Clinical chem final

What are the important roles of lipids?

• Act as hormones

• serves as an energy source

• Assisting in digestion

• Acting as structural components in cell membranes

What are lipoproteins?

Particles that transport lipids in our blood

What is atherosclerosis?

• A common disorder that occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques

  • Common cause of cardiovascular disease

Describe the chemical properties and structural characteristics of lipids, including their solubility, composition, and behavior in biological systems. In your answer, explain what makes some lipids amphipathic and discuss the structure and role of phospholipids in cell membranes, including any notable exceptions.

• Lipid applies to a class of compounds that are soluble in organic solvents having little or no polarity but nearly insoluble in water

• Properties and structure

  • Amphipathic

    • Lipids primarily contain nonpolar carbon-hydrogen bonds and often yield fatty acids and/or complex alcohols after hydrolysis

    • Contains charged or polar groups

  • Phospholipids

    • Amphipathic class of lipids that are a major components of all cell membranes as they form lipid bilayers

    • Most contain diglyceride, a phosphate group, and a simple organic molecule such as choline (exception is sphingomyelin - derived from sphingosine instead of glycerol)

Describe the structure and properties of cholesterol, including its chemical composition, polarity, and why it is able to function as an important component of cell membranes.

• Cholesterol is found exclusively in animals and is a key membrane of all cells

• A steroid alcohol with 27 carbon atoms that are arranged in a tetracyclical sterane ring system

  • Cholesterol is highly hydrophobic due to overwhelming size of non polar hydrocarbon skeleton

    • Contains a polar hydroxyl group on A ring

Explain how dietary cholesterol is processed and absorbed in the body. In your answer, include the typical daily intake and absorption rate, the role of cholesterol esterases in digestion, and the process of emulsification—highlighting the components of mixed micelles and the importance of bile acids.

• The average western diet contains around 300-450 mg of cholesterol per day (derived mostly from animal dairy but only 30-60% is absorbed

• Processing and absorption

  • esterified cholesterol contains a fatty acid attached to the hydroxyl group on the A ring is rapidly hydrolyzed in the intestine to free cholesterol and fatty acids by cholesterol esterase secreted from the pancreas and small intestine

  • Before it’s absorbed, cholesterol is first solubilized through a process called emulsification (involves formation of mixed micelles that contain unesterified cholesterol, fatty acids, monoglycerides, phospholipids, and conjugated bile acids)

    • Bile acids

      • Act as detergents and are the most critical factor in micelle formation

Explain the factors that influence cholesterol absorption in the small intestine. In your answer, discuss how dietary fat affects absorption, identify the primary sites of absorption, and describe the role of the NPC1L1 transporter, including how it is targeted by ezetimibe.

• Increased amounts of fat favor the absorption of cholesterol by the formation of more micelles

• Most cholesterol absorption occurs in the middle jejunum and the terminal ileum of the small intestine

  • Mediated by the enterocyte protein (NPC1L1) which is the target for the drug ezetimibe (blocks cholesterol absorption)

Describe what happens to cholesterol after it is absorbed into intestinal mucosal cells. In your answer, explain how it is packaged and transported in the body, the role of chylomicrons, and where cholesterol is synthesized, including an overview of the stages of its biosynthesis.

• Once cholesterol enters the intestinal mucosal cell, it’s packaged with triglycerides, phospholipids and a large protein (apolipoprotein - apo B-48) into large lipoprotein particles called chylomicrons

  • Chylomicrons are secreted into the lymph and eventually enter the circulation, where they deliver the absorbed dietary lipid to the liver and peripheral tissues

  • Cholesterol is synthesized by all cells in the body (mainly by liver and intestine)

    • Biosynthesis occurs in 3 stages

Describe the 3 stages of biosynthesis of cholesterol

• 1st stage

  • Acetyl-coenzyme A (CoA) forms the 6 carbon thioester 3-hydroxy-3-methyl-glutaryl (HMG)-CoA

• 2nd stage

  • HMG-CoA is reduced to mevalonate, which is then decarboxylated to a series of 5 carbon isoprene units that further condense to form a 10 carbon and then a 15 carbon intermediate (farnesyl pyrophosphate)

  • 2 of these 15 C molecules then combine to produce squalene (30 carbon acyclic hydrocarbon

  • This stage is important as it contains a step involving the microsomal enzyme HMG-CoA reductase, which is the rate-limiting enzyme in cholesterol biosynthesis

    • It’s inhibited by statins (most effective class of current cholesterol-lowering drugs)

  • 3rd stage

    • Occurs in the endoplasmic reticulum

    • Series of oxidation decarboylation reactions

      • A number of side chains are removed from the tetracyclical sterane ring structure to form the 27 C molecule of cholesterol

Explain how cholesterol is esterified in the body. In your answer, describe the roles of ACAT and LCAT, where these processes occur, and how cholesteryl esters are formed, stored, and transported.

• Cholesterol is esterified to a fatty acid to form cholesteryl ester by 2 different enzymes

  • Acylcholesterol acyltransferase (ACAT)

    • Helps reduce the cytotoxicity of excess free cholesterol, and once esterified, cholesteryl esters are stored in intracellular lipid drops

  • Lecithin cholesterol acyltransferase (LCAT)

  • A plasma enzyme bound to lipoproteins (HDL) that form cholesteryl esters in circulation

• The reaction involves the transfer of a fatty acid from the 2nd carbon position of phosphatidylcholine (lecithin) to cholesterol

Describe the characteristics and fate of cholesteryl esters in the body. In your answer, include their proportion in plasma cholesterol, how esterification affects their polarity and location in lipoproteins, their metabolism in peripheral cells, and why cholesterol must be transported back to the liver for further catabolism.

