GI - Biochemistry - Hormonal Control of Metabolism; Alcohol Metabolism

Question 1

Describe the very general conditions of metabolism in the well-fed state (i.e. state of nutrients in the gut and blood, organs involved, processes involved, hormones involved, etc.).

Answer 1

Question 2

Describe the very general conditions of metabolism in the fasting state (i.e. state of nutrients in the gut and blood, organs involved, processes involved, hormones involved, etc.).

Answer 2

Question 3

Name a few metabolic processes activated in the well-fed state.

Answer 3

Glycogenesis;

protein synthesis;

fatty acid synthesis;

triacylglycerol synthesis;

VLDL synthesis

Question 4

Name a few metabolic processes activated in the fasting state.

Answer 4

Gluconeogenesis;

ketogenesis;

triacylglycerol hydrolysis;

glycogenolysis;

protein catabolism

Question 5

Which protein is useful for cleaving lipids to enter adipocytes when in the well-fed state?

Which protein is useful for cleaving lipids to exit adipocytes when in the fasting state?

Answer 5

Lipoprotein lipase;

hormone-sensitive lipase

Question 6

What is the main metabolic hormone of the well-fed state?

What are the main hormones of the fasting state?

Answer 6

Insulin;

glucagon, epinephrine

(also cortisol and growth hormone)

Question 7

The metabolic goal of the fasting state is to increase plasma levels of what two substances?

Answer 7

Glucose;

ketones

Question 8

What is insulin’s main role at adipose and skeletal muscle tissues?

Answer 8

To increase the amount of GLUT4 in the cell membranes

Question 9

Name some of the transporters and enzymes whose activity/expression is increased by insulin.

Answer 9

GLUT4

Glucokinase

PFK-1 (via PFK-2)

Glycogen synthase

PDC

Acetyl-CoA carboxylase

Lipoprotein lipase

Question 10

Is insulin generally responsible for phosphorylation or dephosphorylation of metabolic enzymes?

Answer 10

Dephosphorylation (via protein phosphatase 1)

Question 11

What is the immediate product of acetyl-CoA carboxylase?

What effect does it have on β-oxidation? How?

Answer 11

Malonyl-CoA;

decreased –> via inhibition of CAT1

Question 12

Name some of the transporters and enzymes whose activity/expression is increased by glucagon.

Answer 12

Glycogen phosphorylase

FBPase-2

PEP carboxykinase

Hormone-sensitive lipase

Perilipin

Question 13

Is glucagon generally responsible for phosphorylation or dephosphorylation of metabolic enzymes?

Answer 13

Phosphorylation (via protein kinase A)

Question 14

Insulin indirectly dephosphorylates metabolic enzymes by activating:

Glucagon indirectly phosphorylates metabolic enzymes by activating:

Answer 14

Protein phosphatase 1

Protein kinase A

Question 15

Describe the respective effects of insulin and glucagon on F2,6BP.

Answer 15

Question 16

Does glucagon activate or inhibit pyruvate kinase?

Answer 16

Inhibit

Question 17

In the well-fed state, lipoprotein lipase expression is elevated in what tissue(s)?

Answer 17

Adipose

Question 18

In the fasting state, lipoprotein lipase expression is elevated in what tissue(s)?

Answer 18

Muscle

Question 19

What effect does xyulose 5-phosphate have on the PFK-2/FBPase-2 bifunctional enzyme?

Answer 19

Activating PFK-2

(similarly to insulin, X5P activates a phosphatase)

Question 20

Glucose 6-phosphate dehydrogenase is inactivated by:

Answer 20

NADPH

Question 21

What two processes account for hepatic ethanol metabolism?

Answer 21

1. Redox NADH and acetate production (basic steps in cytosol and mitochondria involving alcohol dehydrogenase and acetaldehyde dehydrogenase)
2. The microsomal EtOH oxidizing system (hepatic SER)

Question 22

Describe the two main reactions of basic ethanol metabolism.

Where do they occur in the cells?

Answer 22

1. Cytosol: alcohol dehydrogenase turns EtOH into acetaldehyde (converting NAD⁺ –> NADH)
2. Mitochondria: acetaldehyde dehydrogenase turns acetaldehyde into acetate

Question 23

What are the two enzymes of basic alcohol metabolism?

(Where do the reactions take place?)

Answer 23

Alcohol dehydrogenase (cytosol);

alcetaldehyde dehydrogenase (mitochondria)

Question 24

Name the intermediate and final product of basic ethanol metabolism.

