Lipid Metabolism Flashcards
How do carbohydrate metabolism and lipid metabolism connect?
In glycolysis, pyruvate is created. That pyruvate is brought to the mitochondria where it is converted to acetyl-CoA with pyruvate dehydrogenase.
The acetyl-CoA is then involved in lipid metabolism with acetyl-CoA being converted to citrate and then fatty acids. Acetyl-CoA can also be converted to ketones.
What is the purpose of fatty acid metabolism?
Serves as an alternate source for energy
When is Fatty acid catabolism most active? What is involved?
Most active during fasting
Stimulated by glucagon
The liver converts fatty acids into ketone bodies for better distribution
When is fatty acid synthesis most active?
Most active in the fed state
Stimulated by insulin
Cells synthesizing fatty acids participate in removal of glucose from serum
Liver exports newly synthesized fat to adipose tissue
How does a patient present with too low of fatty acid catabolism?
Fatty acid catabolism is supposed to provide an alternative to glucose degradation for ATP production during fasting.
If fatty acid catabolism is too little, the liver does not have enough ATP to conduct gluconeogenesis. Insulin-responsive tissues keep burning glucose instead of fat.
Patient will present with fasting hypoglycemia with absence/low ketones and metabolic acidosis
How does a patient present with too high of fatty acid catabolism?
Fatty acid metabolism is supposed to be shut off in fed state.
Insulin insufficiency (diabetes) leads to fatty acid mobilization in fed state.
Patient will present with hyperlipidemia with high serum concentrations of ketones.
What is the chemistry of apolar lipids?
Form a water-free droplet
Completely hydrophobic
Examples include triacylglycerol, cholesteryl esters
What do all lipids have in common?
Hydrophobic moiety
What is the chemistry of amphipathic lipids?
Hydrophilic and hydrophobic properties
Form membrane bilayers or single layers around lipid droplet
Examples include membrane lipids cholesterol, and fatty acids
How do most lipids travel?
Most diffuse through the plasma membrane.
BUT not when they are inside a large lipid droplet or bound to albumin
Fatty acid binding proteins in membrane facilitate diffusion
What is the structure and chemistry of fatty acids?
Fatty acid is a long alkyl chain ending in carboxyl group
Alkyl chain is hydrophobic, carboxyl group is hydrophilic
Can be unsaturated - double bond between two carbons in alkyl chain
Naturally occurring double bonds are in cis configuration and double bonds in trans configuration are products of chemical processes
Where can human enzymes desaturate lipids? Which are essential fatty acids?
Carbons 2-9
Fatty acids with double bonds beyond carbon 9 are essential
What are examples of fatty acids that are essential and unsaturated?
Linoleate is ω6 (omega-6) and Linolenate is ω3 (omega-3)
Can fatty acids form droplets by themselves?
No! Need glycerol
What is the storage form of fatty acids?
Triacylglycerol (TAG, “fat”)
How are fatty acids released from triacylglycerols? What are the different lipases for digestive tract, circulatory system, and intracellular?
Released by lipases that cleave bonds. Lipases break TAG from the diet or lipid droplet
Lipases of digestive tract - Lingual and pancreatic lipase
Lipase of circulatory system - Lipoprotein lipase
Intracellular lipases - Adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL)
What is able to cross the plasma membrane?
Fatty acids and monoacylglycerol
Where does fatty acid breakdown occur?
Mitochondria and peroxisomes
Mitochondria degrade fatty acids for energy and peroxisomes degrade for other processes.
How are fatty acids activated when they enter the cytoplasm for breakdown?
Activated by binding to CoA. Long chain acyl-CoA (<20 carbons) are shuttled into mitochondria and very long chain acyl-CoA (>22 carbons) enter peroxisome for shortening
Can fatty acids and acyl-CoA cross the inner mitochondrial membrane?
Inner mitochondrial membrane is impermeable to fatty acids and acyl-CoA
Medium and short chain fatty acids can cross without transporter
Carnitine Shuttle
Two step shuttle system that helps import fatty acids into the mitochondrion. FAs shuttled by two carnitine-palmitoyl translocator (CPT) proteins
Steps:
- CPT I moves the activated FA across the outer mitochondrial membrane and swaps CoA for a carnitine moiety
- CPT II moves acyl-carnitine across the inner mitochondrial membrane and swaps the carnitine moiety back with CoA
Carnitine
Small quaternary ammonium compound. Only known function is FA transport. Most carnitine taken up in diet
What occurs with disorders to the carnitine shuttle? How do patients present?
Defects in any components of shuttle affect muscle function - muscles use FA even in fed state so defects range from mild muscle cramping to cardiomyopathy, death in infancy
Patient presents with fasting hypoglycemia –> Pt’s instructed to avoid periods of fasting
Genetic conditions:
- CPT I and CPT II translocase deficiency
- Primary carnitine deficiency - strictly vegetarian diet, poor uptake and transport of carnitine
What happens once fatty acids enter the mitochondria?
Will be degraded
How is the activated fatty acid degraded in the mitochondria?
Beta oxidation
Two oxidation reactions at Beta-carbon produce FADH and NADH
How does beta oxidation occur?
- Thiolase transfers a 2 carbon fragment of the fatty acid to coenzyme A to produce acetyl-CoA
- During one cycle, acyl-CoA shortened by 2 carbons and electrons removed from FA are used to produce one molecule of FADH and NADH. Also produces acetyl-CoA
- Acetyl-CoA oxidized in citric acid cycle and is further oxidized to Co2 and water in the mitochondria
What happens to propionyl CoA after beta oxidation of odd chained fatty acids?
Becomes carboxylated to a four carbon molecule and becomes succinyl-CoA and participates in citric acid cycle or gluconeogenesis
What is the energy content of fat?
Fat has 9 kcal/g of energy
Fat droplet do not contain water so they have higher energy than glycogen granules.
What occurs with beta oxidation of odd chain fatty acids?
Beta oxidation of odd chain fatty acids produces one propionyl CoA (3 carbon)
Propionyl CoA converted into succinyl CoA (4 carbons) which can enter gluconeogenesis
What needs to happen to unsaturated fatty acids in beta oxidation?
Require an additional enzyme for degradation - double bond in unsaturated FA is moved and isomerized, which produces the trans ∆2 - enoyl CoA intermediate
Enzyme is cis ∆3 enoyl-CoA
isomerase
What enzymes catalyze the initial step of Beta oxidation?
Family of acyl-CoA dehydrogenases. Four isoforms for the different chain links - short, medium, long, and very long acyl-CoA dehydrogenases
What is the most common Beta Oxidation disorder and what occurs with it?
Medium Acyl-CoA dehydrogenase (MCAD) is most common
Results in hypoketotic fasting hypoglycemia
See accumulation of C6-C12 fatty acids in urine, acyl-carnitines in blood
How does the body deal with the problem that fatty acid uptake into cells and mitochondria is slow?
Liver produces ketone bodies from acetyl-CoA - they do not need to bind to albumin so they diffuse quickly
Liver produces a large amount of acetyl-CoA during fasting. 2 acetyl-CoA make one ketone body
How does acetyl-CoA make ketones?
- 3 Acetyl-CoA make 1 HMG-CoA
- HMG-CoA lyase produces acetoacetate and acetyl CoA
- Reduction of acetoacetate produces hydroxybutyrate
- Decarboxylation of acetoacetate produces acetone
What are the ketones produced by acetyl CoA?
Acetoacetate and hydroxybutyrate and Acetone
What happens to acetoacetate and hydroxybutyrate and acetone after they are made?
Diffuse into the mitochondria of target cells
Ketones activated by transfer CoA
Acetoacetyl CoA split into 2 acetyl CoA - Ketone metabolism transfers acetyl-CoA from liver mitochondria to all other mitochondria
Acetone evaporates and is lost in breath - “fruity” breath
