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Lipid Metabolism
- Triacylglycerols (TAGs) and glycogen are the two major forms of stored energy in vertebrates
- Glycogen can supply ATP for muscle contraction for less than an hour
- Glycogen stores depleted 12-15 h after eating and shorter if exercising
- Fats are the most highly concentrated form of stored biological energy
- Long-term storage solution!
- Important for migratory birds who fly incredibly long distances
- Ruby-throated hummingbird winters in Central America and nests in southern Canada – often flies non-stop! Store large amounts of TAGs % dry-weight body fat = 70% when migration begins; 30% or less for non-migratory birds
- Sustained work is fueled by metabolism of TAGs which are very efficient energy stores because: (1) They are stored in an anhydrous form (no water present) (2) Their fatty acids are more reduced than monosaccharides. Must go through many more oxidation steps than carbohydrates before completely broken down to CO 2
- Fats have 9 calories/g whereas carbohydrates have 4 calories/g (alcohol = 7 cal/g) β - OXIDATION FA! Acetyl-CoA β - OXIDATION FA! Acetyl-CoA
- Long chain fatty acids are the ideal storage fuel: hold more calories, and body has a virtually unlimited capacity to store fat; 70 kg man with 11% body fat has over 10 0,000 kcal stored as fat in abdominal cavity; only about 600 kcal in glycogen
- Fats can support body for long time: 60-90 days; obese people can survive for over a year without food. How is this stored energy used? - Fatty acids released from TAGs, transported to cytoplasm and then mitochondria of peripheral tissues (muscle cells) for degradation - Catabolized by process called β−oxidation
- 4 step process
- Yields Acetyl-CoA units that feed into the TCA cycle - When too much fuel is around, fatty acids are made, linked to glycerol (TAGs are made) and stored in adipocytes.
- LOCALIZATION OF PROCESSES: - Degradation = mitochondrial matrix - Synthesis = cytosol METABOLISM OF FATS: Adsorption and Mobilization of Fatty Acids § Fatty acids need to be delivered to cells for β−oxidation to occur – how?
- Two major sources for fatty acids (FA) and glycerol for metabolic fuels are obtained from triacylglycerols: (1) In the diet (2) Stored in adipocytes (fat storage cells) Free fatty acids occur only in trace amounts in cells Storage and Mobilization of Fatty Acids in Fat Cells § TAGs are stored in adipocytes, and fatty acids are released to supply energy demands § Liberation of fatty acids from TAGs in adipose tissue is regulated by hormones o Epinephrine o Glucagon o Released into blood stream when there are low glucose levels in blood
1. Emulsification starts in the stomach and continues in the lumen of the small
intestine
- Starts as a big glob of hydrophobic fat – has limited surface area to attack
- In the stomach the fat is heated to liquify, peristaltic movements help emulsify (like a washing machine) (mixer making mayonaise)
2. In the small intestine, fat particles are coated with bile salts and digested by
pancreatic lipases
Bile salts : Biological Detergents
Bile salts are amphipathic: synthesized in liver, stored and secreted by gall bladder to intestine. Made from cholesterol: retain the ring structure but have more hydroxyl groups and a polar side chain – can act as DETERGENTS - Serve to convert water-insoluble lipids to dispersible micellar aggregates
- They emulsify fat globules into smaller micelles, increasing the surface area accessible to lipid- hydrolyzing enzymes. Aid in lipid digestion and are essential for the absorption of lipid digestion products
- Also required for efficient intestinal absorption of lipid-soluble vitamins A, D, E, and K
- Taurocholate and glycocholate (cholesterol derivatives) are the most abundant bile salts Amphipathic : hydrophilic (blue), hydrophobic (black)
- Form MICELLES
- Hydrophobic portions interact with lipids while the hydrophilic groups remain exposed to water
- Disc-like shapes - free fatty acids and bile
- Recycled through hepatic portal vein from intestine back to liver
LIPASES: Action of pancreatic lipase § Duct at the junction of pancrease and duodenum enters pancreatic juice – contains lipases (among other things, including colipase : small protein that the lipase needs around to keep it active with all the bile salts around. § Lipases degrade TAGs to free fatty acids (FA) and a 2 - monoacylglycerol (MAG) by hydrolysis at the C-1 and C- 3 positions § Dietary phospholipids are degraded by phospholipases Dietary cholesterol § Most dietary cholesterol is unesterified § Any Cholesteryl esters are hydrolyzed by an intestinal esterase to yield free § Free cholesterol is solublized by bile-salt micelles for absorption