Answer 24

EtOH –> Acetaldehyde –> Acetate

Question 25

The final product of basic ethanol metabolism is \_\_\_\_\_\_\_\_\_\_. What happens to this product next?

Answer 25

Acetate; it enters the bloodstream and is turned into acetyl-CoA in extrahepatic tissues

Question 26

Which of the two basic ethanol metabolism steps produces NAD⁺? Which of the two basic ethanol metabolism steps produces NADH?

Answer 26

Neither; both

Question 27

For every one molecule of EtOH metabolized, ___ NADH are produced.

Answer 27

2

Question 28

What is the basic explanation for the effects of alcohol on body metabolism?

Answer 28

The buildup of NADH leads to a **depletion of NAD⁺** that is needed for the CAC and many other reactions

Question 29

What change in the NAD⁺:NADH ratio occurs during alcohol use?

Answer 29

A decrease | (insufficient NAD⁺ for body reactions)

Question 30

**True/False**. Most basic EtOH metabolism occurs via the microsomal EtOH oxidizing system in the hepatic ER.

Answer 30

**False**. This is only induced when EtOH levels are high and, even then, only accounts for 10 - 20% of EtOH converted to acetaldehyde.

Question 31

When is the microsomal EtOH oxidizing system active?

Answer 31

It is **induced/increased in expression** by high levels of EtOH

Question 32

Which form of alcohol metabolism is present at baseline, low levels of EtOH?

Answer 32

The _alcohol dehydrogenase_ / _acetaldehyde dehydrogenase_ system *(the microsomal EtOH oxidizing system is only active/induced when EtOH levels are high)*

Question 33

What is cytochrome P450? In what tissue(s)/organelle(s) is it found in high concentrations?

Answer 33

A mixed-function oxidase; hepatic ER

Question 34

What are the substrates and products of the microsomal ethanol oxidizing system?

Answer 34

Substrates: **EtOH, NADPH** (+ H⁺ + O₂) Products: **Acetaldehyde, NADP⁺** (+ 2 H₂O)

Question 35

What enzyme is responsible for the microsomal ethanol oxidizing system? Where does it take place?

Answer 35

Cytochrome P450; the hepatic ER

Question 36

What hepatic function is increased by chronic EtOH use? How much?

Answer 36

Cytochrome P450 (CYP2E1); an induced 5- to 10-fold increase

Question 37

What electron carrier is involved as a substrate of basic hepatic EtOH metabolism? What electron carrier is involved as a substrate of the microsomal ethanol oxidizing system?

Answer 37

NAD⁺; NADPH

Question 38

What product of EtOH metabolism is most responsible for liver damage in chronic alcoholism?

Answer 38

Acetaldehyde ## Footnote *(produced by the microsomal EtOH oxidizing system)*

Question 39

What hepatic enzyme produces **acetaldehyde** **from** **ethanol** in the _cytosol_? What hepatic enzyme produces **acetaldehyde** **from** **ethanol** in the _endoplasmic reticulum_? What hepatic enzyme produces **acetate** **from** **acetaldehyde** in the _mitochondria_?

Answer 39

Alcohol dehydrogenase; cytochrome P450 (of the MEOS); acetaldehyde dehydrogenase

Question 40

What hepatic enzyme produces acetaldehyde from ethanol in the cytosol?

Answer 40

Alcohol dehydrogenase

Question 41

What hepatic enzyme produces acetaldehyde from ethanol in the endoplasmic reticulum?

Answer 41

Cytochrome P450 (of the MEOS)

Question 42

What hepatic enzyme produces acetate from acetaldehyde in the mitochondria?

Answer 42

Acetaldehyde dehydrogenase

Question 43

What are the three main damaging effects of cytochrome P450 induction by chronic alcoholism?

Answer 43

**1.** [Acetaldehyde] increase **2.** [Free-radical oxygen species] increase **3.** P450 now less available for drug/xenobiotic metabolism (may result in toxic drug levels)

Question 44

Describe the respective issue with each of the following three polymorphisms involving enzymes of EtOH metabolism: **ADH1\*B1** (alcohol dehydrogenase)

Answer 44

Underactive isoform ## Footnote * (homozygotes are at increased risk for Wernicke-Korsakoff;* * increased EtOH leads to decreased thiamine uptake in the gut)*

Question 45

Describe the respective issue with each of the following three polymorphisms involving enzymes of EtOH metabolism: **ADH1\*B2** (alcohol dehydrogenase)

Answer 45

Overactive isoform ## Footnote *(acetaldehyde production \> acetate production --\> acetaldehyde builds up)*

Question 46

Describe the respective issue with each of the following three polymorphisms involving enzymes of EtOH metabolism: **ALDH2** (acetaldehyde dehydrogenase)

Answer 46

Underactive isoform (Km increases --\> acetaldehyde builds up; patient has severe sensitivity to alcohol --\> nausea and vomiting)

Question 47

What drug blocks acetaldehyde dehydrogenase and causes nausea and vomiting in those that drink EtOH? Why these symptoms?

