomes, and cholesterol is translocated into the cell. The receptors are recycled to the cell surface. This influx of cholesterol inhibits in a coordinated manner HMG-CoA synthase, HMG-CoA reductase, and, therefore, cholesterol synthesis; stimulates ACAT activ ity; and down-regulates synthesis of the LDL receptor. Thus, the number of LDL receptors on the cell surface is regulated by the cholesterol requirement for membranes, steroid hormones, or bile acid synthesis (Figure 26-5). The apo B-100, E receptor is a "high-affinity" LDL receptor, which may be saturated under most circumstances. Other "low-affinity" LDL receptors also appear to be present in addition to a scavenger pathway, which is not regulated.

CHOLESTEROL IS TRANSPORTED BETWEEN TISSUES IN PLASMA LIPOPROTEINS (Figure 26-6)

In Western countries, the total plasma cholesterol in humans is about 5.2 mmol/L, rising with age, though there are wide variations between individuals. The greater part is found in the esterified form. It is transported in lipoproteins of the plasma, and the highest proportion of cholesterol is found in the LDL. Dietary cholesterol equilibrates with plasma cholesterol in days

CELL MEMBRANE

CELL MEMBRANE

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by preß HDL binding to the ABC-1 transporter protein via apo A-I. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol; CE, cholesteryl ester; PL, phospholipid; ACAT, acyl-CoA:cholesterol acyltransferase; LCAT, lecithin:cholesterol acyltransferase; A-I, apolipoprotein A-I; LDL, low-density lipoprotein; VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by preß HDL binding to the ABC-1 transporter protein via apo A-I. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol; CE, cholesteryl ester; PL, phospholipid; ACAT, acyl-CoA:cholesterol acyltransferase; LCAT, lecithin:cholesterol acyltransferase; A-I, apolipoprotein A-I; LDL, low-density lipoprotein; VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

and with tissue cholesterol in weeks. Cholesteryl ester in the diet is hydrolyzed to cholesterol, which is then absorbed by the intestine together with dietary unesteri-fied cholesterol and other lipids. With cholesterol synthesized in the intestines, it is then incorporated into chylomicrons. Of the cholesterol absorbed, 80-90% is esterified with long-chain fatty acids in the intestinal mucosa. Ninety-five percent of the chylomicron cholesterol is delivered to the liver in chylomicron remnants, and most of the cholesterol secreted by the liver in VLDL is retained during the formation of IDL and ultimately LDL, which is taken up by the LDL receptor in liver and extrahepatic tissues (Chapter 25).

Plasma LCAT Is Responsible for Virtually All Plasma Cholesteryl Ester in Humans

LCAT activity is associated with HDL containing apo A-I. As cholesterol in HDL becomes esterified, it cre ates a concentration gradient and draws in cholesterol from tissues and from other lipoproteins (Figures 26-5 and 26-6), thus enabling HDL to function in reverse cholesterol transport (Figure 25-5).

Cholesteryl Ester Transfer Protein Facilitates Transfer of Cholesteryl Ester From HDL to Other Lipoproteins

This protein is found in plasma of humans and many other species, associated with HDL. It facilitates transfer of cholesteryl ester from HDL to VLDL, IDL, and LDL in exchange for triacylglycerol, relieving product inhibition of LCAT activity in HDL. Thus, in humans, much of the cholesteryl ester formed by LCAT finds its way to the liver via VLDL remnants (IDL) or LDL (Figure 26-6). The triacylglycerol-enriched HDL2 delivers its cholesterol to the liver in the HDL cycle (Figure 25-5).

ENTEROHEPATIC CIRCULATION

ENTEROHEPATIC CIRCULATION

Figure 26-6. Transport of cholesterol between the tissues in humans. (C, unesterified cholesterol; CE, cho-lesteryl ester; TG, triacylglycerol; VLDL, very low density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; ACAT, acyl-CoA:cholesterol acyltransferase; LCAT, lecithin:cholesterol acyltransferase; A-I, apolipoprotein A-I; CETP, cholesteryl ester transfer protein; LPL, lipoprotein lipase; HL, hepatic lipase; LRP, LDL receptor-related protein.)

Figure 26-6. Transport of cholesterol between the tissues in humans. (C, unesterified cholesterol; CE, cho-lesteryl ester; TG, triacylglycerol; VLDL, very low density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; ACAT, acyl-CoA:cholesterol acyltransferase; LCAT, lecithin:cholesterol acyltransferase; A-I, apolipoprotein A-I; CETP, cholesteryl ester transfer protein; LPL, lipoprotein lipase; HL, hepatic lipase; LRP, LDL receptor-related protein.)

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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