7. Fatty acids are taken up and degraded by β - oxidation in mitochondrial matrix
Fatty Acid Oxidation
CCHHYYLLOOMMIICCRROONNSS
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- The β - oxidation pathway degrades fatty acids two carbons at a time
- Skeletal muscle, liver, kidney, heart can use FA directly
- Three stages: (1) Activation of fatty acids in the cytosol (2) Transport into the mitochondria (3) Degradation to two-carbon fragments (as acetyl CoA) in the mitochondrial matrix Activation of Fatty Acids
- Fatty acids in the cytosol are activated by conversion to CoA thioesters by acyl-CoA synthetase (ATP dependent)
- Fatty acid attached to CoA-SH
- The PPi released is hydrolyzed by a pyrophosphatase to 2 Pi
- Net of two ATP equivalents are consumed to activate one fatty acid to a thioester
CARNITINE :
- Diet: red meat, dairy, poultry, fish - Body: made in liver and kidneys - Enters cells by specific transporter - Carnitine deficiencies: § Symptoms: - Poor muscle tone - Muscle weakness - Brain dysfunction - Heart dysfunction § Primary Deficiency: Rare disorder due to faulty transporter that allows carnitine into cells § Secondary Deficiency: Poor dietary intake or metabolic diseases that deplete or limit stores § Treatment: Pharmaceutical administration of carnitine to supplemental stores in the body; Can flood system and enough carnitine can enter if due to a faulty transporter - NOTE: NO evidence exists that if normal, taking more supplements of carnitine does anything. Not bad – excess carnitine is not harmful but not necessarily beneficial.
The Reactions of β - oxidation
- One round of β-oxidation: 4 enzyme steps produce acetyl CoA from fatty acyl CoA
- Each round generates one molecule each of: 1 FADH 2 – oxidative phosphorylation 1 NADH – oxidataive phosphorylation 1 Acetyl CoA – enters TCA cycle Fatty acyl CoA ( 2 carbons shorter each round) Process continues until acyl-CoA is completely broken down to Acetyl-CoA groups o Cleavage occurs between the α and β carbons of the acyl-CoA (between 1st^ and 2nd^ C next to carbonyl) o # of acetyl-CoA made = ½ the number of Carbons in the original fatty acid o # of cycles of β-oxidation = # of acetyl-CoAs made minus 1 o Example: § Palmitic acid = 16:
- 8 moles of acetyl-CoA (enter TCA cycle)
- 7 rounds of β - oxidation
SUMMARY OF THE
PRODUCTS OF EACH
CYCLE:
- Acyl-CoA which re- enters β−oxidation - 1 Acetyl-CoA which enters TCA **- 1 FADH 2
ATP Generation from Fatty Acid Oxidation
- Three things to keep in mind as sources of ATP - NADH and FADH 2 produced by β-oxidation cycles - Processing of Acetyl-CoA generated in β-oxidation cycles through TCA cycle and ox phos - How much ATP was USED in activating the FA for degradation o Remember – 2 ATP equivalents are used per mole of fatty acid; 1 ATP but 2 high energy bonds The balanced equation for oxidizing one palmitoyl CoA by seven cycles of β−oxidation Net yield of ATP per palmitate oxidized to 16 CO 2 Each acetyl-CoA that enters TCA: - 1 mole GTP - 3 moles NADH - 1 mole FADH 2 Therefore for palmitate: 80 ATP - 8 GTP = 8 ATP - 24 NADH = 60 ATP - 8 FADH 2 = 12
Palmitoyl CoA + 7 HS-CoA + 7 FAD + 7 NAD+^ + 7 H 2 O
8 Acetyl CoA + 7 FADH 2 + 7 NADH + 7 H+
Palmitoyl CoA + 7 HS-CoA + 7 FAD + 7 NAD+^ + 7 H 2 O
8 Acetyl CoA + 7 FADH 2 + 7 NADH + 7 H+
ATP generated
8 acetyl CoA 80
7 FADH 2 10. 5
7 NADH 17. 5
108 ATP
ATP expended to activate palmitate - 2
Net yield: 106 ATP
β Oxidation of Unsaturated Fatty Acids
- Unsaturated FA are common in nature
- Degradation requires two other enzymes in addition to the β-oxidation pathway enzymes: (1) Enoyl-CoA isomerase (2) 2,4-Dienoyl-CoA-reductase
Ketone Bodies Are Fuel That Are Synthesized in the Liver
- Unbalanced metabolism of fats and carbohydrates changes the flow of nutrients in pathways
- Common factors in abnormal metabolic conditions
- Lack of carbohydrates
- Impaired use of carbohydrates
- Fasting
- Starvation
- Untreated diabetes
- Atkins’ Diet Response to a Fast and Starvation The natural response to glucose and energy deficiency is involves two metabolic processes. Firstly the adrenal cortex secretes glucocorticoids to stimulate gluconeogenesis. Secondly growth hormone is secreted to accelerate lipolysis in adipose tissue to provide fatty acids for oxidation.
