digestion and metabolism of lipids

Cholesteryl ester degradation?

Cholesteryl esters are hydrolyzed by pancreatic cholesteryl ester hydrolase (cholesterol esterase) = yield cholesterol + free fatty acid. activity is greatly increased in the presence of bile salts.

Phosholipid degradation?

Phospholipase A2 removes one fatty acid from carbon 2 of phospholipid, leaving lysophospholipid. the remaining fatty acid at carbon 1 can be removed by lysophophoslipase, leaving a glycerolphosphoryl base that may be excreted in the feces, further degraded or absorbed.

from where can we get liver cholesterol in the body?

dietary cholesterol -> chylomicron remnants or cholesterol from extrahepatic tissues -> HDL or de novo synthesis in the liver.

why emulsification of dietary lipid in the small intestine before breakdown? explain the method.

emulsification increases the surface area of hydrophobic lipid droplets so that the digestive enzymes can act more effectively to diget TAG. (lipids are hydrophobic and poorly soluble in the aqueous environment of the digestive tract, meanwhile lipase is water soluble and can only work at the surface of fat globubles). emulsification uses the detergent properties of the bile salts, and mechanical mixing of peristalsis. Colipase - an amphiphatic protein that binds and anchors lipase at the surface of the emulsion droplet. REMEMBER - bile salts are derivatives of cholesterol - its emulsifying agents (sterol structure with side chain to with glycine or taurine is covalently attached) interact with the lipid particles and stabilizes it as they become smaller, preventing them from re-associating.

where are ketone bodies important sources for energy and why is this?

ketone bodes are important sources of energy for the peripheral tissues because: - they are soluble in aqueous solution and therefore, do not need to be incorporated into lipoproteins or carried by albumin - they are produced in the liver during periods when amount of acetyl CoA present exceeds the oxidative capacity of the liver - they are used in proportion to their concentration in the blood by extrahepatic tissues, such as the skeetal and cardiac muscle and renal cortex. even the brain use ketone bodies to help meet its energy needs if the blood levels rise sufficiently; thus, ketone bodies are "substitutes" of glucose. this is particularly important during prolonged periods of fasting.

name different types of lipids

triacylglycerides (glycerol backbone + fatty acids) phospholipids (derivatives of TAGs, glycerol backbone + 2 fatty acid + phosphate group modified by a polar molecule, such as choline) fatty acid (carboxylic acid grup COO- with long hydrocarbon chain) steroids (4 rings in specific configuration)

what happens in the liver during fasting?

- liver is flooded with fatty acids mobilized from adipose tissue - elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (pyruvate -> acetyl coA) and activates pyruvate carboxylase - the OAA thus produced is used for gluconeogenesis rather than TCA - therefore, acetyl CoA is channeled into ketone body synthesis -> fatty acid oxidation decreases NAD+ to NADH ratio, and the rise in NADH shifts OAA to malate. this pushes acetyl CoA away from gluconeogensis and into ketogenesis.

describe beta oxidation

- major mitochondrial pathway for catabolism of fatty acids - two carbon fragments are successively removed from the carboxyl end of fatty acyl CoA, producing acetyl CoA, NADH and FADH2.

name the main functions of lipids

- major source of energy in the body - provide hydrophobic barrier that permits partioning of the aqueous contents of cells and subcellular structures - form basis of cellular membranes (phospholipid bilyaer) - steroid hormones play major roles in control of body homeostasis

describe the reactions of beta oxidation

- sequence of four reactions involving the β-carbon (carbon 3) that results in shortening the fatty acid chain by two carbons. - oxidation that produces FADH2, a hydration step, a second oxidation that produces NADH, and a thiolytic cleavage that releases a molecule of acetyl CoA. - each step is catalyzed by enzymes with chainlength specificity. - for saturated fatty acids of even-numbered carbon chains, steps are repeated (n/2) - 1 times (where n is the number of carbons) - each cycle producing an acetyl group plus one NADH and one FADH2. - The final thiolytic cleavage produces two acetyl groups. [Note: Acetyl CoA is a positive allosteric effector of pyruvate carboxylase, thus linking fatty acid oxidation and gluconeogenesis.]

describe cholesterol function

- structural component of all cell membranes, modulating their fluidity - in specialized tissue, it is precursor of bile acids, steroid hormones and vitamin D - can be eliminated from the liver as unmodified cholesterol in bile, or be converted to bile salts that are secreted into the intestinal lumen and eliminated in feces. can also serve as component of plasma lipoproteins sent to the peripheral tissues. - part of chylomicron

how is cholesterol synthesized?

- synthesized by virtually all tissues in humans but the largest contribution is in liver, intestine, adrenal cortex, reproductive tissue - carbon atoms in cholesterol are provided by acetate - enzymes involved are partly located in the ER and partly cytoplasm of liver. - first, two acetyl CoA molecules condense to form acetoacetyl CoA. next, a third molecule of acetyl CoA is added, producing HMG CoA, a six carbon compound. The next step is reduction of HMG CoA to mevalonate, catalyzed by HMG CoA reducate and is rate-limiting and key regulated step in cholesterol synthesis, occuring in the cytosol.

describe the structure of cholesterol

- very hydrophobic - four fused hydrocarbon rings (A-D) - has an 8-carbon branched hydrocarbon chain attached to carbon 17 of D ring. - 27 carbons in total - doublebond between C5-C6 (ring B)

describe regulation of cholesterol synthesis

HMG CoA reducate is the rate-limiting enzyme, and a major control point for cholesterol biosynthesis. When sufficient cholesterol is in the cell, transcription of the gene for HMG-CoA reducatse is suppressed and cellular synthesis of cholesterol is decreased = negative feedback regulation. The amount (and, therefore, the activity) of HMG CoA reductase is controlled hormonally. An increase in insulin and thyroxine favors up-regulation of the expression of the gene for HMG CoA reductase. Glucagon and the glucocorticoids have the opposite effect. Statin drugs are structural analogs of HMG CoA, and are reversible, competitive inhibitors of HMG CoA reductase. They are used to decrease plasma cholesterol levels in patients with hypercholesterolemia

TAG degradation - how? why?

