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T1 - Phase 1 - Integrated (II) > GI - Biochemistry - Hormonal Control of Metabolism; Alcohol Metabolism > Flashcards

GI - Biochemistry - Hormonal Control of Metabolism; Alcohol Metabolism Flashcards

1
Q

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.).

A
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2
Q

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.).

A
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3
Q

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

A

Glycogenesis;

protein synthesis;

fatty acid synthesis;

triacylglycerol synthesis;

VLDL synthesis

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4
Q

Name a few metabolic processes activated in the fasting state.

A

Gluconeogenesis;

ketogenesis;

triacylglycerol hydrolysis;

glycogenolysis;

protein catabolism

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5
Q

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?

A

Lipoprotein lipase;

hormone-sensitive lipase

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6
Q

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

What are the main hormones of the fasting state?

A

Insulin;

glucagon, epinephrine

(also cortisol and growth hormone)

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7
Q

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

A

Glucose;

ketones

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8
Q

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

A

To increase the amount of GLUT4 in the cell membranes

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9
Q

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

A

GLUT4

Glucokinase

PFK-1 (via PFK-2)

Glycogen synthase

PDC

Acetyl-CoA carboxylase

Lipoprotein lipase

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10
Q

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

A

Dephosphorylation (via protein phosphatase 1)

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11
Q

What is the immediate product of acetyl-CoA carboxylase?

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

A

Malonyl-CoA;

decreased –> via inhibition of CAT1

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12
Q

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

A

Glycogen phosphorylase

FBPase-2

PEP carboxykinase

Hormone-sensitive lipase

Perilipin

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13
Q

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

A

Phosphorylation (via protein kinase A)

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14
Q

Insulin indirectly dephosphorylates metabolic enzymes by activating:

Glucagon indirectly phosphorylates metabolic enzymes by activating:

A

Protein phosphatase 1

Protein kinase A

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15
Q

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

A
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16
Q

Does glucagon activate or inhibit pyruvate kinase?

A

Inhibit

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17
Q

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

A

Adipose

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18
Q

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

A

Muscle

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19
Q

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

A

Activating PFK-2

(similarly to insulin, X5P activates a phosphatase)

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20
Q

Glucose 6-phosphate dehydrogenase is inactivated by:

A

NADPH

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21
Q

What two processes account for hepatic ethanol metabolism?

A
  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)
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22
Q

Describe the two main reactions of basic ethanol metabolism.

Where do they occur in the cells?

A
  1. Cytosol: alcohol dehydrogenase turns EtOH into acetaldehyde (converting NAD+ –> NADH)
  2. Mitochondria: acetaldehyde dehydrogenase turns acetaldehyde into acetate
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23
Q

What are the two enzymes of basic alcohol metabolism?

(Where do the reactions take place?)

A

Alcohol dehydrogenase (cytosol);

alcetaldehyde dehydrogenase (mitochondria)

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24
Q

Name the intermediate and final product of basic ethanol metabolism.

A

EtOH –> Acetaldehyde –> Acetate

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25
Q

The final product of basic ethanol metabolism is __________.

What happens to this product next?

A

Acetate;

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

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26
Q

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

Which of the two basic ethanol metabolism steps produces NADH?

A

Neither;

both

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27
Q

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

A

2

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28
Q

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

A

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

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29
Q

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

A

A decrease

(insufficient NAD+ for body reactions)

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30
Q

True/False.

Most basic EtOH metabolism occurs via the microsomal EtOH oxidizing system in the hepatic ER.

A

False.

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

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31
Q

When is the microsomal EtOH oxidizing system active?

A

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

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32
Q

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

A

The alcohol dehydrogenase / acetaldehyde dehydrogenase system

(the microsomal EtOH oxidizing system is only active/induced when EtOH levels are high)

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33
Q

What is cytochrome P450?

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

A

A mixed-function oxidase;

hepatic ER

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34
Q

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

A

Substrates: EtOH, NADPH (+ H+ + O2)

Products: Acetaldehyde, NADP+ (+ 2 H2O)

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35
Q

What enzyme is responsible for the microsomal ethanol oxidizing system?

Where does it take place?

A

Cytochrome P450;

the hepatic ER

36
Q

What hepatic function is increased by chronic EtOH use?

How much?

A

Cytochrome P450 (CYP2E1);

an induced 5- to 10-fold increase

37
Q

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?

A

NAD+;

NADPH

38
Q

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

A

Acetaldehyde

(produced by the microsomal EtOH oxidizing system)

39
Q

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?

A

Alcohol dehydrogenase;

cytochrome P450 (of the MEOS);

acetaldehyde dehydrogenase

40
Q

What hepatic enzyme produces acetaldehyde from ethanol in the cytosol?

A

Alcohol dehydrogenase

41
Q

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

A

Cytochrome P450 (of the MEOS)

42
Q

What hepatic enzyme produces acetate from acetaldehyde in the mitochondria?