• Cholesterol esters account for about 70% of the total cholesterol in plasma

• Once cholesterol is esterified, it loses its free hydroxyl group and becomes nearly completely hydrophobic, moving from the surface of lipoprotein particles to the hydrophobic core

• Most peripheral cells have limited ability to further catabolize cholesterol (except for specialized endocrine cells)

• Cholesteryl esters are hydrolyzed to free cholesterol by various lipases in all cells, but cholesterol has to be returned to the liver to undergo any further catabolism

Explain the conversion and recycling of cholesterol into bile acids. In your answer, include the proportion of cholesterol converted daily, the process of enterohepatic circulation, the site of bile acid reabsorption, and the formation of secondary bile acids by intestinal bacteria.

• 1/3 of the daily production of cholesterol is converted in the liver into bile acids

  • About 90% are reabsorbed in the lower 1/3 of the ileum and are returned to the liver by the enterohepatic circulation

  • Bile acids that enter the large intestine are partially deconjugated by bacterial enzymes to secondary bile acids

Describe the different fates of cholesterol in the liver. In your answer, explain how cholesterol is processed, how it is excreted into bile, the role of bile acids and phospholipids in its solubilization, and how an imbalance can lead to the formation of gallstones.

• Not all cholesterol delivered to the liver is converted into bile salts and much is re-secreted into the circulation of lipoproteins

• Remainder is directly excreted into the bile unchanged, where it is solubilized into mixed micelles by bile acids and phospholipids

• When the amount of cholesterol in bile exceeds the capacity of these solubilizing agents, it is possible for cholesterol to precipitate and form gallstones

Explain how fatty acids are classified based on chain length and degree of saturation. In your answer, include the different categories of chain length, which types are most important in human metabolism, and the distinctions between saturated, monounsaturated, and polyunsaturated fatty acids.

• Classification

  • Short chain (2-4 C)

  • Medium chain (6-10 C)

  • Long chain (12-26 C)

• The most important type in human metabolism and nutrition are those in the long chain class and contain an even amount of C atoms

• Fatty acids are further classified according to their degree of saturation

• Saturated fatty acids have no double bonds between their carbons

• Monounsaturated fatty acids contain 1 double bond

• Polyunsaturated fatty acids contain multiple double bonds

  • The double bonds are usually 3 Cs apart

• Unsaturated fatty acids are prone to oxidation by the nonenzymatic reaction of oxygen with their double bonds

• Numbering of the carbon atoms is done from the carboxyl terminal end or from the methyl terminal end or q-numbering system

  • carbons with alpha (a) are adjacent to the carboxyl group

  • carbons with w are farther away from the carboxyl group

Compare the structural differences between saturated and unsaturated fatty acids. In your answer, describe the flexibility of saturated fatty acids, the presence of cis and trans configurations in unsaturated fatty acids, and explain how trans fatty acids are formed during hydrogenation and their role in food production.

• In saturated fatty acids the chain is extended and flexible (carbon atoms rotate freely around their longitudinal axis)

• In unsaturated fatty acids, they have fixed bends in their chains at each double bond (can either be cis or trans)

  • In mammals, naturally occurring unsaturated fatty acids are of the cis variety

  • Trans fatty acids are usually from isomerization of cis fatty acids during catalytic hydrogenation, in which unsaturated double bonds are chemically reduced to raise their melting point

Discuss the synthesis, forms, and physiological behavior of fatty acids in the body. In your answer, include which fatty acids are considered essential, their metabolic roles, how fatty acids are transported in the blood, their ionization at physiological pH, and how their plasma concentration is regulated.

• Most fatty acids are synthesized by the body (except linoleic acid - made by plants)

  • Linoleic acid is also converted into arachidonic acid (precursor for prostaglandin synthesis)

• Fatty acids exist in the circulation in an unesterified or free state, the latter is primarily bound to albumin or in various esterified forms (triglycerides, phospholipids)

• Free fatty acid carboxyl group has pKa of 4.8, so free fatty acid molecules exist primarily in their ionized forms at a physiological pH

Explain the process of fatty acid catabolism through β-oxidation. In your answer, describe how fatty acids are broken down in the mitochondria, the production of acetyl-CoA, how it enters the Krebs (tricarboxylic acid) cycle, and how this process leads to ATP generation.

• Fatty acids are catabolized in the mitochondria and produce energy by a series of reactions known as B-oxidation

  • Repeated to shorten the fatty acid chain by 2 carbon atoms at a time from carboxyl terminal end

• Acetyl-CoA doesn’t normally accumulate in the cell but is condensed enzymatically with oxaloacetate, derived from carbohydrate metabolism to yield citrate

• The krebs cycle is a common pathway for the final oxidation of nearly all metabolic fuels, whether derived from carbohydrate, fat, or protein, and results in the production of ATP

Explain the role of triglycerides in energy storage and metabolism. In your answer, describe why triglycerides are an efficient form of energy storage, how they differ from carbohydrates in storage, and explain how excessive acetyl-CoA leads to ketone body formation and ketosis during conditions such as starvation or uncontrolled diabetes.

Ch 23 pg 24