Chapter 11: Lipid and Amino Acid Metabolism

Dietary Fats

1. Triacylglycerols 2. Cholesterol 3. Cholesteryl esters 4. Phospholipids 5. Free fatty acids

Two Important Essential Fatty Acids

1. α-linolenic Acid 2. Linoleic Acid These are important in maintaining cell membrane fluidity, which is critical for proper functioning of the cell.

Branched chain fatty acids may also undergo ______-oxidation, depending on the branch points.

Alpha

Fatty Acid Synthase

Also called palmitate synthase--> palmitate is the only fatty acid that humans can synthesize de novo. This enzyme is a large multi-enzyme complex found in the cytosol that is rapidly induced in the liver following a meal high in carbs because of elevated insulin levels. The enzyme complex contains an acyl carrier protein (ACP) that requires vitamin B5. NADPH is also required to reduce the acetyl groups added to the fatty acid. 8 acetyl-CoA groups are required to produce palmitate. SSynthesis includes 5 steps: activation, bond formation, reduction, dehydration, and a second reduction. These steps are repeated 8 times to form palmitic acid, the only fatty acid that humans can synthesize.

T or F? Human adipose tissue responds directly to glucagon.

FALSE! Human adipose tissue does NOT respond directly to glucagon.

Post-Absorptive State

In this state, fatty acids are released from adipose tissue and used for energy.

β-Oxidation

The catabolism of fatty acids to acetyl-CoA. This occurs in the mitochondria; however, β-oxidation also occurs in peroxisomes.

Ileum

The final section of the small intestine. This follows the duodenum and jejunum and is separated from the cecum by the ileocecal value (ICV).

T or F? During fasting periods, muscle will metabolize ketones as rapidly as the liver relates them, preventing accumulation in the bloodstream.

TRUE!

What happens to the CO2 in malonyl-CoA?

The CO2 added to form malonyl-CoA is never actually incorporated into the fatty acid because it is removed by fatty acid synthase during addition of the activated acetyl group to the fatty.

In the fasting state, the liver converts excess acetyl-CoA from β-oxidation of fatty acids into...

The ketone bodies acetoacetate and 3-hydroxybutyrate (β-hydroxybutyrate), which can be used for energy in various tissues.

Lacteals

The lymphatic vessels of the small intestine that absorb digested fats.

Emulsification

The mixing of two normally immiscible liquids (in this case, fat and water)

Carnitine Acyltransferase I

The rate-limiting enzyme of fatty acid oxidation. Very long chain fatty acids (over 20 carbons) are oxidized elsewhere in the cell.

In a fast state, the liver produces more acetyl-CoA from ____ the mis used in the citric acid cycle.

β-oxidation. Much of the acyl-CoA is used to synthesize ketone bodies that are released into the bloodstream and transported to other tissues.

Ranking of Lipoprotein Densities (Low to High)

1. Chylomicrons (least dense, with the highest fat-to-protein ratio) 2. VLDL (very-low-density lipoprotein) 3. IDL (Intermediate-Density) 4. LDL (Low-density) 5. HDL (high-density)

2 Enzymes Required for Unsaturated Fatty Acid Oxidation:

1. Enoyl-CoA Isomerase 2. 2,4-dienoyl-CoA Reductase These are necessary because double bonds can disturb the stereochemistry needed for oxidative enzymes to act on the fatty acid. To functions, theses enzymes can have at most one double bond in their active site; this bond MUST be located between carbons 2 and 3.

Overview of Lipid Digestion

1. Lipid digestion is minimal in the mouth and stomach 2. Lipids are transported to the small intestine essentially intact. 3. Upon entry into the duodenum, emulsification occurs. 4. Formation of an emulsion increase the surface ares of the lipid, which permits greater enzymatic interaction and processing 5. Emulsification is aided by bile, which contains bile salts, pigments, and cholesterol 6. Pancreas secretes pancreatic lipase, colipase, and cholesterol esterase into the small intestine 7. Together, these enzymes hydrolyze the lipid components to 2-monoacylglycerol, free fatty acids, and cholesterol

4 Steps of β-Oxidation

1. Oxidation of the fatty acid to form a double bond 2. Hydration of the double body to form a hydroxyl group 3. Oxidation of the hydroxyl group to form a carboxyl (β-ketoacid) 4. Splitting of the β-ketoacid into a shorter acyl-CoA and acetyl-CoA

Lipid Functions

1. Source of energy 2. Coenzymes 3. Prostaglandins and steroid hormones are necessary in the control and maintenance of homeostasis

apoB-100

A apolipoprotein that permits uptake of LDL by the liver.