Answer 47

Disulfiram (antabuse); acetaldehyde buildup

Question 48

Which has a lower Km for ethanol, alcohol dehydrogenase or CYP2E1 (cytochrome P450 of the MEOS)? So, which is more active in interacting with EtOH?

Answer 48

Alcohol dehydrogenase; alcohol dehydrogenase

Question 49

What are some risk factors for thiamine deficiency?

Answer 49

**Alcoholism** (poor diet; lack of magnesium) **ADH1\*B1 mutation** (buildup of EtOH decreases thiamine uptake in gut) **Hepatic damage** (decreases thiamine pyrophosphate formation)

Question 50

What are some neurological S/Sy of Wernicke-Korsakoff?

Answer 50

Amnestic disorder, cognitive impairment, ophthalmoplegia, abnormal stance/gait

Question 51

A 46-year-old female complains of loss of appetite, fatigue, muscle weakness, and emotional depression. She has had occasional pain in the area of her liver, at times accompanied by nausea and vomiting. Recently fired for absenteeism. Divorced 10 months earlier. **Physical exam**: Patient appears disheveled and pale. Tenderness to light percussion over liver and detectable small amount of ascites fluid within peritoneal cavity. Lower edge of her liver is palpable, appears enlarged, and it feels more firm and nodular than normal. Suggestion of mild jaundice. No obvious neurologic or cognitive abnormalities are present. Hint of alcohol on patient's breath, patient admits drinking gin on a daily basis (4 to 5 drinks, or 68 to 85 g ethanol) and eating infrequently for last 5 or 6 years. **What tests might you run?**

Answer 51

Serum alcohol level Serum ALT and AST Serum ALP

Question 52

What is considered 'moderate drinking'?

Answer 52

Men: 2 drinks / day Women: 1 drink / day *1 drink = EITHER 12 oz. of regular beer, 5 oz. of wine, OR 1.5 oz. distilled spirits (80-proof)*

Question 53

For the purposes of defining moderate drinking, men are limited to ≤ 2 drinks / day and women to ≤ 1 drink / day. What is the definition of 'one drink'?

Answer 53

One drink is ONE of the following: 12 oz. of regular beer, 5 oz. of wine, 1.5 oz. distilled spirits (80-proof)

Question 54

What quantity of beer is considered 'one drink'? What quantity of wine is considered 'one drink'? What quantity of spirits (80-proof) is considered 'one drink'?

Answer 54

12 oz. 5 oz. 1.5 oz.

Question 55

What enzyme category in particular is inhibited by the increase in the NADH:NAD⁺ ratio that alcohol ingestion causes? What is the major result?

Answer 55

Dehydrogenases; inhibition of glycolysis, the CAC, and β-oxidation

Question 56

What results happen after a person ingests alcohol and dehydrogenases are shut down by the increased NADH:NAD⁺ ratio (leading to inhibition of glycolysis, the CAC, and β-oxidation)?

Answer 56

**Lactic acidosis** **Hyperuricemia** (lactate competes with urate for excretion)

Question 57

Does alcohol abuse typically cause hyperglycemia or hypoglycemia?

Answer 57

**Hypoglycemia** *(poor diet + inhibited use of gluconeogenic amino acids)*

Question 58

What effect does alcohol abuse have on serum lipid levels?

Answer 58

Increased synthesis of triglycerides, VLDLs, and ketone bodies --\> **hyperlipidemia and hepatic steatosis**

Question 59

What effect does alcohol abuse have on drug metabolism?

Answer 59

Decreased capacity ## Footnote *(increased risk of overdose because P450 is occupied metabolizing the EtOH)*

Question 60

Name some of the generic outcomes of alcohol abuse on glucose levels, lipid levels, and other metabolites.

Answer 60

Hypoglycemia Hyperlipidemia Hyperuricemia Lactic acidemia

Question 61

What causes hangovers?

