MCAT Biochemistry Chapter 11: Lipid and Amino Acid Metabolism

Lipid Digestion

• occurs mostly intestine

  • Duodenum: emulsification occurs, the mixing of two normally immiscible liquids 

    • Aided by bile salts, pigments, and cholesterol 

    • Emulsion increases surface area of lipid for greater enzymatic activity

• Pancreatic lipase, colipase and cholesterol esterase (from pancreas) hydrolyze lipid components to 2-monoacylglycerol, free fatty acids, and cholesterol

Micelles

• clusters of amphipathic lipids soluble in aqueous environments 

  • Aid in digestion, transport, and absorption of lipid soluble substances from duodenum to ileum 

  • Have water soluble exterior and lipid soluble interior 

  • Formed from free fatty acids, cholesterol, 3-monoacylglycerol, and bile salts

Absorption of Lipids

absorbed as micelles

• Micelles diffuse to brush border of intestinal mucosal cells where they are absorbed in mucosa, re-esterified to form triacylglycerols and cholesterol esters, and packaged into chylomicrons

Lipid Mobilization

key transport proteins

• hormone -sensitive lipase (HSL):

• Lipoprotein lipase (LPL):

hormone -sensitive lipase (HSL)

• hydrolyzes triacylglycerols, yielding fatty acids and glycerol ; effective within adipose cells

  • key in lipid mobilzation

  • activated by glucagon and epinephrine

Lipoprotein lipase (LPL)

• necessary for metabolism of chylomicrons and very-low density lipoproteins 

  • Releases free fatty acids from triacylglycerols in lipoproteins 

  • inhibited by glucagon and activated by insulin

Lipoproteins

• ggreagates of apolilproteins and lipids

  • Named according to their density, which increases in direct proportion to the percentage of protein in the particle 

  • aid in lipid transport

Lipoprotein Organization

• From least dense to most

1. Chylomicrons

2. VLDL (Very low density lipoprotein)

3. IDL (intermediate density lipoprotein

4. LDL ( low density lipoprotein)

5. HDL (high density lipoprotein) 

Chylomicrons

transports dietary triacylglycerols, cholesterol, and cholesteryl esters from intestines to tissues

VLDL (very low density lipoproteins)

transports triacylglycerols and fatty acids from liver to tissues

IDL (intermiediate density lipoprotein)

• remnants of VLDLs

  • pick up cholesteryl esters from HDL to become LDL

  • picked up by the liver

LDL (low density lipoproteins)

picks up cholesteryl esters from HDL to become LDL

• picked up by the liver

HDL (high density lipoproteins)

picks up cholesterol aacumulating in blood vessels

• delivers choleesterol to liver and steroidogenic tissues

• transfers apolipoproteins to other lipoproteins

Apoliproteins

• Receptor molecules that are involved in signaling 

  • Has specific types that signal different lipoproteins along lipid transport pathway

Lipid Transport in Lipoproteins

Cholesterol

a ubiquitous component of all cells in the human body 

• Plays major role in the synthesis of cell membrane, bile acids, and vitamin D

Sources of Cholesterol

• Most are derived from LDL or HDL but some may be synthesized (de novo) in the liver 

  • De novo synthesis is driven by acetyl CoA and ATP 

    • Citrate shuttle carries mitochondrial acetyl-CoA into cytoplasm, where synthesis occurs 

Rate limiting Enzyme of CHolesterol Synthesis

• 3-hydroxy-3-methylglutaryl (HMG) CoA reductase 

  • Involved in synthesis of mevalonic acid in smooth endoplasmic reticulum 

Regulatin of Cholesterol Synthesis

• Increased levels of cholesterol inhibit further synthesis (feedback inhibition)

• Insulin promotes cholesterol synthesis 

• Regulation of HMG-CoA reductase gene expression

Special Enzymes of Cholesterol Transport

• Lecithin-cholesterol acyltransferase (LCAT)

• Cholesterol ester transfer proteins

Cholesterol ester transfer proteins

• transfer these to HDL; their addition to lipoproteins can form other lipoproteins (ex: IDL to LDL)

Lecithin-cholesterol acyltransferase (LCAT)

• enzyme in bloodstream activate by HDL apoprotiens

  • Adds a fatty acid to cholesterol, producing soluble cholesteryl esters 

Fatty Acids

 long chain carboxylic acids; carboxyl carbon is the alpha carbon 

• Named by number and isomerism (trans or cis) of double bonds

• Capable of forming micelles or are esterified to other compounds 

• 𝞪-linoeic acid and linoeic acid:

  • Polyunsaturated fatty acids important in maintaining structure and fluidity of cell membrane 

Nontemplate Synthesis

process where production does not rely on coding of a nucleic acid 

• describes synthesis of fatty acids

Fatty Acid Biosynthesis

Occurs in liver; products are transported to adipose tissue for storage 

• Major enzymes (acetyl-CoA carboxylase and fatty acid synthase) are stimulated by insulin

• inhibited by glucagon and epinephrine

Acetyl-CoA Shuttling

• occurs when cell becomes energetically satisfieda and acetyl-CoA accumulates in mitochondrial matrix

  •  isocitrate dehydrogenase causes citrate accumulation 

citrate Synthase and Acetyl-CoA Inhibitoin

• slows citric acid cycle and causes citrate accumulation 

  • Citrate lyase splits citrate back in to acetyl-CoA and oxaloacetate 

  • Oxaloacetate can return to mitochondria to continue moving acetyl-CoA

ACetyl-CoA Carboxylase

• Activated in cytoplasm for incorporation into fatty acids

• Requires biotin and ATO to function; adds CO₂ to acetyl-CoA to form malonyl-CoA 

Fatty Acid Synthase

• Large multienzyme complex found in the cytosol that is rapidly induced in the liver following a meal high in carbohydrates (because of elevated insulin) 

  • Contains an acyl carrier protein that requires pantothenic acid (vitamin B₅)

  • NADPH is requied to reduce acetyl group added to it 

• utilizes process that is exact opposite of beta oxidation synthesis 

Triacylglycerol (triglyeride) Synthesis

• process of storing fatty acids 

  • Formed by attaching three fatty acids to glycerol 

    • Occurs primarily in the liver and somewhat in adipose tissue 

    • Are packaged and sent to adipose tissue as VLDLs

    • activated by insulin

    • injhibited by glucagon and epinephrine

Fatty Acid CoA synyhetase

• activates fatty acids before being metabolized to form fatty acyl-CoA,

  • prepares for beta-oxdiation

Fatty Acid Oxidation

• Fatty acid catabolism proceeds via beta-oxidation that occurs in mitochondria 

  • Branched-chain fatty acids may also undergo alpha oxidation 

  • Insulin inhibits beta-oxidation indirectly  while glucagon stimulates it 

Fatty Acid Entry into Mitochondria

• Short chain and medium chain fatty acids diffuse freely into mitochondria where they are oxidized

• Long chains require transport via carnitine acyltransferase I 

  • Rate limiting enzyme of fatty acid oxidation 

Beta-Oxidation of Fatty Acids (process)

• Reverses the process of fatty acid synthesis by oxidizing and releasing molecules of acetyl-CoA 

• Pathway utilizes repetition of four steps

  • Each four step cycle releases one acetyl-CoA and reduces NAD+ and FAD which are then used to make ATP in electron transport chain

Beta-oxidation of Fatty Acids (yield)

• Even numbered fatty acids yield two acetyl-CoA molecules

• odd numbered fatty acids yield one acetyl-CoA and one propionyl-CoA 

Oxidation of unsaturated Fatty Acids

• Two additoinal enzymes are necessary because double bonds can disturb stereochemistry needed for oxidative enzymes to act on the fatty acid;

  • these enzymes have at most one double bond in their active site 

    • enoyl-CoA isomerase

    • 2,4-dienoyl-CoA

Enoyl-CoA isomerase

• rearrangese cis bonds at the 3,4 position to trans double bonds at the 2,3 position once enough acetyl-CoA has been liberated 

2,4-dienoyl-CoA

 in polyunsaturated fatty acids, converts two conjugated double bonds to just one double bond at the 3,4 position to undergo rearrangement as monounsaturated fatty acid (via enoyl-CoA isomerase)

Ketogenesis

Occurs in the mitochondria of liver cells when excess acetyl-Coa accumulates in the fasting state

Ketolysis

catabolism of ketone bodies; acetoacetate picked up from blood is activated in the mitochondria by succinyl-CoA acetoaceetyl-CoA-transferase  (thiophorase) 

• Liver does not possess this enzyme and is unable to catabolize ketone bodies it produces

Ketolysis and Ketogenesis

Ketolysis in the Brain

• When ketones are metabolized to acetyl-CoA, pyruvate dehydrogenase is inhibited 

• Glycolysis and glucose uptake in the brain decreases, spares essential proteins in the body

Protein Catobilism

Used in extreme conditions when no other form of energy is present 

• Proteolysis: breakdown of proteins 

  • begins in the stomach with pepsin and continues with pancreatic proteases trypsin, chymotrypsin, and carboxypeptidases A and B; all secreted as zymogens 

  • Brush border enzymes, dipeptidase and aminopeptidase, complete digestion in the small intestine 

Absorption of free aminos, dipeptides, and tripeptides

• Luminal membrane: Secondary active transport linked to sodium

• Basal membrane: simple and facilitated diffusion into bloodstream 

Catabolism of Body Protein

• occurs in liver; lose amino group through transamination or deamination

• Carbon skeleton used for energy

• Remaining aminos can be potentially toxic to the body and removed via the urea cycle