- Liver glycogen stores are depleted
- Fatty acids can be used by heart, kidney, skeletal muscle and liver
- Fatty acids are not used as fuel by the brain because they do not cross the blood- brain barrier
- Survival during starvation is mainly determined by the size of the stored triacylglycerol pool
- After several days of starvation, acetyl- CoA is made in abnormally high amounts:
- Due to excessive fatty acid breakdown since glucose/glycogen is not available
- Glucose is the primary source of fuel for the human brain, therefore the rate of gluconeogenesis has to increase
- During fasting or carbohydrate starvation, oxaloacetate in liver is depleted from the TCA cycle because it is used for gluconeogenesis (making glucose for the brain)
- Impedes entry of acetyl-CoA into the TCA cycle.
- Excessive Acetyl-CoA is converted in liver mitochondria to ketone bodies
- Ketone bodies can be thought of as “soluble fats” – exported to cells that need it They are transportable forms of fatty acids!
- There is a limited amount of mitochondrial CoA-SH so need to regenerate it for further fatty acid catabolism
- Ketone Bodies :
- β - Hydroxybutyrate
- Acetoacetate
- Acetone – expelled in breath
- Ketone bodies are acids – can cause lowering of blood pH leading to acidosis (ketosis) ; untreated can lead to coma and death
- Ketone bodies can fuel brain cells during starvation
- Use of ketone bodies minimizes protein breakdown
- Able to cross blood-brain barrier
- Major energy source for brain during starvation
- β - Hydroxybutyrate and acetoacetate used as fuel
- Acetone – expelled in breath
- Cells, metabolically starved, turn to gluconeogenesis and fat/protein catabolism
- Processes of TAG hydrolysis, fatty acid oxidation, gluconeogenesis accelerated
- OAA is low, due to excess gluconeogenesis, so Acetyl-CoA from fat/protein catabolism does not go to TCA, but rather to ketone body production
- Blood levels of ketone bodies are elevated
- Lowered pH of blood
- Increased elimination of water and electrolytes, causing dehydration and lowered blood volume
- Acetone can be detected on breath
ATKINS DIET
- High protein/High Fat/Low to no carbohydrate diets - In a carbohydrate free diet, newly ingested fatty acids are immediately oxidized by all tissues except brain - When diet contains carbohydrates, ingested fatty acids are transported to fat cells for storage ( Insulin signals fat storage) - Effective because body fat is metabolized for energy - Also effective because lots of water is lost (excessive urination) - BUT: No idea of what long term effects of being in constant ketosis are or other side-effects - Potentially Problematic Side Effects : v Dehydration – caused by excessive urination to rid body of acids v Electrolyte Imbalance – Loss of Na + and K + in urine v Difficulty in Concentration – Low fuel availability to brain v GI Problems – No fiber v Bad Breath – Acetone expulsion v Heartbeat Irregularities v Kidney Stress or Damage § Excessive urination to flush out toxins created by ketosis § Processes by-products of protein breakdown v Excessive proteins can cause Ca+2^ loss from bones which can lead to osteoporosis – esp. bad for women v Acidosis and Death v Depression – Lack of carbohydrates can result in lowered serotonin production – a mood stabilizing compound in the brain v Workouts suffer – due to depleted energy stores - Hard to stick with this diet – weight gain common afterwards
- If on this type of diet, be sure to drink lots of water and supplement with vitamins and salt - BE BALANCED! Weight loss = Eat fewer calories and increase exercise - 1 pound of fat = 3500 calories o Cut 500 calories/day and lose 1 pound per week o Safe weight loss that will last = 2 pounds per week - EVERYTHING IN MODERATION to keep body in balance – eat all food groups
Integration of Metabolic Pathways:
