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52 Cards in this Set
- Front
- Back
When do fatty acids become the major fuel for the body?
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During the post absorptive period or fasting (4 hour after meal); conserves glucose for the brain and RBCs
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What is lipolysis? What are the products?
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A catabolic pathway resulting in the hydrolysis of TAG to supply FA for fuel and glycerol
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When does lipolysis occur?
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During fasting when glucose levels are low
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Where does lipolysis occur?
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Adipose tissue
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What catalyzes the rate-limiting step in lipolysis?
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Hormone sensitive lipase (HSL)
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Where is HSL located?
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Surface of lipid droplet in white adipose tissue
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What are the effects of HSL?
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TAG to DAG and a free FA
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What happens to the products of Lipolysis?
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(1) Uneserified FA moves to blood stream and bind to albumin for transport to tissues (2) Glycerol travels to the liver and is used for gluconeogenesis
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How is HSL regulated?
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Covalent regulation through (1) High Epinephrine (2) Low Insulin
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What is the activated form of HSL?
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HSL-Phosphate (phosphorylated)
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What are the effects of HSL regulators?
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(1) Epinephrine binds Beta3-receptors in adipose tissue to activate protein kinase to phosphorylate HSL (2) Low insulin levels are required for epinephrine to activate HSL
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What are the effects of DM on lipolysis?
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Low insulin levels (T1DM) or insulin resistance (T2DM) leads to low insulin, which means HSL activation by epinephrine, resulting to more lipolysis
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Lipolysis liberates 2x FA as needed. What happens to the excess?
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Excess FA are converted back into TAG in the liver and placed in VLDL for return to adipose tissue and muscle
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What are the effects of Niacin?
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Inhibit lipolysis in adipose tissue (decreasing production of VLDLs and LDLs) and lowers serum TAG and serum cholesterol
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What are the effects of Thiazolidinediones (TZD) (aka Glitazones)?
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(1) Bind transcription factor in the nucleus PPAR Gamma (2) Increases insulin sensitivity in adipose, liver, and skeletal muscle (3) Decreases lipolysis
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What is a ADE of TZD?
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Weight gain
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What is Beta-Oxidation?
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Catabolic pathway which removes 2C at a time from the carboxyl (-COOH) end of fatty acyl CoA
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What are the products of Beta-Oxidation?
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Acetyl CoA, FADH2, NADH
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When does Beta-Oxidation occur?
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(1) When blood glucose is low (Fasting) (2) High-fat, low-carbohydrate diet (3) Exercise
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Where does Beta-Oxidation occur?
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In the mitochondrial matrix
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Where does FA synthesis occur?
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In the cytosol on the surface of the smooth endoplasmic reticulum
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Fatty acids must be activated to be metabolized. What activates FA?
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Thiokinase (fatty acyl CoA synthetase) [Also seen in resynthesis of TAG in Enterocytes, Lecture 21]
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Describe how fatty acyl CoAs enter the inner mitochondrial membrane for Beta-Oxidation
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(1) Fatty acyl CoA with less than 12C easily enter mitochondria (2) Long-chain fatty acyl CoA use Carnitine shuttle
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Describe the Carnitine Shuttle
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(1) CPT I (Carnitine palmitoyl-transferase I) turns FA CoA to FA carnitine (2) FA carnitine moves across inner mitochondrial membrane using carnitine/acyl carnitine translocase (3) Inside the mitochondrial matrix, CPT II (Carnitine palmitoyl-transferase II) turns FA carnitine back to FA CoA
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Where does Beta-oxidation occur on the FA?
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On the Beta-Carbon of the FA
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When does Beta-oxidation stop its cycle?
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The final round of Beta-oxidation starts with a 4C FA CoA and yields 2 acetyl CoA groups rather than one acetyl CoA group and a FA CoA
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What does the Beta-oxidation of palmitate require?
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Palmitate - 16C; 7 rounds of Beta-oxidation; yields 8 acetyl CoAs, 7 FADH2, and 7 NADH
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What is the rate limiting enzyme in Beta-oxidation?
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CPT I
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How is Beta-oxidation regulated?
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Malonyl CoA is a negative allosteric inhibitor of CPT I; (1) Fed state - Malonyl CoA levels are high, inhibits CPT I (2) Fasted state - Malonyl CoA levels are low due to AMPK activation, which inhibits ACC and decreases Malonyl CoA - CPT I is not inhibited
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What is Ketogenesis?