Brush Border

A brush border (striated border or brush border membrane) is the microvilli-covered surface of simple cuboidal epithelium and simple columnar epithelium cells found in certain locations of the body.

Thoracic Duct

A long lymphatic vessel that empties into the left subclavian vein at the base of the neck.

Bile

A substance produced by the liver that breaks up fat particles.

Cholesterol

A ubiquitous component of all cells in the human body and plays a major role in the synthesis of cell membranes, steroid hormones, bile acids, and vitamin D.

Absorption of Digested Proteins

Absorption of amino acids and small peptides through the luminal membrane is accomplished by secondary active transport linked to sodium. At the basal membrane, simple and facilitated diffusion transports amino acids into the bloodstream.

Ketolysis

Acetoacetate picked up from the blood is activated in the mitochondria by succinylcholine-CoA acetoacetyl -CoA transferase (commonly called thoiphorase), an enzyme present only in tissues outside the liver. During this reaction, 3-hydroxybutyrate is oxidized to acetoacetate. The liver lacks this enzyme so it cannot catabolize the ketone bodies that is produces.

Acetyl-CoA Carboxylase

Acetyl-CoA is activated in the cytoplasm for incorporation into fatty acids by acetyl-CoA carboxylase, the rating-limiting enzyme of fatty acid biosynthesis. This enzyme requires biotin and ATP to function, and adds CO2 to acetyl-CoA to form malonyxl-CoA. This enzyme is activated by insulin and citrate.

Lipoproteins

Aggregates of apolipoproteins and lipids. The transport mechanism for lipids within the circulatory and lymphatic systems; includes chylomicrons and VLDL, which transport triacylglycerols; and HDL, IDL, and LDL, which transport cholesterol and cholesterol ester.

Free fatty acids are transported through the blood in association with ____, a carrier protein.

Albumin

Apolipoproteins

Also referred to as apoproteins, the protein components of lipoproteins. _____ are receptor molecules and are involved in signaling. It is highly unlikely that specific functions of each apolipoproteins will be tested on the MCAT.

The amino groups removed by transamination or deamination constitute a protein toxin to the body in the form of ____, and must excreted safely.

Ammonia--> the urea cycle occurs in the liver and is the body's primary way of removing excess nitrogen from the body.

Why are lipid and carbohydrate synthesis often called non-template synthesis?

Because they do not rely directly on the coding of a nucleic acid, unlike protein an nucleic acid synthesis.

Lipoprotein Lipase (LPL)

Enzyme necessary for the metabolism of chylomicrons and very-low-density lipoproteins (VLGL). This enzyme can related freely fatty acids from triacylglycerols in these lipoproteins. Lipids are mobilized by lipoproteins by this enzyme.

_____ and ____ can also activate HSL.

Epinephrine and cortisol

LDL and HDL both are primarily _____ particles.

Cholesterol

Double bonds in natural fatty acids are generally in the ___ conformation.

Cis formation

Omega-oxidation in the ER produces ________.

Dicarboxylic acids

Ketolysis in the Brain

During a prolonged fast (longer than 1 week), the brain begins to derive up to 2/3 of its energy from ketone bodies. In the brain, when ketones are metabolized to acetyl-CoA, pyruvate dehydrogenase is inhibited. Glycolysis and glucose uptake in the brain decreases. This important switch spares essential protein in the body, which otherwise would be catabolized to form glucose by gluconeogenesis in the liver, and allows the brain to indirectly metabolize fatty acids as ketone bodies.

Micelle Formation

Emulsification is followed by absorption of fats by intestinal cells. Free fatty acids, cholesterol, 2-monoacylglycerol, and bile salts contribute to the formation of micelles. _____ are clusters of amphipathic lipids the tare soluble in the aqueous environment of the intestinal lumen. These are viral in digestion, transport, and absorption of lipid-soluble substances starting for the duodenum all the way to the end of the ileum. At the end of the ileum, bile salts are actively reabsorbed and recycled; any fat that remains in the intestine will pass into the colon, and ultimately ends up in the stools.

After transamination or deamination, the remain carbon skeleton can be used for ____.

Energy

Enoyl-CoA Isomerase

Enzyme involved in the oxidation of unsaturated fatty acids that rearranges cis double bonds at the 3,4 position to trans double bonds at the 2,3 position once enough acetyl-COA has been liberated to isolate the double bond within the first 3 carbons. In monounsaturated fatty acids this single step permits β-oxidation to proceed.

Ketone Bodies

Essentially two acetyl-CoA molecules linked together.