Answer 61

Acetaldehyde and ROS buildup and subsequent cellular toxicity

Question 62

How does acetaldehyde damage cells? What are some specific examples?

Answer 62

By binding amino acids and proteins * Impairs microtubules (decreases vesicle secretion) * Impairs glutathione (ROS increase)

Question 63

What immediate non-metabolic effect does alcohol-induced damage of mitochondria by free radicals have on the cell?

Answer 63

A further increase in [acetaldehyde] and [ROS]

Question 64

What are the stages of hepatic damage?

Answer 64

Question 65

Describe some of the effects of decreased liver function due to severe hepatic disease.

Answer 65

Loss of albumin --\> **ascites** Loss of coagulation factors --\> **increased PTT** Loss of VLDL synthesis and gluconeogenesis --\> **hypoglycemia** Lack of glutathione --\> **hemolytic anemia** Decreased bilirubin conjugation, bile acid synthesis, ammonia excretion --\> **jaundice and hyperammonemia**

Question 66

ALT and AST are 10x their normal values. What do you suspect?

Answer 66

Acute viral hepatitis

Question 67

ALT and AST are increased but \<4x their normal values. What do you suspect?

Answer 67

Chronic alcohol-hepatitis

Question 68

ALT and AST are increased but \<4x their normal values. What do you suspect? ALT and AST are \>10x their normal values. What do you suspect?

Answer 68

Chronic alcohol-hepatitis Acute viral hepatitis

Question 69

A decreased BUN indicates: An increased BUN indicates:

Answer 69

Liver dysfunction; renal dysfunction

Question 70

Serum γ-glutamyl transferase is elevated. What does this indicate? Serum total bilirubin is elevated. What does this indicate?

Answer 70

Liver disease; liver disease (non-specific)

Question 71

PTT elevation can be caused by dysfunction of what GI organ?

Answer 71

The liver

Question 72

Decreased total serum protein or serum albumin indicate an issue with what organ system(s)?

Answer 72

Liver or kidneys

Question 73

An increase in alkaline phosphatase (ALP) indicates an issue with which organ(s)?

Answer 73

Liver or bone

Question 74

**True/False**. Elevated ALT and creatinine can be indicators for cardiac damage, not just liver dysfunction.

Answer 74

**False**. Elevated **_AST_** and creatinine can be indicators for cardiac damage, not just liver dysfunction.

Question 75

An individual presents with elevated serum alkaline phosphatase and a normal serum γ-glutamyl transferase. What is the likely organ system involved?

Answer 75

Bone

Question 76

A patient presents with an ALT/AST ratio \>1. What do you suspect?

Answer 76

Acute viral hepatitis

Question 77

A patient presents with an ALT/AST ratio \<1. What do you suspect?

Answer 77

Chronic alcohol-hepatitis

Question 78

What is the normal ALT/AST ratio?

Answer 78

1

Question 79

Why might serum folate, vitamin B12, and iron levels be slightly depressed in an alcoholic?

Answer 79

Poor nutrition ## Footnote *(vitamin B12 and iron are also dependent on the liver for their carrier proteins)*

Question 80

What steps should an alcoholic be encouraged to take?

Answer 80

**1**. Abstain from alcohol immediately **2**. Improve nutritional status **3**. Seek counseling from a drug and alcohol rehabilitation unit, for the appropriate psychological, social and supportive counseling. **4**. Keep regular follow-up appointments to monitor liver function.

Question 81

Via what basic mechanism does alcohol use cause hypoglycemia?

Answer 81

By impairing gluconeogenesis

Question 82

What vitamin does EtOH competitively inhibit at retinol dehydrogenase? What other effect does it have on this vitamin?

Answer 82

Vitamin A; induction of MEOS, which may further increase vitamin A catabolism

Question 83

How is methanol metabolized by the body? How would you treat a methanol poisoning?

Answer 83

It is converted to formaldehyde (then formic acid); **fomepizole** (blocks alcohol dehydrogenase so the MeOH can be excreted in the urine without being turned into formaldehyde)

Question 84

How is ethylene glycol metabolized by the body? How would you treat a methanol poisoning?

Answer 84

It is converted to three acids (glycolic acid, glyoxylic acid and oxalic acid), causing metabolic acidosis; **fomepizole** (blocks alcohol dehydrogenase so the MeOH can be excreted in the urine)

Question 85

Fomepizole blocks what enzyme?

Answer 85

Alcohol dehydrogenase