Chem 40 Lipid Metabolism

Hormones
Epinephrine and glucagon regulates the release of fatty acids from adipocytes Bind to receptor sites on the surface of adipocytes and initiate a process that generates an intracellular second messenger, cyclic AMP

Fatty Acids in Muscle Cells

Fatty acids are activated and at the same time labeled for energy degradation through thioester linkage to coenzyme A Acyl-CoA synthetase catalyze the activation process:

Ketone Bodies
Low carbohydrate diets, fasting, starvation and untreated diabetes excessive breakdown of fatty acids producing large amounts of acetyl-CoA Extra acetyl-CoA is diverted to production of ketone bodies predominantly in the liver but they can be distributed throughout the body via blood

 Oxidation of Unsaturated Fatty Acids

Unsaturated fatty acids are absorbed, transported, and activated in the same way as saturated

 Oxidation of Fatty Acids with Odd Numbers of Carbon

Catabolized by normal oxidation, only that the final cleavage yields an acetyl-CoA and a 3-C unit, propionyl-CoA Propionyl-CoA does not enter the citric acid cycle, instead, they are transformed first to succinyl-CoA

Biosynthesis of Fatty Acids

The amount of fat that can be stored in animals including humans is unlimited Glucose and other carbohydrates ingested in excess are also converted to fat

Enzymes for fatty acid synthesis are in the cytoplasm

Synthesis of Palmitate
Begins at the terminal methyl end and proceeds toward the carboxylate end C16-C15 comes directly from acetyl-CoA while other carbons come from acetyl-CoA activated as malonyl-CoA

Synthesis of Palmitate
Acetyl-CoA carboxylase (biotin requiring enzyme) catalyzes the formation of malonyl-CoA from acetyl-CoA

Positive modulator of the allosteric enzyme citrate Inhibitor palmitoyl-CoA which is the end-product

-ketoacyl-ACP synthase

-ketoacyl-ACP synthase

palmitoyl thioesterase

 Synthesized in the endoplasmic reticulum by enzymes called fatty acyl-CoA desaturases

Biosynthesis of Unsaturated Fatty Acids

Catalyze redox reactions where O2 can act as electron acceptor Linoleate (18:29,12) and linolenate (18: 18:39,12,15) essential for proper growth, cannot be synthesized and must be obtained from diet so they are called essential fatty acids

Regulation of Fatty Acid Metabolism

If glucose is high, high levels of citrate are produced Citrate is a positive modulator for acetyl-CoA carboxylase which catalyzes the formation of malonyl-CoA

So with increasing citrate, fatty acid synthesis is high

Regulation of Fatty Acid Metabolism

Malonyl-CoA produced in fatty acid synthesis can inhibit the oxidation of fatty acids prevent substrate cycle Malonyl-CoA blocks the action of carnitine acyltransferase I, which transport the fatty acylCoA into the mitochondrial matrix The rate of fatty acid synthesis is regulated by the end product, palmitoyl-CoA which inhibits acetylCoA carboxylase

Regulation of Fatty Acid Metabolism

With abundant glucose, fatty acid oxidation is turned off and fatty acid synthesis is active but regulated by levels of palmitoyl-CoA During fasting, hormones stimulate lipase to release fatty acid from adipocyte Low level of malonyl-CoA to inhibit carnitine acyltransferase I so fatty acid can go inside the matrix of the mitochondria so enhanced oxidation

Cholesterol As Precursor

Bile Salt
Polar, steroid derivatives synthesized in the liver, stored in the gallbladder, and secreted into the intestines to assist in the solubilization of dietary fats

Essential process not only for the production of the digestion-aiding chemicals but also for the degradation and removal of cholesterol
Natural elimination of cholesterol

-ketoacyl-ACP synthase

palmitoyl thioesterase

Steroidal Hormones
Progesterone regulates physiological changes in pregnancy Glucocorticoids influence metabolism by promoting gluconeogenesis, glycogen formation and fat breakdown Mineralocorticoids regulate absorption of Na+, Cl- and HCO3in the kidney Androgens promote development of male sex characteristics Estrogen - promote development of female sex characteristics

Vitamin D3
Regulates calcium and phosphorus metabolism Human deficiency of vitamin D3 results in rickets bone malformation resulting from improper calcium and phosphorus metabolism

Transport of Lipids in Blood

Lipoproteins serum particles containing specific proteins called apolipoproteins and diverse combinations of triacylglycerols, cholesterol and cholesteryl esters Lipids and proteins are noncovalently associated into water-soluble complexes Composed of central core of neutral, nonpolar lipid surrounded by a shell of phospholipids and proteins Surface is coated with hydrophilic groups of polar lipids and proteins to interact with water for solubilization.

Major Lipoproteins
Chylomicrons least dense and consist of 98 to 99% lipid material Formed by the association of dietary tryacylglycerols and cholesterol with specific proteins to assist in lipid digestion and transport Assembled in the intestines from dietary lipids and absorbed into the bloodstream, where they are transported to peripheral tissue

Major Lipoproteins
Very Low Density Lipoproteins (VLDL) produced in the liver from triacylglycerols synthesized in the liver

Deliver synthesized lipids to adipose and other peripheral tissue for storage or energy use

Major Lipoproteins
Low Density Lipoproteins (LDL) major carriers of cholesterol on the blood Move cholesterol and cholesteryl esters from the liver, where they are synthesized, to peripheral tissues Regulates cholesterol metabolism

Major Lipoproteins
High Density Lipoproteins have the highest content of protein of any of the lipoproteins (55% protein, 45% lipid) most dense Primary lipids in the core are cholesterol and cholesteryl esters

Transport cholesterol and its esters from peripheral tissue to the liver
Synthesized in the liver but in a rather incomplete form, then they move through the bloodstream where they collect excess cholesterol and transport it to the liver reverse cholesterol transport

Cholesterol and Health

Too much in the blood and tissue leads to its accumulation, especially in the arteries, causing blockage Cholesterol is deposited in arterial plaques which results to hardening of the arteries or atherosclerosis Familial hypercholesterolemia genetic disease that causes cholesterol levels to approach 700mg/100mL of blood Caused by genetic defects in the protein components required for cholesterol transport and uptake