Acetyl-CoA Shuttling

Following a large meal, acetyl-CoA accumulates in the mitochondrial matrix and needs to be moved to the cytosol for fatty acid biosynthesis (Acetyl-CoA is the product of the PDH complex, and it couples with oxaloacetate to form citrate at the beginning of the TCA cycle). As the cell becomes energetically satisfied, it slows the citric acid cycle, which causes citrate accumulation. Citrate can then diffuse across the mitochondrial membrane. In the cytosol, citrate lyase splits citrate back into acetyl-CoA and oxaloacetate. The oxaloacetate can then return to the mitochondrion to continue moving acetyl-CoA.

After HSL activity, related glycerol from fat may be transported to the liver for...

Glycolysis or glyconeogenesis .

HDL

High-density lipoprotein is synthesized in the liver and intestines and related as dense, protein-rich particles into the blood. ___ contains apolipoproteins used for cholesterol recovery- that is, the cleaning up of excess cholesterol from blood vessel for excretion. ___ also delivers some cholesterol to steroideogenic tisses and transfers necessary apolipoproteins to some of the other lipoproteins.

Chylomicrons

Highly soluble lipoproteins in both lymphatic fluid and blood. These function in the transport of dietary triacylglycerols, cholesterol, and cholesterol ester to other tissues. Assembly of chylomicrons occurs in the intestinal lining and results in a nascent chylomicron that contains lipids and apolipoproteins.

Although human adipose tissue does not respond directly to glucagon, a fall in insulin levels activates _______, that hydrolyzes triacylglycerols, yielding fatty acids and glycerol.

Hormone-sensitive lipase (HSL) Lipids are mobilized from adipocytes by this enzyme.

Unsaturated Fatty Acid

Humans can synthesized only a few of the ______; the rest come form essential fatty acids found in the diet that are transported in chylomicrons as triacylglycerols form the intestine.

2,3-Dienoyl-CoA Reductase

In polyunsaturated fatty acids, a further reduction is required using ______ to convert two conjugated double bonds to just one double bond at the 3,4 position, where it will undergo the same rearrangement as monounsaturated fatty acids (enoyl-CoA isomerase).

Insulin indirectly ___ β-oxidation while ______ stimulates this process.

Insulin. Glucagon

IDL

Intermediate-density lipoprotein. Once triacylglycerol is removed from VLDL, the resulting particule is redder to as either a VLDL remnant or IDL. Some IDL is reabsorbed by the liver by apolipoproteins on its exterior, and some is further processed in the bloodstream. For example, some Idl picks up cholesterol esters from HDl to become LDL. IDL thus exists as a transition particle between triacylglycerol transport (associated with chylomicrons and VLDL) and cholesterol transport (associated with LDL and HDL)

Triacylglycerol and cholesterol are transported in the blood as _____.

Lipoproteins

Naming Lipoproteins

Lipoproteins are named according to their density, which increases in direct proportion to the percentage of protein in the particle.

Bile is secreted by the _____ and stored in the _____.

Liver. Gallbladder

Fatty Acids

Long-chain carboxylic acids. The carboxyl carbon is carbon 1, and carbon 2 is referred to as the α-carbon. _____ found within the body occur as salts that are capable of forming micelles or are esterified to other compounds, such as the membrane lipids.

LDL

Low-Density Lipoprotein. The majority of the cholesterol measured in blood is associated with LDL. The normal relationship of LDL is to deliver cholesterol to tissues for biosynthesis. However, cholesterol also plays an important role in cell membranes. In addition, bile acids and salts are made from cholesterol in the liver, and many other tissues require cholesterol for steroid hormones synthesis (steroidogenesis).

Amnio acids are classified by their ability fo ten into specific....

Metabolic Intermediates 1. Glycogenic AAs (All but Leu and Lys, converted into glucose through glycoeogenesis) 2. Ketogenic AAs (can be converted into acetyl-CoA and ketone bodies)

Lipid Absorption Starting in the Intestines

Micelles disuse to the brush border of the intestinal mucosal cells where they are absorbed. The digested lipids pass through the brush border, where they are absorbed into the mucosa and re-esterified to form triacylglycerols and cholesterol esters and packaged, along with certain apoproteins, fat-soluble vitamins, and other lipids, into chylomicrons. Chylomicrons leaves the intestine via lacteals and re-enter the bloodstream via the thoracic duct.

Proteins obtained from the body during prolonged fasting or starvation are catabolized primarily in _____ and _____.