A

Acetaldehyde dehydrogenase

43
Q

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

A

1. [Acetaldehyde] increase

2. [Free-radical oxygen species] increase

3. P450 now less available for drug/xenobiotic metabolism (may result in toxic drug levels)

44
Q

Describe the respective issue with each of the following three polymorphisms involving enzymes of EtOH metabolism:

ADH1*B1 (alcohol dehydrogenase)

A

Underactive isoform

  • (homozygotes are at increased risk for Wernicke-Korsakoff;*
  • increased EtOH leads to decreased thiamine uptake in the gut)*
45
Q

Describe the respective issue with each of the following three polymorphisms involving enzymes of EtOH metabolism:

ADH1*B2 (alcohol dehydrogenase)

A

Overactive isoform

(acetaldehyde production > acetate production –> acetaldehyde builds up)

46
Q

Describe the respective issue with each of the following three polymorphisms involving enzymes of EtOH metabolism:

ALDH2 (acetaldehyde dehydrogenase)

A

Underactive isoform

(Km increases –> acetaldehyde builds up;

patient has severe sensitivity to alcohol –> nausea and vomiting)

47
Q

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

Why these symptoms?

A

Disulfiram (antabuse);

acetaldehyde buildup

48
Q

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?

A

Alcohol dehydrogenase;

alcohol dehydrogenase

49
Q

What are some risk factors for thiamine deficiency?

A

Alcoholism (poor diet; lack of magnesium)

ADH1*B1 mutation (buildup of EtOH decreases thiamine uptake in gut)

Hepatic damage (decreases thiamine pyrophosphate formation)

50
Q

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

A

Amnestic disorder,

cognitive impairment,

ophthalmoplegia,

abnormal stance/gait

51
Q

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?

A

Serum alcohol level

Serum ALT and AST

Serum ALP

52
Q

What is considered ‘moderate drinking’?

A

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)

53
Q

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’?

A

One drink is ONE of the following:

12 oz. of regular beer,

5 oz. of wine,

1.5 oz. distilled spirits (80-proof)

54
Q

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’?

A

12 oz.

5 oz.

1.5 oz.

55
Q

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

What is the major result?

A

Dehydrogenases;

inhibition of glycolysis, the CAC, and β-oxidation

56
Q

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)?

A

Lactic acidosis

Hyperuricemia (lactate competes with urate for excretion)

57
Q

Does alcohol abuse typically cause hyperglycemia or hypoglycemia?

A

Hypoglycemia

(poor diet + inhibited use of gluconeogenic amino acids)

58
Q

What effect does alcohol abuse have on serum lipid levels?

A

Increased synthesis of triglycerides, VLDLs, and ketone bodies

–> hyperlipidemia and hepatic steatosis

59
Q

What effect does alcohol abuse have on drug metabolism?

A

Decreased capacity

(increased risk of overdose because P450 is occupied metabolizing the EtOH)

60
Q

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

A

Hypoglycemia

Hyperlipidemia

Hyperuricemia

Lactic acidemia

61
Q

What causes hangovers?

A

Acetaldehyde and ROS buildup and subsequent cellular toxicity

62
Q

How does acetaldehyde damage cells?

What are some specific examples?

A

By binding amino acids and proteins

  • Impairs microtubules (decreases vesicle secretion)
  • Impairs glutathione (ROS increase)
63
Q

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

A

A further increase in [acetaldehyde] and [ROS]

64
Q

What are the stages of hepatic damage?

A
65
Q

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

A

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

66
Q

ALT and AST are 10x their normal values.

What do you suspect?

A

Acute viral hepatitis

67
Q

ALT and AST are increased but <4x their normal values.

What do you suspect?

A

Chronic alcohol-hepatitis

68
Q

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?

A

Chronic alcohol-hepatitis

Acute viral hepatitis

69
Q

A decreased BUN indicates:

An increased BUN indicates:

A

Liver dysfunction;

renal dysfunction

70
Q

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

Serum total bilirubin is elevated. What does this indicate?

A

Liver disease;

liver disease (non-specific)

71
Q

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

A

The liver

72
Q

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

A

Liver or kidneys

73
Q

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

A

Liver or bone

74
Q

True/False.

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

A

False.

Elevated AST and creatinine can be indicators for cardiac damage, not just liver dysfunction.

75
Q

An individual presents with elevated serum alkaline phosphatase and a normal serum γ-glutamyl transferase.

What is the likely organ system involved?

A

Bone

76
Q

A patient presents with an ALT/AST ratio >1.

What do you suspect?

A

Acute viral hepatitis

77
Q

A patient presents with an ALT/AST ratio <1.

What do you suspect?

A

Chronic alcohol-hepatitis

78
Q

What is the normal ALT/AST ratio?

A

1

79
Q

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

A

Poor nutrition

(vitamin B12 and iron are also dependent on the liver for their carrier proteins)

80
Q

What steps should an alcoholic be encouraged to take?

A

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.

81
Q

Via what basic mechanism does alcohol use cause hypoglycemia?

A

By impairing gluconeogenesis

82
Q

What vitamin does EtOH competitively inhibit at retinol dehydrogenase?

What other effect does it have on this vitamin?

A

Vitamin A;

induction of MEOS, which may further increase vitamin A catabolism

83
Q

How is methanol metabolized by the body?

How would you treat a methanol poisoning?

A

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)

84
Q

How is ethylene glycol metabolized by the body?

How would you treat a methanol poisoning?

A

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)

85
Q

Fomepizole blocks what enzyme?

A

Alcohol dehydrogenase

T1 - Phase 1 - Integrated (II) (23 decks)

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