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Anabolic pathway leading to the formation of ketone bodies from FA
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When does Ketogenesis occur?
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(1) Fasting state (low insulin accelerates lipolysis, increasing FA for Beta-oxidation and Ketogenesis) (2) Uncontrolled DM (usually Type 1) (3) High-fat/Low-carbohydrate diets (i.e. neonates w milk and adults on Atkin's diet)
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Where does Ketogenesis occur?
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In mitochondria of the liver
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What is the function of Ketone bodies?
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Fuel for brain and fetus, decreasing the need for glucose
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What other pathways are active at the same time as Ketogenesis?
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(1) Glycogenolysis (2) Beta-Oxidation of FA (3) Guconeogenesis [Low OAA to form Citrate because OAA is being used to make glucose - accumulation of Acetyl CoA for Ketogenesis] (4) Amino acid catabolism and urea synthesis (provides precursors for gluconeogenesis)
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What is the rate-limiting enzyme in Ketogenesis? What does it do?
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HMG CoA synthase; Converts Acetyl CoA to HMG CoA [Acetoacetate convertion to Beta-Hydroxybutyrate is favored due to high NADH produced from Beta-Oxidation being used; Acetoacetate spontaneously converts to non-metabolic Acetone]
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How is HMG CoA synthase regulated?
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Substrate availability (Acetyl CoA); Acetyl CoA accumulates during fasting due to the high rate of Beta-Oxidation in the liver and the low OAA available to form Citrate due to Gluconeogenesis
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How are Ketone bodies transported?
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Ketone bodies are water soluble, so can easily be transported in the blood
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Explain why the liver cannot utilze ketone bodies
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Acetoacetate has to be converted to acetoacetyl CoA to be metabolized. This is done by Tiophorase, which is missing in the liver.
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During a fast, the liver is a net exporter of ____ and ____ (via what pathways?)
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Glucose (via glycogenolysis and gluconeogenesis) and ketones (ketogenesis)
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What is the preferred fuel in the liver after an 8-hour fast?
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FA
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What are the different Ketone bodies? Which of these are ketones/acids?
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(1) Ketone bodies - Beta-hydroxybutyrate, acetoacetate, acetone (2) Ketones - Acetoacetate and acetone (3) Acids - Acetoacetate and Beta-hydroxybutyrate
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What do Ketostix measure?
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Acetoacetate; Full extent of ketosis is undetected due to Beta-hydroxybutyrate not being detected
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Diabetics in ketoacidosis have very high levels of ____
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NADH (due to excess Beta-oxidation)
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The brain cannot use FA as fuel but can use ketone bodies after ____ fasting
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24 hours
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Explain why ketone bodies spare muscle protein
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With the brain using ketone bodies instead of glucose for ATP, fewer amino acids (protein) is needed to generate glucose
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Where can FA be used (metabolism)?
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FA are used in all cells with mitochondria except fetus, brain, and RBCs
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What happens in FA CoA Dehydrogenase deficiency?
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Beta-oxidation cannot be initiated; Symptoms appear during the first 2 years of life after a fast of more than 12 hours; Treatment includes a carbohydrate rich diet
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What are the possible symptoms of fatty acyl CoA dehydrogenase deficiency?
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(1) Hypoketonemia (no Beta-oxidation) (2) Hyper fatty acidemia (no Beta-oxidation) (3) Hypoglycemia (No ketogenesis - glycogen and glucose being used for energy)
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Describe the role and regulation of Hormone Sensitive Lipase (HSL)
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(1) Rate-limiting step in lipolysis (2) Activated by low insulin and high epinephrine levels
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Describe the role and regulation of CPT I
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(1) Rate-limiting step in Beta-oxidation of FA; first enzyme in the carnitine shuttine (2) Inhibited by high levels of malonyl CoA present in fed state; Malonyl CoA inhibited in fasting state due to low levels of ACC due to AMPK)
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Describe the role and regulation of AMP Kinase
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(1) Enzyme is pivotal in switching metabolism from fed to the fasting pathways (2) AMPK is allosterically activated by AMP; AMPK is covalently activated by glucagon and epinephrine
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Describe the role and regulation of HMG CoA Synthase
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(1) Rate-limiting step in Ketogenesis (2) Enzyme is controlled by substrate (Acetyl CoA) availability (i.e. Acetyl CoA accumulates because of high rate of Beta-Oxidation and lack of OAA)
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