Biochem Lect 23

Front 1

When do fatty acids become the major fuel for the body?

Back 1

During the post absorptive period or fasting (4 hour after meal); conserves glucose for the brain and RBCs

Front 2

What is lipolysis? What are the products?

Back 2

A catabolic pathway resulting in the hydrolysis of TAG to supply FA for fuel and glycerol

Front 3

When does lipolysis occur?

Back 3

During fasting when glucose levels are low

Front 4

Where does lipolysis occur?

Back 4

Adipose tissue

Front 5

What catalyzes the rate-limiting step in lipolysis?

Back 5

Hormone sensitive lipase (HSL)

Front 6

Where is HSL located?

Back 6

Surface of lipid droplet in white adipose tissue

Front 7

What are the effects of HSL?

Back 7

TAG to DAG and a free FA

Front 8

What happens to the products of Lipolysis?

Back 8

(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

Front 9

How is HSL regulated?

Back 9

Covalent regulation through (1) High Epinephrine (2) Low Insulin

Front 10

What is the activated form of HSL?

Back 10

HSL-Phosphate (phosphorylated)

Front 11

What are the effects of HSL regulators?

Back 11

(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

Front 12

What are the effects of DM on lipolysis?

Back 12

Low insulin levels (T1DM) or insulin resistance (T2DM) leads to low insulin, which means HSL activation by epinephrine, resulting to more lipolysis

Front 13

Lipolysis liberates 2x FA as needed. What happens to the excess?

Back 13

Excess FA are converted back into TAG in the liver and placed in VLDL for return to adipose tissue and muscle

Front 14

What are the effects of Niacin?

Back 14

Inhibit lipolysis in adipose tissue (decreasing production of VLDLs and LDLs) and lowers serum TAG and serum cholesterol

Front 15

What are the effects of Thiazolidinediones (TZD) (aka Glitazones)?

Back 15

(1) Bind transcription factor in the nucleus PPAR Gamma (2) Increases insulin sensitivity in adipose, liver, and skeletal muscle (3) Decreases lipolysis

Front 16

What is a ADE of TZD?

Back 16

Weight gain

Front 17

What is Beta-Oxidation?

Back 17

Catabolic pathway which removes 2C at a time from the carboxyl (-COOH) end of fatty acyl CoA

Front 18

What are the products of Beta-Oxidation?

Back 18

Acetyl CoA, FADH2, NADH

Front 19

When does Beta-Oxidation occur?

Back 19

(1) When blood glucose is low (Fasting) (2) High-fat, low-carbohydrate diet (3) Exercise

Front 20

Where does Beta-Oxidation occur?

Back 20

In the mitochondrial matrix

Front 21

Where does FA synthesis occur?

Back 21

In the cytosol on the surface of the smooth endoplasmic reticulum

Front 22

Fatty acids must be activated to be metabolized. What activates FA?

Back 22

Thiokinase (fatty acyl CoA synthetase) [Also seen in resynthesis of TAG in Enterocytes, Lecture 21]

Front 23

Describe how fatty acyl CoAs enter the inner mitochondrial membrane for Beta-Oxidation

Back 23

(1) Fatty acyl CoA with less than 12C easily enter mitochondria (2) Long-chain fatty acyl CoA use Carnitine shuttle

Front 24

Describe the Carnitine Shuttle

Back 24

(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

Front 25

Where does Beta-oxidation occur on the FA?

Back 25

On the Beta-Carbon of the FA

Front 26

When does Beta-oxidation stop its cycle?

Back 26

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

Front 27

What does the Beta-oxidation of palmitate require?

Back 27

Palmitate - 16C; 7 rounds of Beta-oxidation; yields 8 acetyl CoAs, 7 FADH2, and 7 NADH

Front 28

What is the rate limiting enzyme in Beta-oxidation?

Back 28

CPT I

Front 29

How is Beta-oxidation regulated?

Back 29

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

Front 30

What is Ketogenesis?

Back 30

Anabolic pathway leading to the formation of ketone bodies from FA

Front 31

When does Ketogenesis occur?

Back 31

(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)

Front 32

Where does Ketogenesis occur?

Back 32

In mitochondria of the liver

Front 33

What is the function of Ketone bodies?

Back 33

Fuel for brain and fetus, decreasing the need for glucose

Front 34

What other pathways are active at the same time as Ketogenesis?

Back 34

(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)

Front 35

What is the rate-limiting enzyme in Ketogenesis? What does it do?

Back 35

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]

Front 36

How is HMG CoA synthase regulated?

Back 36

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

Front 37

How are Ketone bodies transported?

Back 37

Ketone bodies are water soluble, so can easily be transported in the blood

Front 38

Explain why the liver cannot utilze ketone bodies

Back 38

Acetoacetate has to be converted to acetoacetyl CoA to be metabolized. This is done by Tiophorase, which is missing in the liver.

Front 39

During a fast, the liver is a net exporter of ____ and ____ (via what pathways?)

Back 39

Glucose (via glycogenolysis and gluconeogenesis) and ketones (ketogenesis)

Front 40

What is the preferred fuel in the liver after an 8-hour fast?

Back 40

FA

Front 41

What are the different Ketone bodies? Which of these are ketones/acids?

Back 41

(1) Ketone bodies - Beta-hydroxybutyrate, acetoacetate, acetone (2) Ketones - Acetoacetate and acetone (3) Acids - Acetoacetate and Beta-hydroxybutyrate

Front 42

What do Ketostix measure?

Back 42

Acetoacetate; Full extent of ketosis is undetected due to Beta-hydroxybutyrate not being detected

Front 43

Diabetics in ketoacidosis have very high levels of ____

Back 43

NADH (due to excess Beta-oxidation)

Front 44

The brain cannot use FA as fuel but can use ketone bodies after ____ fasting

Back 44

24 hours

Front 45

Explain why ketone bodies spare muscle protein

Back 45

With the brain using ketone bodies instead of glucose for ATP, fewer amino acids (protein) is needed to generate glucose

Front 46

Where can FA be used (metabolism)?

Back 46

FA are used in all cells with mitochondria except fetus, brain, and RBCs

Front 47

What happens in FA CoA Dehydrogenase deficiency?

Back 47

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

Front 48

What are the possible symptoms of fatty acyl CoA dehydrogenase deficiency?

Back 48

(1) Hypoketonemia (no Beta-oxidation) (2) Hyper fatty acidemia (no Beta-oxidation) (3) Hypoglycemia (No ketogenesis - glycogen and glucose being used for energy)

Front 49

Describe the role and regulation of Hormone Sensitive Lipase (HSL)

Back 49

(1) Rate-limiting step in lipolysis (2) Activated by low insulin and high epinephrine levels

Front 50

Describe the role and regulation of CPT I

Back 50

(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)

Front 51

Describe the role and regulation of AMP Kinase

Back 51

(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

Front 52

Describe the role and regulation of HMG CoA Synthase

Back 52

(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)