CH 12: Lipid metabolism

fatty acids and triacylglycerols: important source of energy for many living cells. In animals most fatty acids are obtained in diet. These are digested in small intestine by pancreatic lipase to form fatty acids and monoacylglycerol. 

monoacylglycerol: transported across the plasma membrane of intestinal wall cells and converted to triacylglycerols. depending on an animals current needs fatty acids may be converted to triacylglycerol or degraded to generate energy or used in membrane synthesis. 

high serum glucose levels: insulin stimulates triacylglcerol formation in adipose tissue. 

low serum glucose levels: many hormones stimulate triacylglycerol degradation to form glycerol and fatty acids. 

lipogenesis: triacylglycerol synthesis, in this pathway glycerol-3-phosphate or dihydroxy acetone phosphate reacts sequentially with three molecules of acyl-CoA (fatty acid esters CoASH). 

phosphatidic acid formation: 2 sequential acylation of glycerol-3-phosphate or by direct acylation of dihydroxy acetone phosphate. 

phosphatidic acid function: converted to diacylglycerol by phosphatidic acid phosphatase. a third acylation reaction forms triacylglycerol. fatty acid derived from diet and de novo (newly synthesized) synthesis are incorporated into triacylglycerol . 

lipolysis: in the body under low energy condition, stored fat is metabolized by this process. 

when does lipolysis occur: during fasting, vigorous exercise, and in response to stress. 

lipolysis activation: hormones like glucagon and epinephrine bind to specific adipocyte plasma membrane receptors begin the sequential activation of lipase enzyme by activating cAMP synthesis. 

products of lipolysis: fatty acids and glycerol are released into the blood. 

glycerol: transported to liver where it can be used to form either glucose or a lipid

fatty acids: bind to serum albumin and are transported to various tissues where they are oxidized to generate energy. 

fatty acids function: degraded to form acetly-CoA within mitochondria in a process referred to as beta-oxidation. beta-oxidation is also known to occur in peroxisomes. certain non-standard fatty acids are oxidized in different pathway known as alph-oxidation. 

alpha oxidation location: primarily occurs in mitochondria. 

step 1 of beta oxidation: fatty acid is activated in reaction with ATP and CoASH catalyzed by Acyl Co-A ligase in mitochondrial outer membrane.

step 2 of beta oxidation: Mitochondrial inner membranes are impermeable to Acyl-CoA, therefore they are attached to carrier protein via attachment to a molecule known as ‘Carnitine’ which transport them to matrix of mitochondria.

step 3 of beta oxidation: Once the Acyl-CoA is in matrix the b-oxidation begins with oxidation-reduction reaction catalyzed by acyl-CoA dehydrogenase, in which one hydrogen atom is removed from the a and b carbons to form Enoyl-CoA. FADH₂ is the byproduct which enters into ETC.

step 4 of beta oxidation: Enoyl-CoA is hydrated by Enoyl-CoA hydrase to form          L-b- Hydroxyacyl-CoA. This is further oxidized by L-b Hydroxyacyl-CoA dehydrogenase to b Ketoacyl-CoA generating NADH. 

step 5 of beta oxidation: In the final step, by thiolytic cleavage an acetyl-CoA molecule is released with Acyl-CoA as the other product. This cycle continues till the formation of last two molecules of Acetyl-CoA.

acetyl-CoA: most is produced during fatty acid oxidation is used by citric cycle or in isoprenoid synthesis. Since fatty acid metabolism is carefully regulated, only small amount of excess  is produced in cell under normal conditions. 

ketogenesis: Acetyl-CoA molecules are converted to acetoacetate, beta  Hydroxybutyrate, and acetone a group of molecules called ‘Ketone bodies’ through this process. 

step 1 of ketogenesis: begins with condensation of two acetyl-CoA to form acetoacetyl-CoA which condenses with another molecule of acetyl-CoA to form b Hydroxy -b methyl-glutaryl-CoA(HMG-CoA).

step 2 of ketogenesis: In the next reaction HMG-CoA is cleaved to form acetyl-CoA and acetoacetate.

step 3 of ketogenesis: Acetoacetate is then reduced to form b-Hydroxybutyrate.

step 4 of ketogenesis: Acetone is formed from acetoacetate by spontaneous decarboxylation at high concentration of acetoacetate.  Ketosis is observed in uncontrolled diabetic conditions. During prolonged starvation brain cells use ketone bodies as energy source. 

cholesterol derivation: derived from diet or synthesized de novo. When enough cholesterol is provided through diet, the synthesis in the body is depressed. Cholesterol biosynthesis is stimulated when the diet is low in cholesterol.

what cells in the body make the most cholesterol: liver cells 

stage one of cholesterol synthesis: Formation of HMG-CoA from acetyl-CoA.

stage two of cholesterol synthesis: Conversion of HMG-CoA to squalene

stage three of cholesterol synthesis: Conversion of squalene to cholesterol.

first phase of cholesterol biosynthesis and ketosis: the same until the formation of HMG-CoA. 

second phase of of cholesterol synthesis: HMG-CoA is reduced to form mevalonate. NADPH is the reducing agent and the reaction is catalyzed by HMG-CoA reductase. Series of cytoplasmic reactions convert mevalonate to farnesylpyrophosphate. Squalene is synthesized when two molecules of farnesylpyrophosphates are condensed by farnesyl transferase or squalene synthase enzyme. This reaction requires NADPH.

conversion of squalene to lanosterol: Multiple enzymes like squalene monooxygenase and 2,3-oxidosqualene lanosterol cyclase

formation of cholesterol: In a series of transformation, lanosterol with the help of NADPH and oxygen, is converted to 7-Dehydrocholesterol which is then reduced by NADPH. 

cholesterol precursor: precursor for all steroid hormones and bile salts. Synthesis of steroid hormones through cholesterol is very complicated but completely understood.

cholesterol degradation: Unlike other biomolecules, cholesterols and steroids can not be degraded to smaller molecules but are derivatized to other products. One of the important such derivatives are bile acids which are formed from cholesterol. Bile acids are synthesized from cholesterol in liver.

bile: used in small intestine to enhance the absorption of dietary fat. Bile salts act as emulsifying agent which break up large droplets into smaller ones. Bile salts are also involved in the formation of biliary micelles, which aid in absorbing fat and the fat soluble vitamins (A,D,E, and K).