TAG molecules are too large to be taken up efficiently by mucosal cells of intestinal villi -> acted upon by pancreatic lipase (esterase) which removes fatty acids at carbon 1 and 3 = 2 monoacylglycerol + free fatty acid. Colipase restores activity to lipase in the presence of inhibitory substances like bile acids that bind the micelles

What is the energy yield from fatty acid oxidation?

The energy yield from the β-oxidation pathway is high. For example, the oxidation of a molecule of palmitoyl CoA to CO2 and H2O produces 8 acetyl CoA, 7 NADH, and 7 FADH2, from which 131 ATP can be gener- ated; however, activation of the fatty acid requires 2 ATP. Thus, the net yield from palmitate is 129 ATP

what happens to the products of lipid digestion once they have entered the enterocytes?

The mixture of lipids absorbed by the enterocytes migrates to the endoplasmic reticulum where biosynthesis of complex lipids takes place. fatty acids and 2-monoacylglycerols are converted to TAGs by the enzyme complex, TAG synthase. Virtually all long-chain fatty acids entering the enterocytes are used in this fashion to form TAGs, phospholipids, and cholesteryl esters. Short- and medium-chain length fatty acids are not converted to their CoA derivatives, and are not reesterified to 2-monoacylglycerol. Instead, they are released into the portal circulation, where they are carried by serum albumin to the liver.

what happens after they have been re-synthesized into TAG?

The newly resynthesized TAGs and cholesteryl esters are very hydrophobic, and aggregate in an aqueous environment. It is, there- fore, necessary that they be packaged as particles of lipid droplets surrounded by a thin layer composed of phospholipids, unesterified cholesterol, and a molecule of the characteristic protein, apolipoprotein B-48. This layer stabilizes the particle and increases its solubility, thereby preventing multiple particles from re-associating. The particles are named chylomicrons and are lipoproteins, special particles that are designed for the transport of lipids in circulation. Chylomicrons are released by exocytosis from enterocytes. Because they are particles, they are too large to enter typical capillaries. Instead they enter lacteals, lymphatic capillaries that poke up into the center of each villus. Chylomicrons then flow into the circulation via lymphatic vessels, which drain into the general circulation at the large veins in the chest. Chylomicrons deliver absorbed TAG to the body's cells. TAG in chylomicrons and other lipoproteins is hydrolyzed (BROKEN DOWN) by lipoprotein lipase, an enzyme that is found in capillary endothelial cells. Monoglycerides and fatty acids released from digestion of TAG then diffuse into cells.

explain the transport of long fatty acid chains into the mitochondria

after long chain fatty acids enters a cell, it is converted in the cytosol to its CoA derivative by LCFA CoA synthase (thiokinase). because beta oxidation happens inside the mitochondria and the mitochondrial membrane is impermeable to CoA, it uses a specialized carrier transport carnitine, and this rate-limiting transport process is called the carnitine shuttle - carnitine is obtained from diet, particularly meat products. it can also be synthesized from lysine and ethionine in liver and kidney. Fatty acids shorter than 12 carbons can cross the inner mitochondrial membrane without the aid of carnitine or the CPT system. Once inside the mitochondria, they are activated to their CoA derivatives by matrix enzymes, and are oxidized.

what are ketone bodies?

an alternative fuel for cells. liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies. ketone bodies are acetoacetate, 3-hydroxybyturate (beta) and acetone (a nonmetabolized side product). acetoacetate and 3-hydroxybyturate are transported in the blood to the peripheral tissues. they they can be reconverted to acetyl coA which can be oxidized by the TCA cycle.

describe fate of free fatty acids and glycerol

fate of free fatty acids: 1. Fate of free fatty acids: The free fatty acids derived from the hydrolysis of TAG may either directly enter adjacent muscle cells or adipocytes, or they may be transported in the blood in association with serum albumin until they are taken up by cells that can oxidize fatty acid to produce TAG molecules, which are stored until the fatty acids are needed by the body. fate of glycerol: Glycerol that is released from TAG is used almost exclusively by the liver to produce glycerol 3-phosphate, which can enter either glycolysis or gluconeogenesis by oxidation to dihydroxyacetone phosphate.

what happens after these lipids have been degraded?

main products after lipid digestion are : free fatty acids free cholesterol 2-monoacylglycerol these + bile salts + fat-soluble vitamins form mixed micelles - disk shaped clusters of amphipathic lipids with hydrophobic groups on the inside and hydrophilic on the outside. These particles approach the primary site of lipid absorption, the brush border membrane of the mucosal cells. This membrane is separated from the liquid contents of the intestinal lumen by an unstirred water layer that mixes poorly with the bulk fluid. The hydrophilic surface of the micelles facilitates the transport of the hydrophobic lipids through the unstirred water layer to the brush border membrane where they are absorbed.