Muscle and the liver

Omega (ω) Numbering System

Nomenclature system also used for unsaturated fatty acids. The ω designation describes the position of the last double bond relative to the end of the chain and identifies the major precursor fatty acid.

Fatty Acid Biosynthesis

Occurs in the liver, and its products are subsequently transported to adipose tissue for storage. Adipose tissue can also synthesis smaller quantities of fatty acids. Both of the major enzymes of fatty acids, acetyl-CoA carboxylase and fatty acid synthase, are also stimulated by insulin.

Ketone Bodies

One of three water-soluble molecules (acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone) that are produced by the liver from fatty acids during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise, alcoholism or in untreated (or inadequately treated) type 1 diabetes mellitus. These ketone bodies are readily picked up by the extra-hepatic tissues, and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy. In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids.

_____ is the primary end product of fatty acid synthesis.

Palmitic Acid (Palmitate)

At night, the body is in the _____ state, utilizing energy stores instead of food for fuel.

Post-Absorptive

Ketogenesis

Process that occurs in the mitochondria of liver cells when excess acetyl-CoA accumulates in the fasting state. HMG-CoA Synthase forms HMG-CoA, and HMG-CoA lyase breaks down HMG-CoA into acetoacetate, which can subsequently be reduced to 3-hydroxybutyrate. Acetone is a minor side product that is formed but will not be used as energy for tissues.

Protein Catabolism

Protein is very rarely used as an energy source because it is so important for other functions; routinely breaking down protein would result in serious illness. However, under conditions of extreme energy deprivation, proteins can be used for energy. In order to provide a reservoir of amino acids for protein building by the cell, proteins must be digested and absorbed.

β-oxidation: Fatty Acid Entry into Mitochondria

Short-chain fatty acids (2-4 carbons) and medium-chain fatty acids (6-12) diffuse freely into mitochondria, where they are oxidized. In contrast, while long-chain fatty acids (14-20 carbons) are also oxidized in the mitochondria, they require transport via a carnitine shuttle.

Nomenclature of Fatty Acids

The total number of carbons is given along with the number of double bonds, written as carbons:double-bonds. Further description can be given by indicating the position and isomerism of the double bonds in an unsaturated fatty acid.

Digestion of Proteins

This process beings in the stomach with pepsin and continues with the pancreatic proteases trypsin, chymotrypsin, and carboxypeptidases A and B, all of which are secreted as zymogens. This process is completed by the small intestinal brush-border enzymes dipeptidase and aminopeptidase. The main end products of protein digestion are amino acids, dipeptides, and tripeptides.

β-oxidation: In Mitochondria

This process reverses the fatty acid synthesis by oxidizing and releasing (rather than reducing and linking) molecules of acetyl-CoA. The pathway is a repetition of 4 steps; each 4-step cycle releases one acetyl-CoA and reduces NAD+ and FAD. The FADH2 and NADH are oxidized in the ETC, producing ATP. In muscle and adipose tissue, acetyl-CoA enters the TCA cycle. In the liver, acetyl-CoA, which cannot be converted to glucose, stimulates gluconeogeneiss by activating pyruvate carboxylase.

Amino acids released from proteins usually lose their amino group through ____ or ______.

Transamination or Deamination

T or F? Odd-carbon fat acids thus represent an exception to the rule that fatty acids cannot be converted to glucose in humans.

True!

How long does β-oxidation continue for?

Until the chain has been shorted to 2-carbons, creating a final acetyl-CoA.

VLDL

Very-low-density lipoprotein metabolism is similar to that of chylomicrons. However, VLDL is produced and assembled in liver cells. Like chylomicrons, the main function of VLDL is the transport of triacylglycerols to other tissues. These also contain fatty acids that are synthesized from excess glucose or retrieved from chylomicron remnants.

Cobalamin

Vitamin B12

What is pantothenic acid?

Vitamin B5

β-oxidation: Activation

When fatty acids are metabolized, they first become activated by attachment to CoA, which is catalyzed by fatty-acyl-CoA synthetase: product = acetyl-CoA or fatty acyl-CoA

Can odd numbered fatty acids undergo β-oxidation?

Yes and in the same manner as even-numbered carbon fatty acids for the most part. The only difference is observed during the final cycle, where even-numbered fatty acids for the most part yield one acetyl-CoA and one propionyl-CoA (from the 5-carbon remaining fragment). Propionyl-CoA is converted to methylmalonyl-CoA is then converted in succinylcholine-CoA by mehtylmalonyl -CoA mutate, which requires cobalamin. Succinyl-CoA is a citric acid cycle intermediate and can also be converted to malate to enter the gluconeogenic pathway in the cytosol.